US20040126754A1 - Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes - Google Patents
Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes Download PDFInfo
- Publication number
- US20040126754A1 US20040126754A1 US10/685,435 US68543503A US2004126754A1 US 20040126754 A1 US20040126754 A1 US 20040126754A1 US 68543503 A US68543503 A US 68543503A US 2004126754 A1 US2004126754 A1 US 2004126754A1
- Authority
- US
- United States
- Prior art keywords
- hcv
- peptide
- peptides
- combination
- related virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 290
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 173
- 241000711549 Hepacivirus C Species 0.000 title abstract description 111
- 108010003533 Viral Envelope Proteins Proteins 0.000 title abstract description 4
- 238000002255 vaccination Methods 0.000 title description 2
- 208000015181 infectious disease Diseases 0.000 claims abstract description 15
- 241000700605 Viruses Species 0.000 claims description 82
- 239000012634 fragment Substances 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 35
- 230000027455 binding Effects 0.000 claims description 27
- 150000001413 amino acids Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 235000001014 amino acid Nutrition 0.000 claims description 21
- 210000001124 body fluid Anatomy 0.000 claims description 20
- 239000010839 body fluid Substances 0.000 claims description 20
- 238000004166 bioassay Methods 0.000 claims description 15
- 125000003729 nucleotide group Chemical group 0.000 claims description 11
- 229920001184 polypeptide Polymers 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 235000018417 cysteine Nutrition 0.000 claims description 10
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002773 nucleotide Substances 0.000 claims description 10
- 230000003993 interaction Effects 0.000 claims description 8
- 239000013600 plasmid vector Substances 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000013518 transcription Methods 0.000 claims description 5
- 230000035897 transcription Effects 0.000 claims description 5
- 108020004511 Recombinant DNA Proteins 0.000 claims description 4
- 238000003149 assay kit Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 241000531123 GB virus C Species 0.000 description 31
- 230000009257 reactivity Effects 0.000 description 31
- 101710091045 Envelope protein Proteins 0.000 description 20
- 101710125507 Integrase/recombinase Proteins 0.000 description 20
- 101710188315 Protein X Proteins 0.000 description 20
- 102100021696 Syncytin-1 Human genes 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 20
- 239000000523 sample Substances 0.000 description 20
- 235000018102 proteins Nutrition 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 17
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 12
- 101710185720 Putative ethidium bromide resistance protein Proteins 0.000 description 11
- QNZLIVROMORQFH-BQBZGAKWSA-N Pro-Gly-Cys Chemical compound C1C[C@H](NC1)C(=O)NCC(=O)N[C@@H](CS)C(=O)O QNZLIVROMORQFH-BQBZGAKWSA-N 0.000 description 9
- 229960005486 vaccine Drugs 0.000 description 9
- YLXAMFZYJTZXFH-OLHMAJIHSA-N Thr-Asn-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O YLXAMFZYJTZXFH-OLHMAJIHSA-N 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- DOSZISJPMCYEHT-NAKRPEOUSA-N Ser-Ile-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O DOSZISJPMCYEHT-NAKRPEOUSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 108010060857 isoleucyl-valyl-tyrosine Proteins 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 229920002477 rna polymer Polymers 0.000 description 6
- DBXXASNNDTXOLU-MXAVVETBSA-N Ile-Leu-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DBXXASNNDTXOLU-MXAVVETBSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- NQJDICVXXIMMMB-XDTLVQLUSA-N Tyr-Glu-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O NQJDICVXXIMMMB-XDTLVQLUSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 102100021277 Beta-secretase 2 Human genes 0.000 description 4
- 206010008909 Chronic Hepatitis Diseases 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 206010019755 Hepatitis chronic active Diseases 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 4
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 4
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- ZTPXSEUVYNNZRB-CDMKHQONSA-N Thr-Gly-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZTPXSEUVYNNZRB-CDMKHQONSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 3
- VYLVOMUVLMGCRF-ZLUOBGJFSA-N Asn-Asp-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O VYLVOMUVLMGCRF-ZLUOBGJFSA-N 0.000 description 3
- SNYCNNPOFYBCEK-ZLUOBGJFSA-N Asn-Ser-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O SNYCNNPOFYBCEK-ZLUOBGJFSA-N 0.000 description 3
- 108090001008 Avidin Proteins 0.000 description 3
- DZLQXIFVQFTFJY-BYPYZUCNSA-N Cys-Gly-Gly Chemical compound SC[C@H](N)C(=O)NCC(=O)NCC(O)=O DZLQXIFVQFTFJY-BYPYZUCNSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000005176 Hepatitis C Diseases 0.000 description 3
- 241001529916 Hepatitis GB virus B Species 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 3
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 3
- 241000682990 Pegivirus A Species 0.000 description 3
- FUVBEZJCRMHWEM-FXQIFTODSA-N Pro-Asn-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O FUVBEZJCRMHWEM-FXQIFTODSA-N 0.000 description 3
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 3
- 108010090804 Streptavidin Proteins 0.000 description 3
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 3
- NHQVWACSJZJCGJ-FLBSBUHZSA-N Thr-Thr-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NHQVWACSJZJCGJ-FLBSBUHZSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- RIFVTNDKUMSSMN-ULQDDVLXSA-N Tyr-His-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(O)=O RIFVTNDKUMSSMN-ULQDDVLXSA-N 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 3
- 229940009098 aspartate Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 108010016616 cysteinylglycine Proteins 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 3
- 229960000310 isoleucine Drugs 0.000 description 3
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 108010026333 seryl-proline Proteins 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- -1 unnatural aa's) Chemical class 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- DRHZYJAUECRAJM-DWSYSWFDSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4s,4ar,6ar,6bs,8r,8ar,12as,14ar,14br)-8a-[(2s,3r,4s,5r,6r)-3-[(2s,3r,4s,5r,6s)-5-[(2s,3r,4s,5r)-4-[(2s,3r,4r)-3,4-dihydroxy-4-(hydroxymethyl)oxolan-2-yl]oxy-3,5-dihydroxyoxan-2-yl]oxy-3,4-dihydroxy-6-methyloxan-2-yl]oxy-5-[(3s,5s, Chemical compound O([C@H]1[C@H](O)[C@H](O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@H]5CC(C)(C)CC[C@@]5([C@@H](C[C@@]4(C)[C@]3(C)CC[C@H]2[C@@]1(C=O)C)O)C(=O)O[C@@H]1O[C@H](C)[C@@H]([C@@H]([C@H]1O[C@H]1[C@@H]([C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@](O)(CO)CO3)O)[C@H](O)CO2)O)[C@H](C)O1)O)O)OC(=O)C[C@@H](O)C[C@H](OC(=O)C[C@@H](O)C[C@@H]([C@@H](C)CC)O[C@H]1[C@@H]([C@@H](O)[C@H](CO)O1)O)[C@@H](C)CC)C(O)=O)[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O DRHZYJAUECRAJM-DWSYSWFDSA-N 0.000 description 2
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 2
- WRDANSJTFOHBPI-FXQIFTODSA-N Ala-Arg-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N WRDANSJTFOHBPI-FXQIFTODSA-N 0.000 description 2
- VHVVPYOJIIQCKS-QEJZJMRPSA-N Ala-Leu-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VHVVPYOJIIQCKS-QEJZJMRPSA-N 0.000 description 2
- ITVINTQUZMQWJR-QXEWZRGKSA-N Arg-Asn-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O ITVINTQUZMQWJR-QXEWZRGKSA-N 0.000 description 2
- YHSNASXGBPAHRL-BPUTZDHNSA-N Arg-Cys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCN=C(N)N)N YHSNASXGBPAHRL-BPUTZDHNSA-N 0.000 description 2
- RKRSYHCNPFGMTA-CIUDSAMLSA-N Arg-Glu-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O RKRSYHCNPFGMTA-CIUDSAMLSA-N 0.000 description 2
- JTZUZBADHGISJD-SRVKXCTJSA-N Arg-His-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JTZUZBADHGISJD-SRVKXCTJSA-N 0.000 description 2
- OWSMKCJUBAPHED-JYJNAYRXSA-N Arg-Pro-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OWSMKCJUBAPHED-JYJNAYRXSA-N 0.000 description 2
- URAUIUGLHBRPMF-NAKRPEOUSA-N Arg-Ser-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O URAUIUGLHBRPMF-NAKRPEOUSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- XWGJDUSDTRPQRK-ZLUOBGJFSA-N Asn-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O XWGJDUSDTRPQRK-ZLUOBGJFSA-N 0.000 description 2
- DAYDURRBMDCCFL-AAEUAGOBSA-N Asn-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N DAYDURRBMDCCFL-AAEUAGOBSA-N 0.000 description 2
- CPYHLXSGDBDULY-IHPCNDPISA-N Asn-Trp-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CPYHLXSGDBDULY-IHPCNDPISA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 101710150190 Beta-secretase 2 Proteins 0.000 description 2
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 2
- 241001227713 Chiron Species 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 2
- DEVDFMRWZASYOF-ZLUOBGJFSA-N Cys-Asn-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DEVDFMRWZASYOF-ZLUOBGJFSA-N 0.000 description 2
- HJXSYJVCMUOUNY-SRVKXCTJSA-N Cys-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N HJXSYJVCMUOUNY-SRVKXCTJSA-N 0.000 description 2
- 108010041986 DNA Vaccines Proteins 0.000 description 2
- 229940021995 DNA vaccine Drugs 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241000710831 Flavivirus Species 0.000 description 2
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 2
- AIGROOHQXCACHL-WDSKDSINSA-N Glu-Gly-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O AIGROOHQXCACHL-WDSKDSINSA-N 0.000 description 2
- GNBMOZPQUXTCRW-STQMWFEESA-N Gly-Asn-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CN)C(O)=O)=CNC2=C1 GNBMOZPQUXTCRW-STQMWFEESA-N 0.000 description 2
- VNBNZUAPOYGRDB-ZDLURKLDSA-N Gly-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)CN)O VNBNZUAPOYGRDB-ZDLURKLDSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 108700008783 Hepatitis C virus E1 Proteins 0.000 description 2
- UCDWNBFOZCZSNV-AVGNSLFASA-N His-Arg-Met Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O UCDWNBFOZCZSNV-AVGNSLFASA-N 0.000 description 2
- YKRIXHPEIZUDDY-GMOBBJLQSA-N Ile-Asn-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YKRIXHPEIZUDDY-GMOBBJLQSA-N 0.000 description 2
- PMMMQRVUMVURGJ-XUXIUFHCSA-N Ile-Leu-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O PMMMQRVUMVURGJ-XUXIUFHCSA-N 0.000 description 2
- YBKKLDBBPFIXBQ-MBLNEYKQSA-N Ile-Thr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)O)N YBKKLDBBPFIXBQ-MBLNEYKQSA-N 0.000 description 2
- QSXSHZIRKTUXNG-STECZYCISA-N Ile-Val-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QSXSHZIRKTUXNG-STECZYCISA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 101710128560 Initiator protein NS1 Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 2
- UBZGNBKMIJHOHL-BZSNNMDCSA-N Leu-Leu-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 UBZGNBKMIJHOHL-BZSNNMDCSA-N 0.000 description 2
- HGLKOTPFWOMPOB-MEYUZBJRSA-N Leu-Thr-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HGLKOTPFWOMPOB-MEYUZBJRSA-N 0.000 description 2
- URJUVJDTPXCQFL-IHPCNDPISA-N Leu-Trp-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CN=CN3)C(=O)O)N URJUVJDTPXCQFL-IHPCNDPISA-N 0.000 description 2
- VAGCEUUEMMXFEX-GUBZILKMSA-N Met-Met-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O VAGCEUUEMMXFEX-GUBZILKMSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 230000004988 N-glycosylation Effects 0.000 description 2
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 101710144127 Non-structural protein 1 Proteins 0.000 description 2
- YYRCPTVAPLQRNC-ULQDDVLXSA-N Phe-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC1=CC=CC=C1 YYRCPTVAPLQRNC-ULQDDVLXSA-N 0.000 description 2
- HNFUGJUZJRYUHN-JSGCOSHPSA-N Phe-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 HNFUGJUZJRYUHN-JSGCOSHPSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- IFMDQWDAJUMMJC-DCAQKATOSA-N Pro-Ala-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O IFMDQWDAJUMMJC-DCAQKATOSA-N 0.000 description 2
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 2
- OZAPWFHRPINHND-GUBZILKMSA-N Pro-Cys-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O OZAPWFHRPINHND-GUBZILKMSA-N 0.000 description 2
- WSRWHZRUOCACLJ-UWVGGRQHSA-N Pro-Gly-His Chemical compound C([C@@H](C(=O)O)NC(=O)CNC(=O)[C@H]1NCCC1)C1=CN=CN1 WSRWHZRUOCACLJ-UWVGGRQHSA-N 0.000 description 2
- VVAWNPIOYXAMAL-KJEVXHAQSA-N Pro-Thr-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VVAWNPIOYXAMAL-KJEVXHAQSA-N 0.000 description 2
- OJPHFSOMBZKQKQ-GUBZILKMSA-N Ser-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO OJPHFSOMBZKQKQ-GUBZILKMSA-N 0.000 description 2
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 2
- MQQBBLVOUUJKLH-HJPIBITLSA-N Ser-Ile-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MQQBBLVOUUJKLH-HJPIBITLSA-N 0.000 description 2
- NUEHQDHDLDXCRU-GUBZILKMSA-N Ser-Pro-Arg Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NUEHQDHDLDXCRU-GUBZILKMSA-N 0.000 description 2
- XTWXRUWACCXBMU-XIRDDKMYSA-N Ser-Trp-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)O)NC(=O)[C@H](CO)N XTWXRUWACCXBMU-XIRDDKMYSA-N 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- BSNZTJXVDOINSR-JXUBOQSCSA-N Thr-Ala-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BSNZTJXVDOINSR-JXUBOQSCSA-N 0.000 description 2
- TWLMXDWFVNEFFK-FJXKBIBVSA-N Thr-Arg-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O TWLMXDWFVNEFFK-FJXKBIBVSA-N 0.000 description 2
- GZYNMZQXFRWDFH-YTWAJWBKSA-N Thr-Arg-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O GZYNMZQXFRWDFH-YTWAJWBKSA-N 0.000 description 2
- TZKPNGDGUVREEB-FOHZUACHSA-N Thr-Asn-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O TZKPNGDGUVREEB-FOHZUACHSA-N 0.000 description 2
- VXMHQKHDKCATDV-VEVYYDQMSA-N Thr-Asp-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VXMHQKHDKCATDV-VEVYYDQMSA-N 0.000 description 2
- NLJKZUGAIIRWJN-LKXGYXEUSA-N Thr-Asp-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O NLJKZUGAIIRWJN-LKXGYXEUSA-N 0.000 description 2
- QQWNRERCGGZOKG-WEDXCCLWSA-N Thr-Gly-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O QQWNRERCGGZOKG-WEDXCCLWSA-N 0.000 description 2
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 2
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 2
- QGVBFDIREUUSHX-IFFSRLJSSA-N Thr-Val-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O QGVBFDIREUUSHX-IFFSRLJSSA-N 0.000 description 2
- MDDYTWOFHZFABW-SZMVWBNQSA-N Trp-Gln-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 MDDYTWOFHZFABW-SZMVWBNQSA-N 0.000 description 2
- FEZASNVQLJQBHW-CABZTGNLSA-N Trp-Gly-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O)=CNC2=C1 FEZASNVQLJQBHW-CABZTGNLSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- VPEFOFYNHBWFNQ-UFYCRDLUSA-N Tyr-Pro-Tyr Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 VPEFOFYNHBWFNQ-UFYCRDLUSA-N 0.000 description 2
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 2
- KZKMBGXCNLPYKD-YEPSODPASA-N Val-Gly-Thr Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O KZKMBGXCNLPYKD-YEPSODPASA-N 0.000 description 2
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 2
- MIKHIIQMRFYVOR-RCWTZXSCSA-N Val-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N)O MIKHIIQMRFYVOR-RCWTZXSCSA-N 0.000 description 2
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 108010068380 arginylarginine Proteins 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- ASKSDLRLUXEOOR-SUFRFZPQSA-N gbv-c Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC(C)C)=CNC2=C1 ASKSDLRLUXEOOR-SUFRFZPQSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 2
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 108010025306 histidylleucine Proteins 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 230000003278 mimic effect Effects 0.000 description 2
- 108091005601 modified peptides Proteins 0.000 description 2
- 239000000816 peptidomimetic Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- PKOHVHWNGUHYRE-ZFWWWQNUSA-N (2s)-1-[2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)NCC(=O)N1CCC[C@H]1C(O)=O PKOHVHWNGUHYRE-ZFWWWQNUSA-N 0.000 description 1
- YHQZWWDVLJPRIF-JLHRHDQISA-N (4R)-4-[[(2S,3R)-2-[acetyl-[(3R,4R,5S,6R)-3-amino-4-[(1R)-1-carboxyethoxy]-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]amino]-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoic acid Chemical compound C(C)(=O)N([C@@H]([C@H](O)C)C(=O)N[C@H](CCC(=O)O)C(N)=O)C1[C@H](N)[C@@H](O[C@@H](C(=O)O)C)[C@H](O)[C@H](O1)CO YHQZWWDVLJPRIF-JLHRHDQISA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- IMIZPWSVYADSCN-UHFFFAOYSA-N 4-methyl-2-[[4-methyl-2-[[4-methyl-2-(pyrrolidine-2-carbonylamino)pentanoyl]amino]pentanoyl]amino]pentanoic acid Chemical compound CC(C)CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C1CCCN1 IMIZPWSVYADSCN-UHFFFAOYSA-N 0.000 description 1
- DVWVZSJAYIJZFI-FXQIFTODSA-N Ala-Arg-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DVWVZSJAYIJZFI-FXQIFTODSA-N 0.000 description 1
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 1
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 1
- FOWHQTWRLFTELJ-FXQIFTODSA-N Ala-Asp-Met Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N FOWHQTWRLFTELJ-FXQIFTODSA-N 0.000 description 1
- HFBFSOAKPUZCCO-ZLUOBGJFSA-N Ala-Cys-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N HFBFSOAKPUZCCO-ZLUOBGJFSA-N 0.000 description 1
- CXZFXHGJJPVUJE-CIUDSAMLSA-N Ala-Cys-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)O)N CXZFXHGJJPVUJE-CIUDSAMLSA-N 0.000 description 1
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 1
- IFTVANMRTIHKML-WDSKDSINSA-N Ala-Gln-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O IFTVANMRTIHKML-WDSKDSINSA-N 0.000 description 1
- NHLAEBFGWPXFGI-WHFBIAKZSA-N Ala-Gly-Asn Chemical compound C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N NHLAEBFGWPXFGI-WHFBIAKZSA-N 0.000 description 1
- PCIFXPRIFWKWLK-YUMQZZPRSA-N Ala-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N PCIFXPRIFWKWLK-YUMQZZPRSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 1
- FCXAUASCMJOFEY-NDKCEZKHSA-N Ala-Leu-Thr-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O FCXAUASCMJOFEY-NDKCEZKHSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- BDQNLQSWRAPHGU-DLOVCJGASA-N Ala-Phe-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)O)N BDQNLQSWRAPHGU-DLOVCJGASA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 1
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- FSXDWQGEWZQBPJ-HERUPUMHSA-N Ala-Trp-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FSXDWQGEWZQBPJ-HERUPUMHSA-N 0.000 description 1
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N MUGAESARFRGOTQ-IGNZVWTISA-N 0.000 description 1
- DCGLNNVKIZXQOJ-FXQIFTODSA-N Arg-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N DCGLNNVKIZXQOJ-FXQIFTODSA-N 0.000 description 1
- IIABBYGHLYWVOS-FXQIFTODSA-N Arg-Asn-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O IIABBYGHLYWVOS-FXQIFTODSA-N 0.000 description 1
- ZTKHZAXGTFXUDD-VEVYYDQMSA-N Arg-Asn-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZTKHZAXGTFXUDD-VEVYYDQMSA-N 0.000 description 1
- XVLLUZMFSAYKJV-GUBZILKMSA-N Arg-Asp-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XVLLUZMFSAYKJV-GUBZILKMSA-N 0.000 description 1
- VSPLYCLMFAUZRF-GUBZILKMSA-N Arg-Cys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCN=C(N)N)N VSPLYCLMFAUZRF-GUBZILKMSA-N 0.000 description 1
- DGFXIWKPTDKBLF-AVGNSLFASA-N Arg-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCCN=C(N)N)N DGFXIWKPTDKBLF-AVGNSLFASA-N 0.000 description 1
- HCIUUZGFTDTEGM-NAKRPEOUSA-N Arg-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N HCIUUZGFTDTEGM-NAKRPEOUSA-N 0.000 description 1
- OGSQONVYSTZIJB-WDSOQIARSA-N Arg-Leu-Trp Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O OGSQONVYSTZIJB-WDSOQIARSA-N 0.000 description 1
- YLVGUOGAFAJMKP-JYJNAYRXSA-N Arg-Met-Tyr Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YLVGUOGAFAJMKP-JYJNAYRXSA-N 0.000 description 1
- FOQFHANLUJDQEE-GUBZILKMSA-N Arg-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CS)C(=O)O FOQFHANLUJDQEE-GUBZILKMSA-N 0.000 description 1
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
- VYZBPPBKFCHCIS-WPRPVWTQSA-N Arg-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N VYZBPPBKFCHCIS-WPRPVWTQSA-N 0.000 description 1
- GOVUDFOGXOONFT-VEVYYDQMSA-N Asn-Arg-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GOVUDFOGXOONFT-VEVYYDQMSA-N 0.000 description 1
- KXFCBAHYSLJCCY-ZLUOBGJFSA-N Asn-Asn-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O KXFCBAHYSLJCCY-ZLUOBGJFSA-N 0.000 description 1
- VKCOHFFSTKCXEQ-OLHMAJIHSA-N Asn-Asn-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VKCOHFFSTKCXEQ-OLHMAJIHSA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- FTCGGKNCJZOPNB-WHFBIAKZSA-N Asn-Gly-Ser Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FTCGGKNCJZOPNB-WHFBIAKZSA-N 0.000 description 1
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 1
- NVWJMQNYLYWVNQ-BYULHYEWSA-N Asn-Ile-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O NVWJMQNYLYWVNQ-BYULHYEWSA-N 0.000 description 1
- BKFXFUPYETWGGA-XVSYOHENSA-N Asn-Phe-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BKFXFUPYETWGGA-XVSYOHENSA-N 0.000 description 1
- JXMREEPBRANWBY-VEVYYDQMSA-N Asn-Thr-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JXMREEPBRANWBY-VEVYYDQMSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- CXBOKJPLEYUPGB-FXQIFTODSA-N Asp-Ala-Met Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N CXBOKJPLEYUPGB-FXQIFTODSA-N 0.000 description 1
- FAEIQWHBRBWUBN-FXQIFTODSA-N Asp-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N)CN=C(N)N FAEIQWHBRBWUBN-FXQIFTODSA-N 0.000 description 1
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 1
- RDRMWJBLOSRRAW-BYULHYEWSA-N Asp-Asn-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O RDRMWJBLOSRRAW-BYULHYEWSA-N 0.000 description 1
- PXLNPFOJZQMXAT-BYULHYEWSA-N Asp-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O PXLNPFOJZQMXAT-BYULHYEWSA-N 0.000 description 1
- NURJSGZGBVJFAD-ZLUOBGJFSA-N Asp-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O NURJSGZGBVJFAD-ZLUOBGJFSA-N 0.000 description 1
- WYOSXGYAKZQPGF-SRVKXCTJSA-N Asp-His-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC(=O)O)N WYOSXGYAKZQPGF-SRVKXCTJSA-N 0.000 description 1
- SEMWSADZTMJELF-BYULHYEWSA-N Asp-Ile-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O SEMWSADZTMJELF-BYULHYEWSA-N 0.000 description 1
- XSXVLWBWIPKUSN-UHFFFAOYSA-N Asp-Leu-Glu-Asp Chemical compound OC(=O)CC(N)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(O)=O)C(O)=O XSXVLWBWIPKUSN-UHFFFAOYSA-N 0.000 description 1
- YWLDTBBUHZJQHW-KKUMJFAQSA-N Asp-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N YWLDTBBUHZJQHW-KKUMJFAQSA-N 0.000 description 1
- VWWAFGHMPWBKEP-GMOBBJLQSA-N Asp-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(=O)O)N VWWAFGHMPWBKEP-GMOBBJLQSA-N 0.000 description 1
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 1
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 description 1
- 108010003545 C1 peptide Proteins 0.000 description 1
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 1
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 108010039939 Cell Wall Skeleton Proteins 0.000 description 1
- 241000710777 Classical swine fever virus Species 0.000 description 1
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 1
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 1
- JIVJXVJMOBVCJF-ZLUOBGJFSA-N Cys-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)C(=O)N JIVJXVJMOBVCJF-ZLUOBGJFSA-N 0.000 description 1
- ZWNFOZNJYNDNGM-UBHSHLNASA-N Cys-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N ZWNFOZNJYNDNGM-UBHSHLNASA-N 0.000 description 1
- SKSJPIBFNFPTJB-NKWVEPMBSA-N Cys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CS)N)C(=O)O SKSJPIBFNFPTJB-NKWVEPMBSA-N 0.000 description 1
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 1
- RWVBNRYBHAGYSG-GUBZILKMSA-N Cys-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)N RWVBNRYBHAGYSG-GUBZILKMSA-N 0.000 description 1
- QQOWCDCBFFBRQH-IXOXFDKPSA-N Cys-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CS)N)O QQOWCDCBFFBRQH-IXOXFDKPSA-N 0.000 description 1
- MBRWOKXNHTUJMB-CIUDSAMLSA-N Cys-Pro-Glu Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O MBRWOKXNHTUJMB-CIUDSAMLSA-N 0.000 description 1
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 1
- PNEAWXSKCKCHDK-XIRDDKMYSA-N Cys-Trp-His Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CS)N)C(O)=O)C1=CN=CN1 PNEAWXSKCKCHDK-XIRDDKMYSA-N 0.000 description 1
- 238000011238 DNA vaccination Methods 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- SHAUZYVSXAMYAZ-JYJNAYRXSA-N Gln-Leu-Phe Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N SHAUZYVSXAMYAZ-JYJNAYRXSA-N 0.000 description 1
- IOFDDSNZJDIGPB-GVXVVHGQSA-N Gln-Leu-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IOFDDSNZJDIGPB-GVXVVHGQSA-N 0.000 description 1
- LURQDGKYBFWWJA-MNXVOIDGSA-N Gln-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N LURQDGKYBFWWJA-MNXVOIDGSA-N 0.000 description 1
- CMFBOXUBWMZZMD-BPUTZDHNSA-N Gln-Trp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N CMFBOXUBWMZZMD-BPUTZDHNSA-N 0.000 description 1
- WZZSKAJIHTUUSG-ACZMJKKPSA-N Glu-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O WZZSKAJIHTUUSG-ACZMJKKPSA-N 0.000 description 1
- ATRHMOJQJWPVBQ-DRZSPHRISA-N Glu-Ala-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ATRHMOJQJWPVBQ-DRZSPHRISA-N 0.000 description 1
- IYAUFWMUCGBFMQ-CIUDSAMLSA-N Glu-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)CN=C(N)N IYAUFWMUCGBFMQ-CIUDSAMLSA-N 0.000 description 1
- GZWOBWMOMPFPCD-CIUDSAMLSA-N Glu-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N GZWOBWMOMPFPCD-CIUDSAMLSA-N 0.000 description 1
- OAGVHWYIBZMWLA-YFKPBYRVSA-N Glu-Gly-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(O)=O OAGVHWYIBZMWLA-YFKPBYRVSA-N 0.000 description 1
- BRKUZSLQMPNVFN-SRVKXCTJSA-N Glu-His-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BRKUZSLQMPNVFN-SRVKXCTJSA-N 0.000 description 1
- FBEJIDRSQCGFJI-GUBZILKMSA-N Glu-Leu-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FBEJIDRSQCGFJI-GUBZILKMSA-N 0.000 description 1
- CBOVGULVQSVMPT-CIUDSAMLSA-N Glu-Pro-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O CBOVGULVQSVMPT-CIUDSAMLSA-N 0.000 description 1
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 1
- ZNOHKCPYDAYYDA-BPUTZDHNSA-N Glu-Trp-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZNOHKCPYDAYYDA-BPUTZDHNSA-N 0.000 description 1
- PYTZFYUXZZHOAD-WHFBIAKZSA-N Gly-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CN PYTZFYUXZZHOAD-WHFBIAKZSA-N 0.000 description 1
- FKJQNJCQTKUBCD-XPUUQOCRSA-N Gly-Ala-His Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O FKJQNJCQTKUBCD-XPUUQOCRSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- FEUPVVCGQLNXNP-IRXDYDNUSA-N Gly-Phe-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FEUPVVCGQLNXNP-IRXDYDNUSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 1
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 241000134307 Hepatitis C virus genotype 1 Species 0.000 description 1
- 241001093325 Hepatitis C virus genotype 3 Species 0.000 description 1
- 241001466980 Hepatitis C virus genotype 4 Species 0.000 description 1
- VYMGAXSNYUFVCK-GUBZILKMSA-N His-Gln-Asn Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N VYMGAXSNYUFVCK-GUBZILKMSA-N 0.000 description 1
- IGBBXBFSLKRHJB-BZSNNMDCSA-N His-Lys-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 IGBBXBFSLKRHJB-BZSNNMDCSA-N 0.000 description 1
- PYNPBMCLAKTHJL-SRVKXCTJSA-N His-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O PYNPBMCLAKTHJL-SRVKXCTJSA-N 0.000 description 1
- IAYPZSHNZQHQNO-KKUMJFAQSA-N His-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC2=CN=CN2)N IAYPZSHNZQHQNO-KKUMJFAQSA-N 0.000 description 1
- FCPSGEVYIVXPPO-QTKMDUPCSA-N His-Thr-Arg Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FCPSGEVYIVXPPO-QTKMDUPCSA-N 0.000 description 1
- UPJODPVSKKWGDQ-KLHWPWHYSA-N His-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O UPJODPVSKKWGDQ-KLHWPWHYSA-N 0.000 description 1
- ISQOVWDWRUONJH-YESZJQIVSA-N His-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CN=CN3)N)C(=O)O ISQOVWDWRUONJH-YESZJQIVSA-N 0.000 description 1
- KDDKJKKQODQQBR-NHCYSSNCSA-N His-Val-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N KDDKJKKQODQQBR-NHCYSSNCSA-N 0.000 description 1
- 101000957351 Homo sapiens Myc-associated zinc finger protein Proteins 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- LEDRIAHEWDJRMF-CFMVVWHZSA-N Ile-Asn-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LEDRIAHEWDJRMF-CFMVVWHZSA-N 0.000 description 1
- QSPLUJGYOPZINY-ZPFDUUQYSA-N Ile-Asp-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N QSPLUJGYOPZINY-ZPFDUUQYSA-N 0.000 description 1
- KUHFPGIVBOCRMV-MNXVOIDGSA-N Ile-Gln-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)O)N KUHFPGIVBOCRMV-MNXVOIDGSA-N 0.000 description 1
- CMNMPCTVCWWYHY-MXAVVETBSA-N Ile-His-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC(C)C)C(=O)O)N CMNMPCTVCWWYHY-MXAVVETBSA-N 0.000 description 1
- NNVXABCGXOLIEB-PYJNHQTQSA-N Ile-Met-His Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 NNVXABCGXOLIEB-PYJNHQTQSA-N 0.000 description 1
- BCISUQVFDGYZBO-QSFUFRPTSA-N Ile-Val-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O BCISUQVFDGYZBO-QSFUFRPTSA-N 0.000 description 1
- RQZFWBLDTBDEOF-RNJOBUHISA-N Ile-Val-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N RQZFWBLDTBDEOF-RNJOBUHISA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 1
- ZRLUISBDKUWAIZ-CIUDSAMLSA-N Leu-Ala-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O ZRLUISBDKUWAIZ-CIUDSAMLSA-N 0.000 description 1
- SUPVSFFZWVOEOI-UHFFFAOYSA-N Leu-Ala-Tyr Natural products CC(C)CC(N)C(=O)NC(C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 SUPVSFFZWVOEOI-UHFFFAOYSA-N 0.000 description 1
- MLTRLIITQPXHBJ-BQBZGAKWSA-N Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O MLTRLIITQPXHBJ-BQBZGAKWSA-N 0.000 description 1
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 1
- IASQBRJGRVXNJI-YUMQZZPRSA-N Leu-Cys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)NCC(O)=O IASQBRJGRVXNJI-YUMQZZPRSA-N 0.000 description 1
- CIVKXGPFXDIQBV-WDCWCFNPSA-N Leu-Gln-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CIVKXGPFXDIQBV-WDCWCFNPSA-N 0.000 description 1
- KUEVMUXNILMJTK-JYJNAYRXSA-N Leu-Gln-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KUEVMUXNILMJTK-JYJNAYRXSA-N 0.000 description 1
- DZQMXBALGUHGJT-GUBZILKMSA-N Leu-Glu-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O DZQMXBALGUHGJT-GUBZILKMSA-N 0.000 description 1
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- USLNHQZCDQJBOV-ZPFDUUQYSA-N Leu-Ile-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O USLNHQZCDQJBOV-ZPFDUUQYSA-N 0.000 description 1
- KUIDCYNIEJBZBU-AJNGGQMLSA-N Leu-Ile-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O KUIDCYNIEJBZBU-AJNGGQMLSA-N 0.000 description 1
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- MVVSHHJKJRZVNY-ACRUOGEOSA-N Leu-Phe-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MVVSHHJKJRZVNY-ACRUOGEOSA-N 0.000 description 1
- AEDWWMMHUGYIFD-HJGDQZAQSA-N Leu-Thr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O AEDWWMMHUGYIFD-HJGDQZAQSA-N 0.000 description 1
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 1
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 1
- AAKRWBIIGKPOKQ-ONGXEEELSA-N Leu-Val-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AAKRWBIIGKPOKQ-ONGXEEELSA-N 0.000 description 1
- VKVDRTGWLVZJOM-DCAQKATOSA-N Leu-Val-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O VKVDRTGWLVZJOM-DCAQKATOSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- ABHIXYDMILIUKV-CIUDSAMLSA-N Lys-Asn-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ABHIXYDMILIUKV-CIUDSAMLSA-N 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ACYHZNZHIZWLQF-BQBZGAKWSA-N Met-Asn-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ACYHZNZHIZWLQF-BQBZGAKWSA-N 0.000 description 1
- SCKPOOMCTFEVTN-QTKMDUPCSA-N Met-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCSC)N)O SCKPOOMCTFEVTN-QTKMDUPCSA-N 0.000 description 1
- YGNUDKAPJARTEM-GUBZILKMSA-N Met-Val-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O YGNUDKAPJARTEM-GUBZILKMSA-N 0.000 description 1
- VEKRTVRZDMUOQN-AVGNSLFASA-N Met-Val-His Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 VEKRTVRZDMUOQN-AVGNSLFASA-N 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 102100038750 Myc-associated zinc finger protein Human genes 0.000 description 1
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 1
- 108700015872 N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine Proteins 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 1
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 0.000 description 1
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 1
- 101710144111 Non-structural protein 3 Proteins 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 241000710778 Pestivirus Species 0.000 description 1
- AJOKKVTWEMXZHC-DRZSPHRISA-N Phe-Ala-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 AJOKKVTWEMXZHC-DRZSPHRISA-N 0.000 description 1
- LXUJDHOKVUYHRC-KKUMJFAQSA-N Phe-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N LXUJDHOKVUYHRC-KKUMJFAQSA-N 0.000 description 1
- MGBRZXXGQBAULP-DRZSPHRISA-N Phe-Glu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MGBRZXXGQBAULP-DRZSPHRISA-N 0.000 description 1
- MMYUOSCXBJFUNV-QWRGUYRKSA-N Phe-Gly-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N MMYUOSCXBJFUNV-QWRGUYRKSA-N 0.000 description 1
- GPSMLZQVIIYLDK-ULQDDVLXSA-N Phe-Lys-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O GPSMLZQVIIYLDK-ULQDDVLXSA-N 0.000 description 1
- QSWKNJAPHQDAAS-MELADBBJSA-N Phe-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O QSWKNJAPHQDAAS-MELADBBJSA-N 0.000 description 1
- SHUFSZDAIPLZLF-BEAPCOKYSA-N Phe-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N)O SHUFSZDAIPLZLF-BEAPCOKYSA-N 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- OLHDPZMYUSBGDE-GUBZILKMSA-N Pro-Arg-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O OLHDPZMYUSBGDE-GUBZILKMSA-N 0.000 description 1
- XJROSHJRQTXWAE-XGEHTFHBSA-N Pro-Cys-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJROSHJRQTXWAE-XGEHTFHBSA-N 0.000 description 1
- JFNPBBOGGNMSRX-CIUDSAMLSA-N Pro-Gln-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O JFNPBBOGGNMSRX-CIUDSAMLSA-N 0.000 description 1
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 1
- FDMCIBSQRKFSTJ-RHYQMDGZSA-N Pro-Thr-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O FDMCIBSQRKFSTJ-RHYQMDGZSA-N 0.000 description 1
- YIPFBJGBRCJJJD-FHWLQOOXSA-N Pro-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@@H]3CCCN3 YIPFBJGBRCJJJD-FHWLQOOXSA-N 0.000 description 1
- ZYJMLBCDFPIGNL-JYJNAYRXSA-N Pro-Tyr-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1)C(O)=O ZYJMLBCDFPIGNL-JYJNAYRXSA-N 0.000 description 1
- PGSWNLRYYONGPE-JYJNAYRXSA-N Pro-Val-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PGSWNLRYYONGPE-JYJNAYRXSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 1
- IYCBDVBJWDXQRR-FXQIFTODSA-N Ser-Ala-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O IYCBDVBJWDXQRR-FXQIFTODSA-N 0.000 description 1
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 1
- JJKSSJVYOVRJMZ-FXQIFTODSA-N Ser-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N)CN=C(N)N JJKSSJVYOVRJMZ-FXQIFTODSA-N 0.000 description 1
- VAIZFHMTBFYJIA-ACZMJKKPSA-N Ser-Asp-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(N)=O VAIZFHMTBFYJIA-ACZMJKKPSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- HVKMTOIAYDOJPL-NRPADANISA-N Ser-Gln-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVKMTOIAYDOJPL-NRPADANISA-N 0.000 description 1
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 1
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 1
- HBTCFCHYALPXME-HTFCKZLJSA-N Ser-Ile-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HBTCFCHYALPXME-HTFCKZLJSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- IUXGJEIKJBYKOO-SRVKXCTJSA-N Ser-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N IUXGJEIKJBYKOO-SRVKXCTJSA-N 0.000 description 1
- VZQRNAYURWAEFE-KKUMJFAQSA-N Ser-Leu-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VZQRNAYURWAEFE-KKUMJFAQSA-N 0.000 description 1
- ASGYVPAVFNDZMA-GUBZILKMSA-N Ser-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)N ASGYVPAVFNDZMA-GUBZILKMSA-N 0.000 description 1
- WBAXJMCUFIXCNI-WDSKDSINSA-N Ser-Pro Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WBAXJMCUFIXCNI-WDSKDSINSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 1
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- VLMIUSLQONKLDV-HEIBUPTGSA-N Ser-Thr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VLMIUSLQONKLDV-HEIBUPTGSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- VASYSJHSMSBTDU-LKXGYXEUSA-N Thr-Asn-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)O VASYSJHSMSBTDU-LKXGYXEUSA-N 0.000 description 1
- LXWZOMSOUAMOIA-JIOCBJNQSA-N Thr-Asn-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O LXWZOMSOUAMOIA-JIOCBJNQSA-N 0.000 description 1
- LYGKYFKSZTUXGZ-ZDLURKLDSA-N Thr-Cys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)NCC(O)=O LYGKYFKSZTUXGZ-ZDLURKLDSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- SIMKLINEDYOTKL-MBLNEYKQSA-N Thr-His-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C)C(=O)O)N)O SIMKLINEDYOTKL-MBLNEYKQSA-N 0.000 description 1
- UYTYTDMCDBPDSC-URLPEUOOSA-N Thr-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N UYTYTDMCDBPDSC-URLPEUOOSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- BVOVIGCHYNFJBZ-JXUBOQSCSA-N Thr-Leu-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O BVOVIGCHYNFJBZ-JXUBOQSCSA-N 0.000 description 1
- MUAFDCVOHYAFNG-RCWTZXSCSA-N Thr-Pro-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MUAFDCVOHYAFNG-RCWTZXSCSA-N 0.000 description 1
- GVMXJJAJLIEASL-ZJDVBMNYSA-N Thr-Pro-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O GVMXJJAJLIEASL-ZJDVBMNYSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-N 0.000 description 1
- FRQRWAMUESPWMT-HSHDSVGOSA-N Thr-Trp-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCSC)C(=O)O)N)O FRQRWAMUESPWMT-HSHDSVGOSA-N 0.000 description 1
- NJGMALCNYAMYCB-JRQIVUDYSA-N Thr-Tyr-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O NJGMALCNYAMYCB-JRQIVUDYSA-N 0.000 description 1
- PMIJXCLOQFMOKZ-BPUTZDHNSA-N Trp-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N PMIJXCLOQFMOKZ-BPUTZDHNSA-N 0.000 description 1
- HXNVJPQADLRHGR-JBACZVJFSA-N Trp-Glu-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N HXNVJPQADLRHGR-JBACZVJFSA-N 0.000 description 1
- WSGPBCAGEGHKQJ-BBRMVZONSA-N Trp-Gly-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WSGPBCAGEGHKQJ-BBRMVZONSA-N 0.000 description 1
- HNIWONZFMIPCCT-SIXJUCDHSA-N Trp-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N HNIWONZFMIPCCT-SIXJUCDHSA-N 0.000 description 1
- UKWSFUSPGPBJGU-VFAJRCTISA-N Trp-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O UKWSFUSPGPBJGU-VFAJRCTISA-N 0.000 description 1
- RCMHSGRBJCMFLR-BPUTZDHNSA-N Trp-Met-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 RCMHSGRBJCMFLR-BPUTZDHNSA-N 0.000 description 1
- ABEVJDLMFPTGPS-SZMVWBNQSA-N Trp-Met-Met Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(O)=O ABEVJDLMFPTGPS-SZMVWBNQSA-N 0.000 description 1
- GEGYPBOPIGNZIF-CWRNSKLLSA-N Trp-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)O GEGYPBOPIGNZIF-CWRNSKLLSA-N 0.000 description 1
- QHWMVGCEQAPQDK-UMPQAUOISA-N Trp-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O QHWMVGCEQAPQDK-UMPQAUOISA-N 0.000 description 1
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- OOEUVMFKKZYSRX-LEWSCRJBSA-N Tyr-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OOEUVMFKKZYSRX-LEWSCRJBSA-N 0.000 description 1
- YWXMGBUGMLJMIP-IHPCNDPISA-N Tyr-Cys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC3=CC=C(C=C3)O)N YWXMGBUGMLJMIP-IHPCNDPISA-N 0.000 description 1
- KEHKBBUYZWAMHL-DZKIICNBSA-N Tyr-Gln-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O KEHKBBUYZWAMHL-DZKIICNBSA-N 0.000 description 1
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 1
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 1
- WPXKRJVHBXYLDT-JUKXBJQTSA-N Tyr-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N WPXKRJVHBXYLDT-JUKXBJQTSA-N 0.000 description 1
- FBHBVXUBTYVCRU-BZSNNMDCSA-N Tyr-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CN=CN1 FBHBVXUBTYVCRU-BZSNNMDCSA-N 0.000 description 1
- MXFPBNFKVBHIRW-BZSNNMDCSA-N Tyr-Lys-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O MXFPBNFKVBHIRW-BZSNNMDCSA-N 0.000 description 1
- SBLZVFCEOCWRLS-BPNCWPANSA-N Tyr-Met-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CC=C(C=C1)O)N SBLZVFCEOCWRLS-BPNCWPANSA-N 0.000 description 1
- KHUVIWRRFMPVHD-JYJNAYRXSA-N Tyr-Met-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O KHUVIWRRFMPVHD-JYJNAYRXSA-N 0.000 description 1
- SCZJKZLFSSPJDP-ACRUOGEOSA-N Tyr-Phe-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O SCZJKZLFSSPJDP-ACRUOGEOSA-N 0.000 description 1
- VYTUETMEZZLJFU-IHRRRGAJSA-N Tyr-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)N[C@@H](CS)C(=O)O VYTUETMEZZLJFU-IHRRRGAJSA-N 0.000 description 1
- HZWPGKAKGYJWCI-ULQDDVLXSA-N Tyr-Val-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C)C(O)=O HZWPGKAKGYJWCI-ULQDDVLXSA-N 0.000 description 1
- 108010064997 VPY tripeptide Proteins 0.000 description 1
- KKHRWGYHBZORMQ-NHCYSSNCSA-N Val-Arg-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KKHRWGYHBZORMQ-NHCYSSNCSA-N 0.000 description 1
- QGFPYRPIUXBYGR-YDHLFZDLSA-N Val-Asn-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N QGFPYRPIUXBYGR-YDHLFZDLSA-N 0.000 description 1
- PVPAOIGJYHVWBT-KKHAAJSZSA-N Val-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N)O PVPAOIGJYHVWBT-KKHAAJSZSA-N 0.000 description 1
- YODDULVCGFQRFZ-ZKWXMUAHSA-N Val-Asp-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O YODDULVCGFQRFZ-ZKWXMUAHSA-N 0.000 description 1
- FPCIBLUVDNXPJO-XPUUQOCRSA-N Val-Cys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FPCIBLUVDNXPJO-XPUUQOCRSA-N 0.000 description 1
- AAOPYWQQBXHINJ-DZKIICNBSA-N Val-Gln-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N AAOPYWQQBXHINJ-DZKIICNBSA-N 0.000 description 1
- DJEVQCWNMQOABE-RCOVLWMOSA-N Val-Gly-Asp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N DJEVQCWNMQOABE-RCOVLWMOSA-N 0.000 description 1
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 1
- JPPXDMBGXJBTIB-ULQDDVLXSA-N Val-His-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N JPPXDMBGXJBTIB-ULQDDVLXSA-N 0.000 description 1
- FTKXYXACXYOHND-XUXIUFHCSA-N Val-Ile-Leu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O FTKXYXACXYOHND-XUXIUFHCSA-N 0.000 description 1
- SDUBQHUJJWQTEU-XUXIUFHCSA-N Val-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C(C)C)N SDUBQHUJJWQTEU-XUXIUFHCSA-N 0.000 description 1
- QWCZXKIFPWPQHR-JYJNAYRXSA-N Val-Pro-Tyr Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QWCZXKIFPWPQHR-JYJNAYRXSA-N 0.000 description 1
- UGFMVXRXULGLNO-XPUUQOCRSA-N Val-Ser-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O UGFMVXRXULGLNO-XPUUQOCRSA-N 0.000 description 1
- CFIBZQOLUDURST-IHRRRGAJSA-N Val-Tyr-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CS)C(=O)O)N CFIBZQOLUDURST-IHRRRGAJSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- ODUHAIXFXFACDY-SRVKXCTJSA-N Val-Val-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C ODUHAIXFXFACDY-SRVKXCTJSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 238000007818 agglutination assay Methods 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- NWMHDZMRVUOQGL-CZEIJOLGSA-N almurtide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)CO[C@@H]([C@H](O)[C@H](O)CO)[C@@H](NC(C)=O)C=O NWMHDZMRVUOQGL-CZEIJOLGSA-N 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 229940001007 aluminium phosphate Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000004520 cell wall skeleton Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 108010004073 cysteinylcysteine Proteins 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 125000001965 gamma-lactamyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- VOWCXSYDBWCCCF-QIBOXNKSSA-N gbv-b Chemical compound C([C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 VOWCXSYDBWCCCF-QIBOXNKSSA-N 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 1
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- SHFKGANKURXVMY-LCWPZEQJSA-N hcv e2 protein Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)CC1=CC=CC=C1 SHFKGANKURXVMY-LCWPZEQJSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000004904 long-term response Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 108010087904 neutravidin Proteins 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 108010036387 trimethionine Proteins 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
- C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
Definitions
- the present invention relates to multi-mer peptides derived from hepatitis C virus envelope proteins which react with the majority of anti-HCV antibodies present in patient sera. Consequently, the present invention relates to the usage of the latter peptides to diagnose, and to vaccinate against, an infection with hepatitis C virus.
- HCV infection is a major health problem in both developed and developing countries. It is estimated that about 1 to 5% of the world population is affected by the virus, amounting up to 175 million chronic infections worldwide. HCV infection appears to be the most important cause of transfusion-associated hepatitis and frequently progresses to chronic liver damage. Moreover, there is evidence implicating HCV in induction of hepatocellular carcinoma. Consequently, the demand for reliable diagnostic methods and effective therapeutic agents is high. There is also an urgent need to characterize new epitopes which can be used in the design of effective vaccines against hepatitis C.
- HCV is a positive stranded RNA virus of about 9,8 kilobases which code for at least three structural and at least six non-structural proteins.
- the structural proteins have not yet been functionally assigned, but are thought to consist of a single core protein and two envelope proteins E1 and E2.
- the E1 protein consists of 192 amino acids and contains 5 to 6 N-glycosylation sites, depending on the HCV genotype, whereas the E2 protein consists of 363 to 370 amino acids and contains up to 11 N-glycosylation sites, depending on the HCV genotype (for review see Maertens and Stuyver, 1997).
- E1 and E2 proteins are currently not included in HCV antibody (Ab) assays, primarily because of their complex conformational structures which require expression in mammalian cells as well as non-denaturing purification techniques. Indeed, after expression of E2 in Escherichia coli , the reactivity of HCV sera with the recombinant protein ranged from 14 (Yokosuka et al., 1992) to 17% (Mita et al., 1992), whereas expression in eukaryotic systems yields reactivities of 13 to 97% (Inoue, 1992; Chien, 1993).
- the present invention relates to the surprising finding that multi-mer peptides (eg 30- to 45-mer peptides) are able to recognize the majority of anti-E1 and anti-E2 Ab's in sera from HCV patients. It should be clear that this is a surprising finding because there is no guidance which would suggest that 30- to 45-mer peptides derived from E1 and E2 would acquire proper folding and would efficiently recognize the majority of HCV envelope Ab's. In contrast, one would assume that the chance that multi-mer peptides malfold would be as great, or even greater, than the chance that prokaryotically expressed complete proteins malfold as is suggested above. In the case of the HCV NS3 protein for example, which reacts with more than 90% of patient samples as expressed from E. coli , 20-50 mer peptides only react very weakly.
- HCV-related viruses including HCV, GBV-B virus, GBV-A virus and GBV-C (HGV or hepatitis G virus), are a division of the Flaviviruses, which further comprise Dengue virus, Yellow fever virus, Pestiviruses such as Classical Swine Fever Virus and Bovine Viral Diarrhea Virus (Wengler, 1991).
- the present invention aims at providing a peptide which binds and recognizes an anti-HCV antibody or an anti-HGV antibody present in a sample of body fluid and which is chosen from the group consisting of the sequences as represented in SEQ ID NOs 1 to 38 (see Table 1) or a functionally equivalent variant or fragment thereof.
- the present invention aims specifically at providing a peptide as described above, wherein said anti-HCV antibody present in a sample of body fluid is an anti-HCV-E1 antibody or an anti-HCV-E2 antibody.
- the present invention thus aims also at providing a peptide as described above, wherein said anti-HGV antibody present in a sample of body fluid is an anti-HGV-E1 antibody or an anti-HGV-E2 antibody.
- the present invention aims at providing a peptide as described above, wherein said peptide is synthesized chemically or is synthesized using recombinant DNA techniques.
- the present invention also aims at providing a peptide as described above, wherein said peptide is biotinylated or contains cysteine bridges.
- the present invention aims at providing any combination of peptides as described above, as well as compositions containing said combination of peptides or peptides as described above .
- the present invention aims at providing a method for diagnosing exposure to or infection by HCV-related viruses comprising contacting anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above, determining the binding of anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above.
- the present invention aims at providing an assay kit for detecting the presence of anti-HCV-related virus antibodies within a sample of body fluid comprising a solid support, a peptide as described above or a combination of peptides as described above, appropriate markers which allow to determine the complexes formed between anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or a combination of peptides as described above.
- the present invention aims at providing a bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising contacting anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, determining the binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, adding a modulator (ie a compound which is able to modulate the interaction between an envelope protein and an anti-HCV-related virus antibody) or a combination of modulators to the contacted anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above
- the present invention aims at providing a bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising determining the binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, contacting a modulator with a peptide as described above or a combination of peptides as described above, adding anti-HCV-related virus antibodies to the contacted modulator with the peptide as described above or a combination of peptides as described above, determining the modulation of binding between anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above.
- the present invention aims at providing a modulator, a composition containing a modulator, or a combination of modulators when produced by the bioassay as described above or when identified by the above-described bioassays.
- the present invention aims at providing a composition comprising a plasmid vector comprising a nucleotide sequence encoding a peptide as described above, or a modulator as described above, operably linked to transcription regulatory elements.
- the present invention aims at providing a composition as described above for use to vaccinate or therapeutically treat humans against infection with HCV-related virus or any mutated strain thereof
- an antibody more particularly a monoclonal antibody, characterized in that it specifically recognizes an HCV-related virus polypeptide as described above.
- Table 1 provides information on the envelope protein and the HCV genotype from which the peptides of the present invention are derived. This table also provides the name, the amino acid sequence, the position within the envelope proteins and the sequence identity (SEQ ID) of the peptides of the present invention.
- Table 2 shows ELISA results (in mOD) of reactivities of multimer peptides and recombinant E2 with 60 HCV positive samples and 4 control samples.
- Table 3 shows the analysis for E1 antibodies of 23 sera from responders to interferon treatment.
- Table 4 shows the analysis of E2 antibodies of 23 sera from responders to interferon treatment.
- Table 5 shows the monitoring of disease over time by measuring antibodies to the HCV E1 and E2 regions in 18 patients.
- Table 6 indicates the reactivity of HGV (Hepatitis G virus) RNA positive sera with the HGV E1 peptide V1V2.
- FIG. 3 shows the reactivity of 20-mer E2 peptides.
- the OD values of serum samples from patients with chronic active hepatitis C were added and plotted against the different peptides.
- FIG. 4 shows the reactivity of mulit-mer E2 peptides.
- the OD values of the samples were added and plotted against the different peptides.
- the samples were identical as used for FIG. 3.
- the present invention is based on the finding that multimer peptides, as of a certain length, derived from the envelope proteins of HCV-related viruses, eg HCV and HGV, recognize and bind anti-HCV-related virus antibodies, eg anti-HCV antibodies and anti-HGV antibodies, respectively. Therefore, the present invention provides a peptide of more than 20 contiguous amino acids derived from the envelope region of HCV-related viruses which binds and recognizes anti-HCV-related virus antibodies.
- HCV-related viruses include, but are not limited to HCV, GBV-B virus, GBV-A virus and GBV-C virus (HGV or hepatitis G virus)(Linnen et al., 1996).
- HCV constitutes a genus within the Flaviviridae, and is closely related to hepatitis G virus (26.8% at the amino acid level).
- envelope region of HCV-related viruses is a well-known region by a person skilled in the art (Wengler, 1991), and comprises the E1 protein as well as the E2 protein, which was previously called non-structural protein 1 (NS 1) or E2/NS1.
- the present invention relates to a peptide, which binds and recognizes an anti-HCV antibody or an anti-HGV antibody present in a sample of body fluid, and which is chosen from the group consisting of the sequences as represented in SEQ ID 1 to 38 (see Table 1) or a functionally equivalent variant or fragment thereof.
- the present invention relates also to a peptide as described above, wherein said anti-HCV antibody or said anti-HGV antibody present in a sample of body fluid is an anti-HCV-E1 or anti-HCV-E2 antibody, or an anti-HGV-E1 or anti-HGV-E2 antibody, respectively.
- a peptide refers to a polymer of amino acids (aa's) derived (i.e. containing less aa's) from the well-known HCV-related virus envelope proteins E1 and E2 (Linnen et al., 1996, Maertens and Stuyver, 1997), which binds anti-HCV-related virus antibodies.
- the term “a peptide” refers in particular to a polymer of aa's derived from HCV envelope proteins E1 and E2, which binds anti-HCV antibodies, or from HGV envelope proteins E1 and E2, which binds anti-HGV antibodies.
- an anti-HCV-related virus antibody refers to any polyclonal or monoclonal antibody binding to a HCV-related virus particle or any molecule derived from said viral particle. More particularly, the term “an anti-HCV-related virus antibody” refers to antibodies binding to the natural, recombinant or synthetic E1 and/or E2 proteins derived from HCV or HGV proteins (anti-HCV-E1 or anti-HCV-E2 antibody, or anti-HGV-E1 or anti-HGV-E2 antibody, respectively).
- antibody also refers to humanized antibodies in which at least a portion of the framework regions of an immunoglobulin are derived from human immunoglobulin sequences and single chain antibodies as described in U.S. Pat. No. 4,946,778 and to fragments of antibodies such as F ab , F ′(ab))2 , F v , and other fragments which retain the antigen binding function and specificity of the parent antibody.
- a sample of body fluid refers to a fluid obtained from an organism, such as serum, plasma, saliva, gastric secretions, mucus, spinal cord fluid, and the like.
- the term “the group consisting of the sequences as represented in SEQ ID NOs 1 to 33” as used herein refers to the thirty-eight peptides shown in Table 1 of the present application. In this table, it is indicated:
- position the well-known (Maertens and Stuyver, 1997) aa position of the peptides within the HCV envelope proteins. Note that the position for the E1 envelope protein is not determined, which is denoted as “ND”.
- the term “functionally equivalent” as used in “functionally equivalent variant or fragment thereof” refers to variants and fragments of the peptides represented by SEQ ID 1 to 38, which bind anti-HCV-related virus antibodies.
- the term “variant or fragment” as used in “functionally equivalent variant or fragment thereof” refers to any variant or any fragment of the peptides represented by SEQ ID 1 to 38. Furthermore, the latter terms do not refer to, nor do they exclude, post-translational modifications of the peptides represented by SEQ ID 1 to 38 such as glycosylation, acetylation, phosphorylation, modifications with fatty acids and the like.
- peptides containing one or more analogues of an aa including unnatural aa's
- peptides with substituted linkages for examples corresponding to the genotypes HCV, as described in WO 94/12670 to Maertens et al.
- peptides containing disulfide bounds between cysteine residues or other cysteine modifications
- biotinylated peptides as well as other modifications known in the art.
- Modification of the structure of the polypeptides can be for such objectives as increasing therapeutic or prophylactic efficacy, stability (e.g.
- modified peptides when designed to retain at least one activity of the naturally-occurring form of the protein are considered functional equivalents of the polypeptides described in more detail herein.
- modified peptides can be produced, for instance, by amino acid substitution, deletion, or addition. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid (i.e.
- amino acids that are related in their side chains. Genetically encoded amino acids can be divided into four families: (1) acidic: aspartate, glutamate; (2) basic: lysine, arginine, histidine; (3) nonpolar: alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar: glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine.
- amino acid repertoire can be grouped as (1) acidic: aspartate, glutamate; (2) basic: lysin, arginine histidine, (3) aliphatic: glycine, alanine, valine, leucine, isoleucine, serine, threoaine, with serine and threonine optionally be grouped separately as aliphatic-hydroxyl; (4) aromatic: phenylalanine, tyrosine, tryptophan, (5) amide: asparagine, glutamine; and (6) sulfur-containing: cysteine and methionine. (see, for example, Biochemistry, 2nd ed., Ed. by L. Stryer, W H Freeman and Co.: 1981).
- Whether a change in the amino acid sequence of a peptide results in a functional homologue can be readily determined by assessing the ability of the variant peptide to produce a response in e.g. ELISAs in a fashion similar to the wild-type protein, or to competitively inhibit such a response.
- Polypeptides in which more than one replacement has been introduced can be readily tested in the same manner. It should also be clear that the region of a peptide represented by SEQ ID 1 to 38 which bind to an antibody (the so-called epitope) need not to be composed of a contiguous aa sequence.
- fragment includes any fragment which comprises these non-contiguous binding regions or parts thereof.
- fragments which include these binding regions may be separated by a linker, which is not a functional part of the epitope.
- This linker does not need to be an amino acid sequence, but can be any molecule, eg organic or inorganic, that allows the formation of the desired epitope by two or more fragments.
- variants and fragments of SEQ ID NOs 1 to 5, 7 to 9, and 18 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's or 33 aa's, or 34 aa's.
- variants and fragments of SEQ ID NO 6 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's.
- variants and fragments of SEQ ID NO 10 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's.
- variants and fragments of SEQ ID NOs 11, 15, 21, 34 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's.
- variants and fragments of SEQ ID NOs 12, 24 or 32 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's. or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, or 35 aa's.
- variants and fragments of SEQ ID NOs 13, 22, or 34 used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's.
- variants and fragments of SEQ ID NO 16 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's.
- variants and fragments of SEQ ID NO 17 as used herein refers to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's.
- variants and fragments of SEQ ID NO 19 as used herein refers to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's.
- variants and fragments of SEQ ID NOs 20 and 30 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's.
- variants and fragments of SEQ ID NO 23 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's, or 42 aa's, or 43 aa's.
- variants and fragments of SEQ ID NOs 25 or 29 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's.
- variants and fragments of SEQ ID NO 26 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's or 29 aa's.
- variants and fragments of SEQ ID NO 27 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's, or42 aa's, or 43 aa's, or 44 aa's.
- variants and fragments of SEQ ID NO 28 or 31 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's.
- variants and fragments of SEQ ID NO 33 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's.
- variants and fragments of SEQ ID NOs 14 or 37 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's.
- amino acid regions of the peptides which are disclosed in the present invention and that bind anti-HCV antibodies, can be delineated in more detail by experimentation.
- variants and fragments of the peptides represented by SEQ ID 1 to 38, as herein described can be prepared by any method known in the art such as classical chemical synthesis, as described by Houbenweyl (1974) and Atherton & Shepard (1989), or by means of recombinant DNA techniques as described by eg Maniatis et al. (1982), or Sambrook et al. (1989).
- the peptides represented by SEQ ID 1 to 38 of the present invention can be prepared by any method known in the art and more particularly by means of classical chemical synthesis, as described by Houbenweyl (1974) and Atherton & Shepard (1989), or by means of recombinant DNA techniques such as described by eg Maniatis et al. (1982), or Sambrook et al. (1989).
- the present invention further relates to the peptides represented by SEQ ID 1 to 38 and functionally equivalent variants or fragments thereof, all as defined above, which are biotinylated or contain cysteine bridges.
- Biotinylated peptides can be obtained by any method known in the art, such as the one described in WO93/18054 to De Leys. Methods for obtaining peptides containing inter- and/or intramolecular cysteine bridges are extensively described in WO 96/13590 to Maertens & Stuyver.
- the present invention also relates to any combination of peptides represented by SEQ ID 1 to 38 and functionally equivalent variants or fragments thereof as defined above.
- the terms “any combination” refers to any possible mixture of above-described peptides or any possible linkage (covalently or otherwise) between above-described peptides. Examples of the latter peptide combinations are simple mixtures, homo- or hetero-branched peptides, combinations of biotinylated peptides presented on streptavidin, avidin or neutravidin, chemically cross-linked peptides with or without spacer, condensed peptides and recombinantly produced peptides.
- the present invention relates also an antibody, more particularly a monoclonal antibody, characterized in that it specifically recognizes an HCV-related virus polypeptide as described above.
- the present invention also relates to a method for diagnosing exposure to or infection by HCV-related viruses comprising contacting anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above, and, determining the binding of anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above.
- a method for diagnosing refers to any immunoassay known in the art such as assays which utilize biotin and avidin or streptavidin, ELISAs and immunoprecipitation and agglutination assays. A detailed description of these assays is given in WO 96/13590 to Maertens & Stuyver.
- the present invention also relates to an assay kit for detecting the presence of anti-HCV-related virus antibodies comprising a solid support, a peptide as described above or a functionally equivalent variant or fragment thereof, or combination of peptides as described above, and appropriate markers which allow to determine the complexes formed between anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above, or a functionally equivalent variant or fragment thereof, or combination of peptides as described above.
- a solid support refers to any solid support known in the art.
- a method for diagnosing encompasses screening, detection, confirmation, monitoring and serotyping methods.
- the present invention further pertains to a bioassay for identifying compounds which modulate the binding between a peptide and an anti-HCV-related virus antibody, comprising contacting anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, and determining the binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, adding a modulator or a combination of modulators to the contacted anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, and finally determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above.
- the present invention features a bioassay for identifying compounds which modulate the binding between a peptide and an anti-HCV-related virus antibody, comprising determining the binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, contacting a modulator with a peptide as described above, or a combination of peptides as described above, adding anti-HCV-related virus antibodies to the contacted modulator with a peptide as described above, or a combination of peptides as described above, determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above.
- the term “compound” as used herein refers to a composition, which has a molecular weight of less than about 25 KDa, preferably less than 10 KDa, and most preferably less than 5 KDa.
- Compounds can be nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules, or antibodies which may be generated by the host itself upon vaccination.
- binding indicates that a peptide as described above is physically connected to, and interacts with antibodies. Binding of the peptide to the antibody can be demonstrated by any method or assay known in the art such as binding-, ELISA, and RIA-type of assays or competition assays (eg see Examples section and Current protocols in immunology).
- modulation refers to both upregulation (i.e., activation or stimulation (e.g., by agonizing or potentiating)) and downregulation (i.e. inhibition or suppression (e.g. by antagonizing, decreasing or inhibiting) of the binding between a peptide and an anti-HCV antibody.
- upregulation i.e., activation or stimulation (e.g., by agonizing or potentiating)
- downregulation i.e. inhibition or suppression (e.g. by antagonizing, decreasing or inhibiting) of the binding between a peptide and an anti-HCV antibody.
- modulator refers to the ability of a compound as described above to modulate as described above.
- peptidomimetics refers to molecules which can be manufactured and which mimic those residues of peptides which modulate the interaction of the antibody with the peptide as described above.
- non-hydrolyzable peptide analogs of such residues can be generated using benzodiazepine (e.g., see Freidinger et al. in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), azepine (e.g., see Huffman et al. in Peptides: Chemistry and Biology, G. R.
- the present invention pertains to a modulator produced by a bioassay as described above.
- the present invention pertains also to a modulator for the interaction between a peptide and an anti-HCV-related virus antibody, when said modulators are identified by a bioassay as described above.
- the present invention features a composition comprising as an active substance a peptide as described above or a combination of peptides as described above.
- the present invention features also a composition
- a composition comprising as an active substance a modulator as described above or a combination of modulators as described above.
- the present invention relates to a composition
- a composition comprising a plasmid vector comprising a nucleotide sequence encoding a peptide as described above, operably linked to transcription regulatory elements.
- said plasmid vector Upon introduction in a human tissue said plasmid vector induces the expression in vivo, of the nucleotide sequence thereby producing the encoded protein. If said protein elicits an immunogenic response it is referred to as a DNA vaccine.
- variations or derivatives of the nucleotide sequence can be produced which alter the nucleotide sequence.
- the altered polynucleotide may have an altered nucleic sequence, yet still encodes a protein as described above, and which reacts with anti-HCV-related virus antibodies, and is considered a to be functional equivalent
- the present invention relates to a composition as described herein for use as to vaccinate humans against infection with HCV-related virus or any mutated strain thereof.
- the present invention relates to a composition as described herein for use as to therapeutically treat humans against infection with HCV-related virus or any mutated strain thereof.
- a composition of the present invention can be, as appropiate, any of the preparations described herein, including peptides, functionally equivalent variants or fragments thereof, a combination of peptides, or modulators (e.g. as identified in the bioassay provided herein).
- a composition relates to an immunogenic composition capable of eliciting protection against HCV-related virus, in particular against HCV and/or HGV, whether partial or complete.
- the term “as an active substance” relates to the component of the vaccine composition which elicits protection against HCV-related viruses, in particular against HCV and/or HGV.
- An active substance e.g.
- the peptides or the modulators of the present invention can be used as such, in a biotinylated form (as explained in WO 93/18054) and/or complexed to Neutralite Avidin according to the manufacturer's instruction sheet (Molecular Probes Inc., Eugene, Oreg.).
- a composition comprises, in addition to an active substance, a suitable excipient, diluent, carrier and/or adjuvant which, by themselves, do not induce the production of antibodies harmful to the individual receiving the composition nor do they elicit protection.
- Suitable carriers are typically large slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric aa's, aa copolymers and inactive virus particles. Such carriers are well known to those skilled in the art.
- Preferred adjuvants to enhance effectiveness of the composition include, but are not limited to: aluminium hydroxide, aluminium in combination with 3-0-deacylated monophosphoryl lipid A as described in WO 93/19780, aluminium phosphate as described in WO 93/24148, N-acetyl-muramyl-L-threonyl-D-isoglutamine as described in U.S. Pat. No.
- any of the three components MPL, TDM or CWS may also be used alone or combined 2 by 2.
- adjuvants such as Stimulon (Cambridge Bioscience, Worcester, Mass.), MF 57 (Chiron) or SAF-1 (Syntex) may be used, as well as adjuvants such as combinations between QS21 and 3-de-O-acetylated monophosphoryl lipid A (WO94/00153), or MF-59 (Chiron), or poly[di(carboxylatophenoxy) phosphazene] based adjuvants (Virus Research Institute), or blockcopolymer based adjuvants such as Optivax (Vaxcel) or GammaInulin (Anutech), or Gerbu (Gerbu Biotechnik).
- a composition will further contain excipients and diluents, which are inherently non-toxic and non-therapeutic, such as water, saline, glycerol, ethanol, wetting or emulsifying agents, pH buffering substances, preservatives, and the like.
- excipients and diluents which are inherently non-toxic and non-therapeutic, such as water, saline, glycerol, ethanol, wetting or emulsifying agents, pH buffering substances, preservatives, and the like.
- a vaccine composition is prepared as an injectable, either as a liquid solution or suspension. Solid forms, suitable for solution on, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or encapsulated in liposomes for enhancing adjuvant effect.
- compositions which can be used as a vaccine, comprise an immunologically effective amount of the polypeptides of the present invention and/or modulators, as well as any other of the above-mentioned components.
- immunologically effective amount means that the administration of that amount to an individual, either in a single dosis or as part of a series, is effective for prevention or treatment This amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated (e.g.
- compositions which can be used as a vaccine are conventionally administered parenterally, typically by injection, for example, subcutaneously or intramuscularly.
- DNA vaccines particular useful methods for eliciting an immune response include the coating of gold particles with the plasmid vector encoding the desired peptide, and injecting them under high pressure into the epidermis and/or dermis, eg by means of a device called gene gun (eg as produced by Powderject Vaccines, Madison, Wis., USA).
- gene gun eg as produced by Powderject Vaccines, Madison, Wis., USA.
- Additional formulations suitable for other methods of administration include oral formulations and suppositories.
- Dosage treatment may be a single dose schedule or a multiple dose schedule.
- the vaccine may be administered in conjunction with other immunoregulatory agents. It should be noted that a vaccine may also be useful for treatment of an individual, in which case it is used as a to “therapeutically treat humans”.
- plasmid vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- Preferred vectors are those capable of autonomous replication and/or expression of nucleic acids to which they have been linked.
- plasmid vectors are circular double stranded DNA loops which, in their vector form, are not bound to the chromosome.
- promoters are required.
- a very suitable promoter is the Major Immediate Early (MIE) of human cytomegalovirus.
- nucleotide sequence refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA).
- DNA deoxyribonucleic acid
- RNA ribonucleic acid
- the term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and single (sense or antisense) and double-stranded polynucleotides.
- transcription regulatory elements refers to a nucleotide sequence which contains essential regulatory elements, ie such that upon introduction into a living vertebrate cell it is able to direct the cellular machinery to produce translation products encoded by the polynucleotide.
- operably linked refers to a juxtaposition wherein the components are configured so as to perform their usual function.
- transcription regulatory elements operably linked to a nucleotide sequence are capable of effecting the expression of said nucleotide sequence.
- the present invention provides a method to immunize humans against infection with HCV-related virus or any mutated strain thereof, comprising the use of a peptide as described above or a combination of peptides as described above.
- peptides from the C1, C2, and C4 regions may be particularly useful in monitoring the course on HCV-related virus disease. More specifically, antibodies to the Cl region may better neutralize HCV as compared to anti-C4 antibodies.
- the C1 domain may therefore be functionally important, eg exhibit receptor-binding activity. Neutralization of this region may therefore result in lesser activity of the disease and may lead to resolvement
- the E2-C1 region may therefore be particularly useful in therapeutic interventions. It should also be noted that, once reactivity to a given domain is established, it can be further mapped to smaller peptides, e.g. reactivities of 1 chimpanzee serum to C3 could be mapped to smaller region of 25 amino acids (peptide C3′′).
- results of E2 antibody tests as described in example 2 are given for consecutive samples obtained from patients with response to interferon therapy.
- a decline in E2Ab, and to a larger extend E1Ab, has been described in PCT/EP 95/03031 in case of a long-term response to interferon treatment.
- Reactivities to several peptides of the present invention also show similar declining levels.
- Peculiar reactivities could sometimes be detected as exemplified in patient 2: upon the detection of reappearing virus, antibody responses to the (E1)V4V5 region and the (E2)HVRII region could be detected; these quickly disappeared simultaneously with viral clearance.
- (E1)V4V5 and (2)HVRII may therefore be particularly useful peptides for disease monitoring, especially in treatment of disease.
- Other peptides such as (E2)C1 (example 2) and those shown in bold in Table 5 also seem to be useful for purposes such as monitoring.
- Table 2 also shows the presence of reactivity in patient 2 to a new peptide HVRI-C1, which overlaps the junction between HVRI and C1 (Table 2), in the absence of detectable reactivity to the HVRI or C1 peptides.
- peptide C4-bc encompassing the region between C4-b and C4-c (Table 2), was tested in this series, and showed almost identical reactivities as compared to peptide C4-b.
- the C4-b epitope lies between aa 658 and 673, but surprisingly, the epitope does not seem to be presented in peptide SEQ ID 92 of PCT/EP 95/03031 (aa 655-674).
- the C4-c epitope is not present in C4-bc and therefore can be localized between aa 683 and 706.
- HGV E2 protein So far, only reactivity to the complete HGV E2 protein seemed to be useful in the diagnosis of HGV. Peptide epitopes have not yet been described for GBV envelope proteins E1 or E2. Sixteen HGV RNA-positive sera were tested and 1 of these was reactive with the E1 peptide as shown in Table 6. Antibody reactivity to the recombinant HGV E2 protein (but not to HGV E2 peptides) is found in up to 15% of the European population, but cases with both HGV RNA and E2Ab are rare as they probably represent cases in which seroconversion and elimination of the virus is ongoing. Antibody reactivity to the HGV E1 protein has not yet been reported.
- HGV E1 peptide V1V2 is new and it may display higher reactivities in a series of HGV anti-E2 reactive sera.
- HGV E2 peptides may also be synthesized. Multimer peptides from GBV-A or GBV-B can be synthesized in a similar approach as described for HCV and HGV.
- E2 peptides listed in Table 1 were analyzed for their reactivity with 32 serum samples from patients with chronic active hepatitis C.
- a series of overlapping 20-mer peptides were synthesized with exactly the same HCV subtype 1b sequence as used for the longer peptides and as shown in Table 1.
- the ELISA test used was the same as described in Example 2.
- FIGS. 3 and 4 show the reactivities of the series of 20-mer and longer peptides, respectively.
- Peptides with a sum of>5 HVR I HVR I/C1, C1a, C1b, C4a, C4b, C4c, C4b-c
- genotype-specific peptides may be a desired way of improving sensitivity of E2 antibody assays.
- a variant of peptide C1a based on a reported HCV type 2a sequence HC-J6 could be LINTNGSWHINRTALNCNDSLHTGFLASLFYTHS, and similar useful variants e.g. based on a genotype 3a sequence, could be synthesized and tested for reactivity.
- the HCV E2 protein may contain insertions or deletions in any given HCV genotype.
- HCV type 2a isolates encode E2 proteins which are 4 aa's longer as compared to type 1 sequences.
- 2 additional amino acids are inserted in HCV type 2a and 2b sequences around hypervariable region II (HVR II). Therefore, a potentially useful variant of peptide HVRII, based on the HC-J6 prototype 2a sequence, would be RSIEAFRVGWGALQYEDNVTNPEDMRPYCW, which is a 30-mer peptide while the subtype 1b sequence-based peptide depicted in Table 1 (SEQ ID 20) is only 28 aa's long.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Multimer peptides (e.g. 30- to 45-mer peptides) derived from hepatitis C virus envelope proteins reacting with the majority of anti-HCV antibodies present in patient sera are described. The usage of the latter peptides to diagnose, and to vaccinate against, an infection with hepatitis C virus is also disclosed.
Description
- The present invention relates to multi-mer peptides derived from hepatitis C virus envelope proteins which react with the majority of anti-HCV antibodies present in patient sera. Consequently, the present invention relates to the usage of the latter peptides to diagnose, and to vaccinate against, an infection with hepatitis C virus.
- Hepatitis C virus (HCV) infection is a major health problem in both developed and developing countries. It is estimated that about 1 to 5% of the world population is affected by the virus, amounting up to 175 million chronic infections worldwide. HCV infection appears to be the most important cause of transfusion-associated hepatitis and frequently progresses to chronic liver damage. Moreover, there is evidence implicating HCV in induction of hepatocellular carcinoma. Consequently, the demand for reliable diagnostic methods and effective therapeutic agents is high. There is also an urgent need to characterize new epitopes which can be used in the design of effective vaccines against hepatitis C.
- HCV is a positive stranded RNA virus of about 9,8 kilobases which code for at least three structural and at least six non-structural proteins. The structural proteins have not yet been functionally assigned, but are thought to consist of a single core protein and two envelope proteins E1 and E2. The E1 protein consists of 192 amino acids and contains 5 to 6 N-glycosylation sites, depending on the HCV genotype, whereas the E2 protein consists of 363 to 370 amino acids and contains up to 11 N-glycosylation sites, depending on the HCV genotype (for review see Maertens and Stuyver, 1997).
- The E1 and E2 proteins are currently not included in HCV antibody (Ab) assays, primarily because of their complex conformational structures which require expression in mammalian cells as well as non-denaturing purification techniques. Indeed, after expression of E2 inEscherichia coli, the reactivity of HCV sera with the recombinant protein ranged from 14 (Yokosuka et al., 1992) to 17% (Mita et al., 1992), whereas expression in eukaryotic systems yields reactivities of 13 to 97% (Inoue, 1992; Chien, 1993). Others demonstrated that the E1 protein expressed as a single protein from eukaryotic cells did not shown high reactivity with patient sera (from 6 to 60%; Kohara et al. (1992), Hsu et al. (1992), Chien et al. (1993)). We previously reported that high prevalences of Ab's to both of the purified recombinant E1 and E2 proteins, which were expressed in mammalian cells, could be found in sera from chronic hepatitis C patients (WO 96/04385 to Maertens et al.). In this regard, we also demonstrated that the majority of anti-E1 and anti-E2 antibodies in sera from HCV patients could not be mapped using 20-mer peptides (WO 96/04385 to Maertens et al.). Indeed, although all of the murine monoclonal Ab's against E1 could be mapped to reactivity with two 20-mer peptides, denoted as epitope A (amino acids (aa) 313-326) and epitope B (aa 208-224), at most 50% of patient sera reactive with recombinant proteins recognized epitope A and B. With regard to the E2 protein, only three out of twenty four murine monoclonal Ab's could be mapped using 20-mer peptides. These three Ab's were mapped to the hypervariable region I (HVR I) covered by peptide E2-67 (aa 394-413) and to a region covered by a peptide denoted E2-13B (aa 523-542). The remaining twenty-one Ab's could not be mapped using 20-mer peptides. The relative map positions of seven of these Ab's could be deduced from competition studies using recombinant E2 protein.
- Taken together, it appears that anti-E1 and anti-E2 Ab's might be highly prevalent in sera of HCV patients. However, determining the presence of these Ab's is problematic due to the need to use eukaryotically expressed E1 and E2, which have to be purified using cumbersome non-denaturing techniques. As an alternative, chemically synthesized 20-mer peptides derived from the E1 and/or E2 proteins were produced. However, these synthesized 20-mer peptides were not able to recognize the anti-E1 and anti-E2 Ab's in sera from HCV patients.
- There is thus a need to design alternative methods to screen for HCV envelope Ab's.
- It is clear from the literature cited above that the E1 and E2 proteins probably have complex conformational structures which are essential for recognizing (and binding to) the anti-E1 and anti-E2 Ab's in sera from HCV patients. This could explain why prokaryotically expressed complete or near-complete E1 and E2 proteins, which might be malfolded due to the lack of glycosylations, relevant chaperones or correct cysteine bridles, and 20-mer peptides, which might be unable to mimic a complex conformational structure, are not able to recognize these Ab's.
- The present invention relates to the surprising finding that multi-mer peptides (eg 30- to 45-mer peptides) are able to recognize the majority of anti-E1 and anti-E2 Ab's in sera from HCV patients. It should be clear that this is a surprising finding because there is no guidance which would suggest that 30- to 45-mer peptides derived from E1 and E2 would acquire proper folding and would efficiently recognize the majority of HCV envelope Ab's. In contrast, one would assume that the chance that multi-mer peptides malfold would be as great, or even greater, than the chance that prokaryotically expressed complete proteins malfold as is suggested above. In the case of the HCV NS3 protein for example, which reacts with more than 90% of patient samples as expressed fromE. coli, 20-50 mer peptides only react very weakly.
- Therefore, the present invention aims at providing a peptide of more than 20 contiguous amino acids derived from the envelope region of HCV-related viruses which binds and recognizes anti-HCV-related virus antibodies. HCV-related viruses, including HCV, GBV-B virus, GBV-A virus and GBV-C (HGV or hepatitis G virus), are a division of the Flaviviruses, which further comprise Dengue virus, Yellow fever virus, Pestiviruses such as Classical Swine Fever Virus and Bovine Viral Diarrhea Virus (Wengler, 1991).
- More specifically, the present invention aims at providing a peptide which binds and recognizes an anti-HCV antibody or an anti-HGV antibody present in a sample of body fluid and which is chosen from the group consisting of the sequences as represented in SEQ ID NOs 1 to 38 (see Table 1) or a functionally equivalent variant or fragment thereof.
- In this respect, the present invention aims specifically at providing a peptide as described above, wherein said anti-HCV antibody present in a sample of body fluid is an anti-HCV-E1 antibody or an anti-HCV-E2 antibody.
- The present invention thus aims also at providing a peptide as described above, wherein said anti-HGV antibody present in a sample of body fluid is an anti-HGV-E1 antibody or an anti-HGV-E2 antibody.
- Moreover, the present invention aims at providing a peptide as described above, wherein said peptide is synthesized chemically or is synthesized using recombinant DNA techniques.
- The present invention also aims at providing a peptide as described above, wherein said peptide is biotinylated or contains cysteine bridges.
- Furthermore, the present invention aims at providing any combination of peptides as described above, as well as compositions containing said combination of peptides or peptides as described above .
- In addition, the present invention aims at providing a method for diagnosing exposure to or infection by HCV-related viruses comprising contacting anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above, determining the binding of anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above.
- In addition, the present invention aims at providing an assay kit for detecting the presence of anti-HCV-related virus antibodies within a sample of body fluid comprising a solid support, a peptide as described above or a combination of peptides as described above, appropriate markers which allow to determine the complexes formed between anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or a combination of peptides as described above.
- In addition, the present invention aims at providing a bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising contacting anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, determining the binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, adding a modulator (ie a compound which is able to modulate the interaction between an envelope protein and an anti-HCV-related virus antibody) or a combination of modulators to the contacted anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above
- In addition, the present invention aims at providing a bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising determining the binding of anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above, contacting a modulator with a peptide as described above or a combination of peptides as described above, adding anti-HCV-related virus antibodies to the contacted modulator with the peptide as described above or a combination of peptides as described above, determining the modulation of binding between anti-HCV-related virus antibodies with a peptide as described above or a combination of peptides as described above.
- Moreover, the present invention aims at providing a modulator, a composition containing a modulator, or a combination of modulators when produced by the bioassay as described above or when identified by the above-described bioassays.
- Moreover, the present invention aims at providing a composition comprising a plasmid vector comprising a nucleotide sequence encoding a peptide as described above, or a modulator as described above, operably linked to transcription regulatory elements.
- Moreover, the present invention aims at providing a composition as described above for use to vaccinate or therapeutically treat humans against infection with HCV-related virus or any mutated strain thereof
- Moreover, it is an aim of the present invention to provide an antibody, more particularly a monoclonal antibody, characterized in that it specifically recognizes an HCV-related virus polypeptide as described above.
- Finally, it is an aim of the present invention to provide a method to immunize humans against infection with HCV-related virus or any mutated strain thereof, comprising the use of a peptide as described above or a combination of peptides as described above.
- All the aims of the present invention are considered to have been met by the embodiments as set out below. Other advantages and features of the instant invention will be evident from the following claims and detailed description.
- Table 1 provides information on the envelope protein and the HCV genotype from which the peptides of the present invention are derived. This table also provides the name, the amino acid sequence, the position within the envelope proteins and the sequence identity (SEQ ID) of the peptides of the present invention.
- Table 2 shows ELISA results (in mOD) of reactivities of multimer peptides and recombinant E2 with 60 HCV positive samples and 4 control samples.
- Table 3 shows the analysis for E1 antibodies of 23 sera from responders to interferon treatment.
- Table 4 shows the analysis of E2 antibodies of 23 sera from responders to interferon treatment.
- Table 5 shows the monitoring of disease over time by measuring antibodies to the HCV E1 and E2 regions in 18 patients.
- Table 6 indicates the reactivity of HGV (Hepatitis G virus) RNA positive sera with the HGV E1 peptide V1V2.
- FIG. 1 demonstrates the positions of the multi-mer peptides of the present invention relative to the conserved and variable regions of the E1 envelope protein of HCV (HVR=hypervariable regions; V=variable regions; C=conserved regions; HR=hydrophobic region; SA=signal anchor domain; Y=glycosylation; I=cysteine).
- FIG. 2 demonstrates the positions of the multi-mer peptides of the present invention relative to the conserved and variable regions of the E2 envelope protein of HCV (HVR=hypervariable regions; V=variable regions; C=conserved regions; SA=signal anchor domain; Y=glycosylation; I=cysteine).
- FIG. 3 shows the reactivity of 20-mer E2 peptides. The OD values of serum samples from patients with chronic active hepatitis C were added and plotted against the different peptides.
- FIG. 4 shows the reactivity of mulit-mer E2 peptides. The OD values of the samples were added and plotted against the different peptides. The samples were identical as used for FIG. 3.
- The invention described herein draws on previously published work and pending patent applications. By way of example, such work consists of scientific papers, patents or pending patent applications. All these publications and applications, cited previously or below are hereby incorporated by reference.
- The present invention is based on the finding that multimer peptides, as of a certain length, derived from the envelope proteins of HCV-related viruses, eg HCV and HGV, recognize and bind anti-HCV-related virus antibodies, eg anti-HCV antibodies and anti-HGV antibodies, respectively. Therefore, the present invention provides a peptide of more than 20 contiguous amino acids derived from the envelope region of HCV-related viruses which binds and recognizes anti-HCV-related virus antibodies.
- HCV-related viruses include, but are not limited to HCV, GBV-B virus, GBV-A virus and GBV-C virus (HGV or hepatitis G virus)(Linnen et al., 1996). HCV constitutes a genus within the Flaviviridae, and is closely related to hepatitis G virus (26.8% at the amino acid level). The term “envelope region” of HCV-related viruses is a well-known region by a person skilled in the art (Wengler, 1991), and comprises the E1 protein as well as the E2 protein, which was previously called non-structural protein 1 (NS 1) or E2/NS1.
- Furthermore, the present invention relates to a peptide, which binds and recognizes an anti-HCV antibody or an anti-HGV antibody present in a sample of body fluid, and which is chosen from the group consisting of the sequences as represented in SEQ ID 1 to 38 (see Table 1) or a functionally equivalent variant or fragment thereof.
- The present invention relates also to a peptide as described above, wherein said anti-HCV antibody or said anti-HGV antibody present in a sample of body fluid is an anti-HCV-E1 or anti-HCV-E2 antibody, or an anti-HGV-E1 or anti-HGV-E2 antibody, respectively.
- The term “a peptide” refers to a polymer of amino acids (aa's) derived (i.e. containing less aa's) from the well-known HCV-related virus envelope proteins E1 and E2 (Linnen et al., 1996, Maertens and Stuyver, 1997), which binds anti-HCV-related virus antibodies. The term “a peptide” refers in particular to a polymer of aa's derived from HCV envelope proteins E1 and E2, which binds anti-HCV antibodies, or from HGV envelope proteins E1 and E2, which binds anti-HGV antibodies.
- The terms “peptide”, “polypeptide” and “protein” are used interchangeably herein.
- The term “an anti-HCV-related virus antibody” refers to any polyclonal or monoclonal antibody binding to a HCV-related virus particle or any molecule derived from said viral particle. More particularly, the term “an anti-HCV-related virus antibody” refers to antibodies binding to the natural, recombinant or synthetic E1 and/or E2 proteins derived from HCV or HGV proteins (anti-HCV-E1 or anti-HCV-E2 antibody, or anti-HGV-E1 or anti-HGV-E2 antibody, respectively).
- The term “monoclonal antibody” used herein refers to an antibody composition having a homogeneous antibody population. The term is not limiting regarding the species or source of the antibody, nor is it intended to be limited by the manner in which it is made.
- In addition, the term “antibody” also refers to humanized antibodies in which at least a portion of the framework regions of an immunoglobulin are derived from human immunoglobulin sequences and single chain antibodies as described in U.S. Pat. No. 4,946,778 and to fragments of antibodies such as Fab, F′(ab))2, Fv, and other fragments which retain the antigen binding function and specificity of the parent antibody.
- The term “a sample of body fluid” as used herein refers to a fluid obtained from an organism, such as serum, plasma, saliva, gastric secretions, mucus, spinal cord fluid, and the like. The term “the group consisting of the sequences as represented in SEQ ID NOs 1 to 33” as used herein refers to the thirty-eight peptides shown in Table 1 of the present application. In this table, it is indicated:
- in the column named “protein” from which HCV envelope protein the peptide is derived, but for the envelope protein of HGV, which is denoted E1(HGV),
- in the column named “genotype” the HCV genotype from which the envelope protein is derived, and thus the peptide is derived, except for HGV which was not determined (ND),
- in the column named “peptide” the assignment of the peptide region.
- the aa sequence of the peptide and,
- in the column named “position”, the well-known (Maertens and Stuyver, 1997) aa position of the peptides within the HCV envelope proteins. Note that the position for the E1 envelope protein is not determined, which is denoted as “ND”.
- The term “functionally equivalent” as used in “functionally equivalent variant or fragment thereof” refers to variants and fragments of the peptides represented by SEQ ID 1 to 38, which bind anti-HCV-related virus antibodies. The term “variant or fragment” as used in “functionally equivalent variant or fragment thereof” refers to any variant or any fragment of the peptides represented by SEQ ID 1 to 38. Furthermore, the latter terms do not refer to, nor do they exclude, post-translational modifications of the peptides represented by SEQ ID 1 to 38 such as glycosylation, acetylation, phosphorylation, modifications with fatty acids and the like. Included within the definition are, for example, peptides containing one or more analogues of an aa (including unnatural aa's), peptides with substituted linkages, mutated versions or natural sequence variations of the peptides (for examples corresponding to the genotypes HCV, as described in WO 94/12670 to Maertens et al.), peptides containing disulfide bounds between cysteine residues, or other cysteine modifications, biotinylated peptides, as well as other modifications known in the art. Modification of the structure of the polypeptides can be for such objectives as increasing therapeutic or prophylactic efficacy, stability (e.g. ex vivo shelf life and in vivo resistance to proteolytic degradation), or post-translational modifications (e.g. to alter the phosphorylation pattern of protein). Such modified peptides, when designed to retain at least one activity of the naturally-occurring form of the protein are considered functional equivalents of the polypeptides described in more detail herein. Such modified peptides can be produced, for instance, by amino acid substitution, deletion, or addition. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar replacement of an amino acid with a structurally related amino acid (i.e. isosteric and/or isoelectric mutations) will not have a major effect on the biological activity of the resulting molecule. Conservative replacements are those that take place within a family of amino acids that are related in their side chains. Genetically encoded amino acids can be divided into four families: (1) acidic: aspartate, glutamate; (2) basic: lysine, arginine, histidine; (3) nonpolar: alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar: glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. In similar fashion, the amino acid repertoire can be grouped as (1) acidic: aspartate, glutamate; (2) basic: lysin, arginine histidine, (3) aliphatic: glycine, alanine, valine, leucine, isoleucine, serine, threoaine, with serine and threonine optionally be grouped separately as aliphatic-hydroxyl; (4) aromatic: phenylalanine, tyrosine, tryptophan, (5) amide: asparagine, glutamine; and (6) sulfur-containing: cysteine and methionine. (see, for example, Biochemistry, 2nd ed., Ed. by L. Stryer, W H Freeman and Co.: 1981). Whether a change in the amino acid sequence of a peptide results in a functional homologue (e.g. functional in the sense that the resulting polypeptide mimics the wild-type form) can be readily determined by assessing the ability of the variant peptide to produce a response in e.g. ELISAs in a fashion similar to the wild-type protein, or to competitively inhibit such a response. Polypeptides in which more than one replacement has been introduced can be readily tested in the same manner. It should also be clear that the region of a peptide represented by SEQ ID 1 to 38 which bind to an antibody (the so-called epitope) need not to be composed of a contiguous aa sequence. In this regard, the term “fragment” includes any fragment which comprises these non-contiguous binding regions or parts thereof. In other words, fragments which include these binding regions may be separated by a linker, which is not a functional part of the epitope. This linker does not need to be an amino acid sequence, but can be any molecule, eg organic or inorganic, that allows the formation of the desired epitope by two or more fragments.
- Moreover, it should be clear that the variants and fragments of SEQ ID NOs 1 to 5, 7 to 9, and 18 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's or 33 aa's, or 34 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 6 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's. Moreover, it should be clear that the variants and fragments of
SEQ ID NO 10 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's. Moreover, it should be clear that the variants and fragments ofSEQ ID NOs 11, 15, 21, 34 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NOs 12, 24 or 32 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's. or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, or 35 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NOs 13, 22, or 34 used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's. Moreover, it should be that clear the variants and fragments of SEQ ID NO 16 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 17 as used herein refers to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 19 as used herein refers to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's. Moreover, it should be clear that the variants and fragments ofSEQ ID NOs 20 and 30 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 23 as used herein include to peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's, or 42 aa's, or 43 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NOs 25 or 29 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 26 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's or 29 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 27 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's, or42 aa's, or 43 aa's, or 44 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 28 or 31 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's. Moreover, it should be clear that the variants and fragments of SEQ ID NO 33 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's, or 40 aa's, or 41 aa's. Moreover it should be clear that the variants and fragments of SEQ ID NOs 14 or 37 as used herein include peptides having a length of at least 21 aa's, or 22 aa's, or 23 aa's, or 24 aa's, or 25 aa's, or 26 aa's, or 27 aa's, or 28 aa's, or 29 aa's, or 30 aa's, or 31 aa's, or 32 aa's, or 33 aa's, or 34 aa's, 35 aa's, or 36 aa's, or 37 aa's, or 38 aa's, or 39 aa's. - In addition, it shall be appreciated by the person skilled in the art that the amino acid regions of the peptides, which are disclosed in the present invention and that bind anti-HCV antibodies, can be delineated in more detail by experimentation.
- In addition, it should be clear that the variants and fragments of the peptides represented by SEQ ID 1 to 38, as herein described, can be prepared by any method known in the art such as classical chemical synthesis, as described by Houbenweyl (1974) and Atherton & Shepard (1989), or by means of recombinant DNA techniques as described by eg Maniatis et al. (1982), or Sambrook et al. (1989).
- Similarly, it should be clear that also the peptides represented by SEQ ID 1 to 38 of the present invention can be prepared by any method known in the art and more particularly by means of classical chemical synthesis, as described by Houbenweyl (1974) and Atherton & Shepard (1989), or by means of recombinant DNA techniques such as described by eg Maniatis et al. (1982), or Sambrook et al. (1989).
- The present invention further relates to the peptides represented by SEQ ID 1 to 38 and functionally equivalent variants or fragments thereof, all as defined above, which are biotinylated or contain cysteine bridges. Biotinylated peptides can be obtained by any method known in the art, such as the one described in WO93/18054 to De Leys. Methods for obtaining peptides containing inter- and/or intramolecular cysteine bridges are extensively described in WO 96/13590 to Maertens & Stuyver.
- The present invention also relates to any combination of peptides represented by SEQ ID 1 to 38 and functionally equivalent variants or fragments thereof as defined above. The terms “any combination” refers to any possible mixture of above-described peptides or any possible linkage (covalently or otherwise) between above-described peptides. Examples of the latter peptide combinations are simple mixtures, homo- or hetero-branched peptides, combinations of biotinylated peptides presented on streptavidin, avidin or neutravidin, chemically cross-linked peptides with or without spacer, condensed peptides and recombinantly produced peptides.
- The present invention relates also an antibody, more particularly a monoclonal antibody, characterized in that it specifically recognizes an HCV-related virus polypeptide as described above.
- The present invention also relates to a method for diagnosing exposure to or infection by HCV-related viruses comprising contacting anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above, and, determining the binding of anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above or with a combination of peptides as described above. As used herein, the term “a method for diagnosing” refers to any immunoassay known in the art such as assays which utilize biotin and avidin or streptavidin, ELISAs and immunoprecipitation and agglutination assays. A detailed description of these assays is given in WO 96/13590 to Maertens & Stuyver.
- In this regard, the present invention also relates to an assay kit for detecting the presence of anti-HCV-related virus antibodies comprising a solid support, a peptide as described above or a functionally equivalent variant or fragment thereof, or combination of peptides as described above, and appropriate markers which allow to determine the complexes formed between anti-HCV-related virus antibodies within a sample of body fluid with a peptide as described above, or a functionally equivalent variant or fragment thereof, or combination of peptides as described above.
- The term “a solid support” refers to any solid support known in the art.
- Similarly, the term “appropriate markers” refers to any marker known in the art.
- It should also be clear that the term “a method for diagnosing” encompasses screening, detection, confirmation, monitoring and serotyping methods.
- The present invention further pertains to a bioassay for identifying compounds which modulate the binding between a peptide and an anti-HCV-related virus antibody, comprising contacting anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, and determining the binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, adding a modulator or a combination of modulators to the contacted anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, and finally determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above.
- In another embodiment the present invention features a bioassay for identifying compounds which modulate the binding between a peptide and an anti-HCV-related virus antibody, comprising determining the binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above, contacting a modulator with a peptide as described above, or a combination of peptides as described above, adding anti-HCV-related virus antibodies to the contacted modulator with a peptide as described above, or a combination of peptides as described above, determining the modulation of binding of anti-HCV-related virus antibodies with a peptide as described above, or a combination of peptides as described above.
- The term “compound” as used herein refers to a composition, which has a molecular weight of less than about 25 KDa, preferably less than 10 KDa, and most preferably less than 5 KDa. Compounds can be nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules, or antibodies which may be generated by the host itself upon vaccination.
- The term “binding” as used herein indicates that a peptide as described above is physically connected to, and interacts with antibodies. Binding of the peptide to the antibody can be demonstrated by any method or assay known in the art such as binding-, ELISA, and RIA-type of assays or competition assays (eg see Examples section and Current protocols in immunology).
- The terms “modulation” or “modulate” as used herein refer to both upregulation (i.e., activation or stimulation (e.g., by agonizing or potentiating)) and downregulation (i.e. inhibition or suppression (e.g. by antagonizing, decreasing or inhibiting) of the binding between a peptide and an anti-HCV antibody.
- The term “modulator” as used herein refer to the ability of a compound as described above to modulate as described above.
- The term “peptidomimetics” as used herein refers to molecules which can be manufactured and which mimic those residues of peptides which modulate the interaction of the antibody with the peptide as described above. For instance, non-hydrolyzable peptide analogs of such residues can be generated using benzodiazepine (e.g., see Freidinger et al. in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), azepine (e.g., see Huffman et al. in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), PNA, substituted gamma lactam rings (Garvey et al. in Peptides: Chemistry and Biology, G. R. Marshall ed., ESCOM Publisher: Leiden, Netherlands, 1988), ketomethylene pseudopeptides (Ewenson et al. (1986) J Med Chem 29:295: and Ewenson et al. in Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium) Pierce Chemical Co. Rockland, Ill., 1985), β-turn dipeptide cores (Nagai et al. (1985) Tetrahedron Lett
- 26:647; and Sato et al. (1986) J Chem Soc Perkin Trans 1:1231), and β-aminoalcohols (Gordon et al. (1985) Biochem Biophys Res Commun, 126:419; and Dann et al. (1986) Biochem Biophys Res Commun 134:71).
- The present invention pertains to a modulator produced by a bioassay as described above.
- The present invention pertains also to a modulator for the interaction between a peptide and an anti-HCV-related virus antibody, when said modulators are identified by a bioassay as described above.
- The present invention features a composition comprising as an active substance a peptide as described above or a combination of peptides as described above.
- The present invention features also a composition comprising as an active substance a modulator as described above or a combination of modulators as described above.
- In another embodiment, the present invention relates to a composition comprising a plasmid vector comprising a nucleotide sequence encoding a peptide as described above, operably linked to transcription regulatory elements. Upon introduction in a human tissue said plasmid vector induces the expression in vivo, of the nucleotide sequence thereby producing the encoded protein. If said protein elicits an immunogenic response it is referred to as a DNA vaccine. It is readily apparent to those skilled in the art that variations or derivatives of the nucleotide sequence can be produced which alter the nucleotide sequence. The altered polynucleotide may have an altered nucleic sequence, yet still encodes a protein as described above, and which reacts with anti-HCV-related virus antibodies, and is considered a to be functional equivalent
- In a preferred embodiment, the present invention relates to a composition as described herein for use as to vaccinate humans against infection with HCV-related virus or any mutated strain thereof.
- In another preferred embodiment, the present invention relates to a composition as described herein for use as to therapeutically treat humans against infection with HCV-related virus or any mutated strain thereof.
- A composition of the present invention can be, as appropiate, any of the preparations described herein, including peptides, functionally equivalent variants or fragments thereof, a combination of peptides, or modulators (e.g. as identified in the bioassay provided herein). Specifically, the term “a composition” relates to an immunogenic composition capable of eliciting protection against HCV-related virus, in particular against HCV and/or HGV, whether partial or complete. The term “as an active substance” relates to the component of the vaccine composition which elicits protection against HCV-related viruses, in particular against HCV and/or HGV. An active substance (e.g. the peptides or the modulators of the present invention) can be used as such, in a biotinylated form (as explained in WO 93/18054) and/or complexed toNeutralite Avidin according to the manufacturer's instruction sheet (Molecular Probes Inc., Eugene, Oreg.).
- It should also be noted that “a composition” comprises, in addition to an active substance, a suitable excipient, diluent, carrier and/or adjuvant which, by themselves, do not induce the production of antibodies harmful to the individual receiving the composition nor do they elicit protection. Suitable carriers are typically large slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric aa's, aa copolymers and inactive virus particles. Such carriers are well known to those skilled in the art. Preferred adjuvants to enhance effectiveness of the composition include, but are not limited to: aluminium hydroxide, aluminium in combination with 3-0-deacylated monophosphoryl lipid A as described in WO 93/19780, aluminium phosphate as described in WO 93/24148, N-acetyl-muramyl-L-threonyl-D-isoglutamine as described in U.S. Pat. No. 4,606,918, N-acetyl-normuramyl-L-alanyl-D-isoglutamine,N-acetylmuramyl-L-alanyl-D-isoglutamyl-L-alanine2(1′2′dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy) ethylamine and RIBI (ImmunoChem Research Inc., Hamilton, Mont.), which may contain one or all of the following elements: monophosphoryl lipid A (detoxified endotoxin), trehalose-6,6-dimycolate, and cell wall skeleton (MPL+TDM+CWS) in a 2% squalene/Tween 80 emulsion. Any of the three components MPL, TDM or CWS may also be used alone or combined 2 by 2. Additionally, adjuvants such as Stimulon (Cambridge Bioscience, Worcester, Mass.), MF 57 (Chiron) or SAF-1 (Syntex) may be used, as well as adjuvants such as combinations between QS21 and 3-de-O-acetylated monophosphoryl lipid A (WO94/00153), or MF-59 (Chiron), or poly[di(carboxylatophenoxy) phosphazene] based adjuvants (Virus Research Institute), or blockcopolymer based adjuvants such as Optivax (Vaxcel) or GammaInulin (Anutech), or Gerbu (Gerbu Biotechnik). Furthermore, Complete Freund's Adjuvant (CFA) and Incomplete Freund's Adjuvant (IFA) may be used for non-human applications and research purposes. “A composition” will further contain excipients and diluents, which are inherently non-toxic and non-therapeutic, such as water, saline, glycerol, ethanol, wetting or emulsifying agents, pH buffering substances, preservatives, and the like. Typically, a vaccine composition is prepared as an injectable, either as a liquid solution or suspension. Solid forms, suitable for solution on, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or encapsulated in liposomes for enhancing adjuvant effect. The polypeptides may also be incorporated into Immune Stimulating Complexes together with saponins, for example Quil A (ISCOMS). Compositions, which can be used as a vaccine, comprise an immunologically effective amount of the polypeptides of the present invention and/or modulators, as well as any other of the above-mentioned components. “Immunologically effective amount” means that the administration of that amount to an individual, either in a single dosis or as part of a series, is effective for prevention or treatment This amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of the individual to be treated (e.g. nonhuman primate, primate, etc.), the capacity of the individual's immune system to mount an effective immune response, the degree of protection desired, the formulation of the vaccine, the treating's doctor assessment, the strain of the infecting HCV and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. Usually, the amount will vary from 0.01 to 1000 μg/dose, more particularly from 0.1 to 100 μg/dose. Compositions, which can be used as a vaccine are conventionally administered parenterally, typically by injection, for example, subcutaneously or intramuscularly.
- In the case of DNA vaccines, particular useful methods for eliciting an immune response include the coating of gold particles with the plasmid vector encoding the desired peptide, and injecting them under high pressure into the epidermis and/or dermis, eg by means of a device called gene gun (eg as produced by Powderject Vaccines, Madison, Wis., USA).
- Additional formulations suitable for other methods of administration include oral formulations and suppositories. Dosage treatment may be a single dose schedule or a multiple dose schedule. The vaccine may be administered in conjunction with other immunoregulatory agents. It should be noted that a vaccine may also be useful for treatment of an individual, in which case it is used as a to “therapeutically treat humans”.
- As used herein, a “plasmid vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Preferred vectors are those capable of autonomous replication and/or expression of nucleic acids to which they have been linked. In general, but not limited to those, plasmid vectors are circular double stranded DNA loops which, in their vector form, are not bound to the chromosome. For expression purposes, promoters are required. For DNA vaccination, a very suitable promoter is the Major Immediate Early (MIE) of human cytomegalovirus.
- As used herein, a “nucleotide sequence” refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and single (sense or antisense) and double-stranded polynucleotides.
- As used herein, the term “transcription regulatory elements” refers to a nucleotide sequence which contains essential regulatory elements, ie such that upon introduction into a living vertebrate cell it is able to direct the cellular machinery to produce translation products encoded by the polynucleotide.
- The term “operably linked” refers to a juxtaposition wherein the components are configured so as to perform their usual function. Thus, transcription regulatory elements operably linked to a nucleotide sequence are capable of effecting the expression of said nucleotide sequence. Those skilled in the art can appreciate that different transcriptional promoters, terminators, carrier vectors or specific gene sequences may be used successfully.
- Finally, the present invention provides a method to immunize humans against infection with HCV-related virus or any mutated strain thereof, comprising the use of a peptide as described above or a combination of peptides as described above.
- The present invention will now be illustrated by reference to the following examples which set forth particularly advantageous embodiments. However, it should be noted that these embodiments are illustrative and can not be construed as to restrict the invention in any way.
- Synthesis of Multimer E1 and E2 Peptides
- We aimed at synthesizing peptides which would display epitopes, similar to the ones present on E1 and E2 peptides expressed in mammalian cells. Since such epitopes do not seem to be present in E1 and E2 proteins expressed inE. coli, the design of such peptides was not an easy task. We first aligned E1 and E2 primary amino acid sequences of different HCV genotypes and delineated variable and constant domains. It was reasoned that these domains, or a combination of two or more of these domains might represent conformational domains, ie form or constitute independent conformational units. If displayed as 3D structure, these conformational domains may also contain conformational epitopes. The latter domains may therefore be able to adopt a native-like structure as is present in the envelope proteins when these envelope proteins are expressed in mammalian cells. In contrast, such structures are absent when the envelope proteins are expressed in prokaryotic cells, like E. coli.
- The following domains were assigned:
- V1, V2, V3, V4, V5, V6=variable regions; C1, C2, C3, C4 conserved domains; HR=hydrophobic region; SA=signal anchor sequence; HVRI, HVRII=hypervariable regions of E2.
Protein Region Amino acid position E1 V1 192-203 C1 204-217 V2 218-223 C2 224-229 V3 230-242 C3 243-247 V4 248-257 HR 258-293 V5 294-303 C4 304-329 V6 330-342 SA 343-383 E2 HVRI 384-411 C1 412-470 HVRII 471-482 C2 483-521 V3 522-548 C3 549-569 V4 570-580 C4 581-704 SA 705-746 - Based on these domains of the BE11 subtype 1b isolate (SEQ ID 50 in PCT/EP 95/03031), we designed a series long peptides of 24 to 45 amino acids. For some extended domains of the envelope proteins more than one multimer peptide was synthesized in order to encompass the domain of interest. Table 1 gives an overview of the peptides with their respective amino acid positions; numbering starts from the first initiation codon of the HCV polyprotein. Peptides were synthesized using t-Boc technology as explained in detail in WO 93/18054.
- Reactivity of Multimer Peptides with E1 and E2 Antibodies in Patient Sera
- A series of 60 randomly chosen samples from patients with chronic active hepatitis C were tested for reactivity with the multimer peptides. These samples did not show any notable reactivity with 20-mer peptides except for some 20-mer peptides derived from the HVRI. For comparison, reactivity with the hydrophylic ectodomain of E2, the recombinant E2h protein, was assayed (E2h extends from aa 384-708 and was cloned from SEQ ID NO 45, and expressed and purified as described in PCT/EP 95/03031). Peptides were coated onto streptavidin-coated plates (5 μg/ml) and antibodies in serum samples were left to react and detected using the reagents and procedures as described in the package insert of the INNOTEST HCV Ab III kit (Innogenetics, Gent, Belgium). Table 2 shows the results of the ELISA tests, in which a cutoff of 150 mOD was used. In this series, 5 sera did not show reactivity with the E2h protein, only one of these reacted with the HVRI peptide. Five out of 60 sera (8%; e.g. sample 17758) only reacted with the E2h protein,
- 34 (57%) recognized HVRI 24(40%) reacted with C1-a, 18 (30%) with C1-b, 21 (35%) with HVRII, 17 (28%) C2-a, 22 (37%) with C2-b, 18 (30%) with C3, 18 (30%) with C3′, 17 (28%) with C3″, 18 (30%) with V4, 22 (37%) with C-4, 21 (35%) with C4-a, 35 (58%) with C4-b, and 24 (40%) with C4-c. This experiment surprisingly learned that, while none of the samples recognized any of the 20-mer peptides, except for those derived from the HVRI, 50 out of 55 (91%) E2h reactive sera could be detected using the peptides of the present invention.
- In a second series of 23 sera derived from chronic hepatitis C patients who were long-term responders to interferon-alpha treatment and 3 HCV infected chimpanzees, E1 and E2 antibodies were tested. Eighteen out of 23 samples (78%) reacted with recombinant E1s protein, expressed and purified from mammalian cells as described in PCT/EP 95/0303 1. Nine samples (39%) reacted with the C4V6 region, another 9 (39%) with the V1V2 region, and 3 with V2V3 (Table 4). For comparative purposes peptide V5, ie SQLFTISPRRHETVQD, is shown.
- Different reactivities to E2 were observed (Table 4) as compared with the first series of samples. 21 samples (91%) reacted with E2h, with 13 (57%) reactive on HVRI, 9 (39%) with C1-a, 11 (48%) with C1-b, 1 with HVRII, C2-a, and C2-b each, 2 with C3, 3 with C4-a, 4 (17%) with C4-b, and 4 (17%) with C4-c. In this series of patients with a benign evolution of disease, the C1 region was more frequently recognized and fewer antibodies to the C4 region were detected as compared to the series of samples obtained from patients with chronic active hepatitis. These results indicate that peptides from the C1, C2, and C4 regions may be particularly useful in monitoring the course on HCV-related virus disease. More specifically, antibodies to the Cl region may better neutralize HCV as compared to anti-C4 antibodies. The C1 domain may therefore be functionally important, eg exhibit receptor-binding activity. Neutralization of this region may therefore result in lesser activity of the disease and may lead to resolvement The E2-C1 region may therefore be particularly useful in therapeutic interventions. It should also be noted that, once reactivity to a given domain is established, it can be further mapped to smaller peptides, e.g. reactivities of 1 chimpanzee serum to C3 could be mapped to smaller region of 25 amino acids (peptide C3″).
- Monitoring of E1 and E2 Antibodies in Patients with Response to Interferon-alpha Therapy
- In Table 5, results of E2 antibody tests as described in example 2 are given for consecutive samples obtained from patients with response to interferon therapy. A decline in E2Ab, and to a larger extend E1Ab, has been described in PCT/EP 95/03031 in case of a long-term response to interferon treatment. Reactivities to several peptides of the present invention also show similar declining levels. Peculiar reactivities could sometimes be detected as exemplified in patient 2: upon the detection of reappearing virus, antibody responses to the (E1)V4V5 region and the (E2)HVRII region could be detected; these quickly disappeared simultaneously with viral clearance. (E1)V4V5 and (2)HVRII may therefore be particularly useful peptides for disease monitoring, especially in treatment of disease. Other peptides such as (E2)C1 (example 2) and those shown in bold in Table 5 also seem to be useful for purposes such as monitoring. Table 2 also shows the presence of reactivity in patient 2 to a new peptide HVRI-C1, which overlaps the junction between HVRI and C1 (Table 2), in the absence of detectable reactivity to the HVRI or C1 peptides. Similarly, peptide C4-bc encompassing the region between C4-b and C4-c (Table 2), was tested in this series, and showed almost identical reactivities as compared to peptide C4-b. Therefore, it is possible that the C4-b epitope lies between aa 658 and 673, but surprisingly, the epitope does not seem to be presented in peptide SEQ ID 92 of PCT/EP 95/03031 (aa 655-674). The C4-c epitope is not present in C4-bc and therefore can be localized between aa 683 and 706.
- Application to Other Flaviviruses
- To examine the applicability of the invention to envelope proteins of other HCV-related viruses, a peptide spanning the V1V2 region of the hepatitis G virus (GBV-C; Linnen et al., 1996; Simons et al., 1996) E1 region was synthesized, see also SEQ ID NO 38 (Table 1): NH2-THACRANGQYFLTNCCAPEDIGFCLEGGCLVALGGK-biotin.
- So far, only reactivity to the complete HGV E2 protein seemed to be useful in the diagnosis of HGV. Peptide epitopes have not yet been described for GBV envelope proteins E1 or E2. Sixteen HGV RNA-positive sera were tested and 1 of these was reactive with the E1 peptide as shown in Table 6. Antibody reactivity to the recombinant HGV E2 protein (but not to HGV E2 peptides) is found in up to 15% of the European population, but cases with both HGV RNA and E2Ab are rare as they probably represent cases in which seroconversion and elimination of the virus is ongoing. Antibody reactivity to the HGV E1 protein has not yet been reported. Therefore, the HGV E1 peptide V1V2 is new and it may display higher reactivities in a series of HGV anti-E2 reactive sera. Using similar approaches as described in the present invention, HGV E2 peptides may also be synthesized. Multimer peptides from GBV-A or GBV-B can be synthesized in a similar approach as described for HCV and HGV.
- Reactivity of 20-mer E2 Peptides Compared to Multimer E2 Peptides.
- E2 peptides listed in Table 1 were analyzed for their reactivity with 32 serum samples from patients with chronic active hepatitis C. In addition, a series of overlapping 20-mer peptides were synthesized with exactly the same HCV subtype 1b sequence as used for the longer peptides and as shown in Table 1. The ELISA test used was the same as described in Example 2. FIGS. 3 and 4 show the reactivities of the series of 20-mer and longer peptides, respectively. Peptides with a sum of>5 (HVR I HVR I/C1, C1a, C1b, C4a, C4b, C4c, C4b-c) were considered to be very useful for the detection of antibodies directed against E2. A total of six of these peptides (peptides C4b-c and C1a were not included as these peptides are almost entirely represented by other peptides) were combined together with 20-mer peptide 1350 (Table 1), which occasionally reacted with some patient sera. The combination of these peptides was tested on a panel of 128 sera from chronic active HCV carriers. Hundred and twenty six of these sera tested positive on recombinant E2s protein. Of these 126 sera, 33 sera showed at least two times higher OD values with the peptide mixture as compared to the recombinant E2 protein, 64 sera showed a similar reactivity, 16 sera showed reactivities which were 2- to 4-fold higher with the recombinant protein than with the peptide mixture, and 13 sera only reacted with the recombinant protein.
- In summary, almost 90% of the sera containing antibodies against recombinant E2 protein could be detected using the above peptide mixture. For 26% of the sera, detection was even better using the peptides of the invention, than using recombinant E2 protein. A sum of OD values of>5, ie exhibited by peptides HVR I, HVR I/C1, C1a, C1b, C4a, C4b, C4c, and C4b-c (FIG. 4) is therefore considered a surprisingly high value for the serodiagnosis of antibodies directed against the E2 protein of HCV. From the experiment described above, it is also clear that a combination of recombinant E2 with the peptides of the invention is a particularly useful composition.
- Given the variability of the E2 protein in different HCV genotypes, the addition of genotype-specific peptides to recombinant E2 proteins may be a desired way of improving sensitivity of E2 antibody assays. For example, a variant of peptide C1a based on a reported HCV type 2a sequence HC-J6 could be LINTNGSWHINRTALNCNDSLHTGFLASLFYTHS, and similar useful variants e.g. based on a genotype 3a sequence, could be synthesized and tested for reactivity. It should be noted that the HCV E2 protein may contain insertions or deletions in any given HCV genotype. For example, while subtype 1a and 1b sequences show contiguous sequences which can be aligned without having to insert gaps, HCV type 2a isolates encode E2 proteins which are 4 aa's longer as compared to type 1 sequences. For example, 2 additional amino acids are inserted in HCV type 2a and 2b sequences around hypervariable region II (HVR II). Therefore, a potentially useful variant of peptide HVRII, based on the HC-J6 prototype 2a sequence, would be RSIEAFRVGWGALQYEDNVTNPEDMRPYCW, which is a 30-mer peptide while the subtype 1b sequence-based peptide depicted in Table 1 (SEQ ID 20) is only 28 aa's long. The two glutamates (symbol E) which are inserted in the subtype 2a sequence are shown underlined. Similar peptides can be easily constructed based on sequences and alignments previously published (e.g. Maertens and Stuyver, 1997).
- Atherton, Shepard (1989) Solid phase peptide synthesis. IRL Press, Oxford.
- Chien D, Choo Q-L, Ralston R, Spaete R, Tong M, Houghton M, Kuo G. Persistence of HCV despite antibodies to both putative envelope proteins.The Lancet 1993; 342: 933.
- Current protocols in immunology. Eds Coligan J., Kruisbeek A., Margulis D., Shevach E. And Strober W. Wiley Interscience, 1992.
- Houbenweyl (1974) Methode der organischen chemie, vol. 15, I & II (ed. Wunch E). Thieme, Stuttgart
- Hsu H, Donets M, Greenberg H., et al. Characterization of hepatitis C virus structural proteins with a recombinant baculovirus expression system.Hepatology 1993; 17: 763-71.
- Inoue Y, Suzuki R, Matsuura Y, et al. Expression of the amino-terminal helf of the NS1 region of the hepatitis C virus genome and detection of an antibody to the expressed protein in patients with liver diseases.J. Gen. Virol. 1992; 73: 2151-4.
- Kohara M, Tsukiyama-Kohara K, Maki N, et al. Expression and characterization of glycoprotein gp35 of hepatitis C virus using recombinant vaccinia virus.J. Gen. Virol. 1992; 73: 2313-8.
- Ling P D, Warren M K, Vogen S N. et al.J. Immunol. 1985; 135: 1857-63.
- Linnen J, Wages J Jr, Zhang-Keck Z, Fry K, Krawczynski K, Alter H, Koonin E, et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent.Science 1996; 271: 505-8.
- Maertens, G. and Stuyver, L. (1997) Genotypes and Genetic variation of hepatitis C virus. In: Molecular Medicine of Hepatitis (Eds. Zuckerman, A. and Harrison, T.), Molecular Medical Science Series (Eds. James, K. and Morris A) John Wiley and Sons Ltd., Chichester, England, Chapter 13, pp183-233.
- Major M. E. and Feinstone S. M. The molecular virology of hepatitis C. Hepatology 1997: 25: 1527-1538.
- Maniatis T, Fritsch E, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
- Mita E, Hayashi N, Ueda K, et al. Expression of MBP-HCV NS1/E2 fusion protein inE. coli and detection of anti-NS1/E2 antibody in type C chronic liver disease. Biochem. Biophys. Res Comm. 1992; 183: 925-30.
- Sambrook J, Fritsch E, Maniatis T (1989) Molecular cloning: a laboratory manual.Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
- Simons J N, Pilot-Matias T J, Leary T P, Dawson G J, Desai S M, Schlauder G G, Muerhoff A S, et al. Identification of two flavivirus-like genomes in the GB hepatitis agent.Proc Natl Acad Sci USA 1996; 92: 3401-5.
- Wengler G. (1991) Family Flaviviridae. In: ‘Classification and Nomenclature of viruses, fifth report of the international committee on Taxonomy and nomenclature of viruses (Eds. Francki R, Fauquet C, Knudson D., and Brown F.) Archives of Virology, Supplementum 2, pp 223-233, Springer-Verlag, Wien, N.Y.
- Yokosuka O, Ito Y, Imazeki F, Ohto M, Omata M. Detection of antibody to hepatitis C E2/NS1 protein in patients with type C hepatitis.Bioch Biophys Res Commun 1992; 189: 565-71.
TABLE 1 GENO SEQ ID PROTEIN TYPE PEPTIDE AMINO ACID SEQUENCE POSITION NUMBER E1 1a V1V2T1a YQVRNSTGLYHVTNDCPNSSIVYEAADAILHTPGC 192-226 Seq ID 1 1b V1V2T1b YEVRNVSGIYHVTNDCSNSSIVYEAADMIMHTPGC 192-226 Seq ID 2 2c V1V2T2c VEVKNNSNSYMATNDCSNSSIIWQLEGAVLHTPGC 192-226 Seq ID 3 2c V1V2T2c′ VEVKNTSTSYMVTNDCSNSSIVWQLEGAVLHTPGC 192-226 Seq ID 4 3a V1V2T3a LEWRNTSGLYVLTNDCSNSSIVYEADDVILHTPGC 192-226 Seq ID 5 3a V2T3a LTNDCSNSSIVYEADDVILHTPGC 203-226 Seq ID 6 4c/4k V1V2T4a INYRNVSGIYHVTNDCPNSSIVYEADHHILHLPGC 192-226 Seq ID 7 5a V1V2T5a VPYRNASGIYHITNDCPNSSIVYEADNLILHAPGC 192-226 Seq ID 8 6a V1V2T6a LTYGNSSGLYHLTNDCSNSSIVLEADAMILHLPGC 192-226 Seq ID 9 1b V2V3 IVYEAADMIMHTPGCVPCVRENNSSRCWV 212-240 Seq ID 10 1b V3V4 VRENNSSRCWVALTPTLAARNASVPTTTIRRHVD 230-263 Seq ID 11 1b PC-V3V4 PCVRENNSSRCWVALTPTLAARNASVPTTTIRRHVD 228-263 Seq ID 12 1b HR HVDLLVGAAAFCSAMYVGDLCGSVFLVSQL 260-290 Seq ID 13 1b V5C4 SQLFTISPRRHETVQDCNCSIYPGHITGHRMAWDMMMNWS 288-327 Seq ID 14 1b C4V6 SIYPGHITGHRMAWDMMMNWSPTTALVVSQLLRI 307-340 Seq ID 15 1b SA PQAVVDMVAGAHWGVLAGLAYYSMVGNWAKVLVVMLLFAGV 341-381 Seq ID 16 1b V4V5 VALTPTLAARNASVPTTTIRRHVDSQLFTISPRRHETVQD 240-303 Seq ID 37 E1(HGV) ND V1V2 THACRANGQYFLTNCCAPEDIGFCLEGGCLVALGGK ND Seq ID 38 E2 1b HVR I HTRVSGGAAASNTRGLVSLFSPGSAQKIQLVN 384-415 Seq ID 17 1b C1a LVNTNGSWHINRTALNCNDSLQTGFFAALFYKHKF 413-447 Seq ID 18 1b C1b NDSLQTGFFAALFYKHKFNSSGCPERLASCRSIDKFAQ 430-467 Seq ID 19 1b HVR II RSIDKFAQGWGPLTYTEPNSSDQRPYCW 460-487 Seq ID 20 1b C2a SDQRPYCWHYAPRPCGIVPASQVCGPVYCFTPSP 480-513 Seq ID 21 1b C2b SQVCGPVYCFTPSPVVVGTTDRFGVPTYNWG 500-530 Seq ID 22 1b V3C3 GVPTYNWGANDSDVLILNNTRPPRGNWFGCTWMNGTGFTKTCGG 523-566 Seq ID 23 1b V3C3′ ANDSDVLILNNTRPPRGNWFGCTWMNGTGFTKTCGG 531-566 Seq ID 24 1b C3″ TRPPRGNWFGCTWMNGTGFTKTCGG 542-566 Seq ID 25 1b V4 TKTCGGPPCNIGGAGNNTLTCPTDCFRKHP 561-590 Seq ID 26 1b C4 TDCFRKHPEATYARCGSGPWLTPRCMVHYPYRLWHYPCTVNFTIF 583-627 Seq ID 27 1b C4′ ARCGSGPWLTPRCMVHYPYRLWHYPCTVNFTIF 595-627 Seq ID 28 1b C4″ LTPRCMVHYPYRLWHYPCTVNFTIF 603-627 Seq ID 29 1b C4a TVNFTIFKVRMYVGGVEHRFEAACNWTR 621-648 Seq ID 30 1b C4b EAACNWTRGERCDLEDRDRSELSPLLLSTTEWQ 641-673 Seq ID 31 1b C4c QWQILPCSFTTLPALSTGLIHLHQNIVDVQYLYGVG 671-706 Seq ID 32 E2 1b SA GVGSAVVSLVIKWEYVLLLFLLLADARICACLWMMLLIAQAE 704-745 Seq ID 33 1b HVR I/C1 NTRGLVSLFSPGSAQKIQLVNTNGSWHINRTALN 395-428 Seq ID 34 1b C4b-c DRSELSPLLLSTTEWQILPCSFTTLPALSTG 658-688 Seq ID 35 1b 1350 VGTTDRFGVPTYNWGANDSD 516-535 Seq ID 36 -
TABLE 2 Sample HVR R c # HVR I C1-a C1-b II C2-a C2-b E2-13 B C3 C3′ C3″ V4 C4 C4-a C4-b C4-c SA E2 17758 69 48 47 52 49 48 47 49 38 44 43 52 44 55 48 46 1355 17763 88 54 44 49 52 48 51 51 46 45 48 49 45 133 104 50 361 17764 100 148 138 134 128 136 141 136 136 65 130 145 144 242 128 127 371 17766 91 97 145 96 80 87 90 90 95 47 75 89 163 139 99 86 173 17771 307 79 54 65 51 50 65 68 50 45 60 65 59 96 132 58 393 17775 49 50 46 39 50 271 43 51 48 45 50 55 52 54 47 50 228 17777 60 133 105 130 129 123 118 118 130 95 119 133 129 357 177 113 850 17779 373 328 285 330 284 343 281 323 316 283 297 318 343 341 309 282 720 17785 81 80 73 71 76 66 81 70 74 70 69 79 79 87 119 73 146 17786 341 863 693 152 164 179 148 139 146 136 137 158 160 163 148 157 720 17788 111 553 120 137 69 121 121 119 111 110 103 140 132 131 48 47 934 17789 1316 49 47 46 49 45 53 51 48 43 42 50 49 52 48 48 1178 17790 234 233 182 223 130 224 185 185 186 184 179 216 218 1347 853 207 1534 17791 269 194 177 192 123 203 172 192 157 184 184 200 195 211 187 190 287 17797 260 264 248 257 240 281 249 237 246 221 223 283 261 272 231 243 1357 17798 52 53 50 47 52 54 50 53 49 51 50 51 50 1036 51 51 1161 17799 225 89 81 86 85 100 76 85 87 82 84 86 92 115 86 76 362 17802 42 51 44 47 50 133 48 52 51 48 51 56 76 773 157 56 882 17807 49 133 60 59 66 62 62 59 57 56 57 63 65 62 57 52 605 17808 89 121 117 109 106 1051 118 875 133 116 123 126 393 228 109 126 1354 17810 327 220 199 222 195 200 221 182 197 182 196 209 266 222 195 199 422 17818 224 134 115 126 118 115 128 108 109 98 111 113 112 117 109 108 230 17821 671 243 214 282 238 232 228 217 234 197 216 222 218 557 810 205 1046 17825 397 320 264 284 282 286 289 277 276 274 276 306 273 391 399 277 514 17826 92 109 111 99 114 126 113 98 104 84 105 121 122 126 145 113 695 17827 45 47 46 47 48 49 48 49 49 47 49 50 50 261 113 47 320 17832 151 65 55 70 78 63 77 72 68 59 64 70 62 54 57 49 288 17838 212 167 166 164 156 165 164 146 160 154 150 165 165 161 272 157 305 17839 48 94 117 61 61 51 58 51 46 52 58 55 87 60 95 66 182 17840 318 323 347 317 329 338 320 305 326 302 312 343 355 322 318 337 417 17842 161 174 185 176 168 163 159 157 163 156 150 168 151 154 138 153 195 17844 122 94 90 88 98 78 92 88 84 77 85 94 61 214 51 73 166 17849 1469 68 75 49 54 629 52 53 46 46 51 54 119 1102 55 47 1393 17870 125 236 148 114 128 133 135 116 132 109 135 151 118 293 120 45 197 17879 209 195 201 222 195 215 225 191 194 181 218 209 209 255 253 199 325 17983 438 54 50 48 52 46 50 54 46 46 51 52 46 55 53 48 216 17999 276 201 200 202 190 187 191 169 176 150 190 205 186 321 535 198 697 8242 162 114 114 127 140 114 120 117 103 120 117 107 112 161 152 128 340 8243 188 191 171 175 204 172 189 174 186 174 176 205 200 206 177 178 225 8247 248 169 137 127 120 110 122 96 111 104 114 128 104 130 150 118 215 8250 129 161 127 150 164 144 154 125 134 122 142 151 125 146 137 140 165 8317 112 131 115 123 113 111 144 95 103 95 108 118 108 158 126 111 198 8320 463 433 337 473 435 445 363 345 503 384 362 369 405 446 432 378 474 8329 119 126 123 160 143 145 142 117 135 121 122 126 131 152 148 132 163 8330 198 271 210 210 207 196 216 178 194 206 209 215 186 356 45 51 536 8332 154 141 128 141 132 116 129 110 123 112 135 140 123 147 312 144 290 8333 57 67 50 51 52 52 50 54 50 50 50 56 48 480 65 52 1108 8334 283 66 64 80 68 69 84 79 65 52 67 74 72 180 191 90 348 8337 162 105 99 108 103 92 104 86 93 80 101 107 108 124 118 110 142 8339 50 49 52 62 54 46 54 51 47 41 51 55 53 413 49 50 247 8344 59 52 50 51 58 48 54 52 47 48 55 53 58 63 63 60 59 8351 163 114 105 111 101 91 98 97 92 78 110 111 115 141 179 112 154 8362 211 54 50 47 55 119 53 53 44 45 51 54 59 60 58 55 165 8364 110 308 106 112 112 107 98 102 108 92 116 152 133 208 169 132 671 8365 69 84 94 67 77 74 55 73 70 69 70 79 73 69 88 66 86 8367 218 189 171 201 204 174 191 156 158 140 183 186 294 197 186 171 303 8374 575 113 95 114 110 93 100 92 106 88 103 125 118 112 111 106 143 8377 364 232 229 225 211 202 233 189 207 170 209 205 230 234 218 221 293 8382 314 211 187 196 207 173 208 181 158 150 181 187 201 223 189 211 265 8383 51 100 102 55 58 48 57 53 53 50 52 57 66 94 63 56 285 V1200 52 55 52 56 55 53 50 54 50 52 51 50 50 52 53 54 50 V1201 118 147 138 136 224 144 123 137 140 111 135 154 166 171 137 155 162 V1202 274 308 284 170 290 286 282 248 277 229 271 306 287 330 268 295 329 V1204 130 134 135 127 141 128 79 113 119 106 131 144 145 144 130 144 159 -
TABLE 3 E1 antigens Sample# No peptide V1V2 V2V3 V3V4 HR/SA V5 C4V6 rec E1s No sample 0.011 0.007 0.011 0.014 0.009 0.007 0.009 0.056 30108 0.03 0.035 0.04 0.034 0.032 0.03 0.234 0.378 30109 0.032 0.033 0.035 0.028 0.024 0.026 0.227 0.368 30110 0.021 0.545 0.02 0.019 0.016 0.017 0.047 0.669 30111 0.017 0.614 0.019 0.018 0.017 0.015 0.064 0.796 30112 0.037 0.069 0.035 0.034 0.031 0.031 0.048 0.187 30113 0.042 0.083 0.136 0.039 0.034 0.035 0.063 0.226 30114 0.042 0.099 0.036 0.035 0.035 0.037 0.058 0.267 30115 0.021 0.114 0.023 0.021 0.02 0.02 0.189 0.339 30116 0.019 0.442 0.025 0.022 0.022 0.018 0.056 0.645 30117 0.027 0.062 0.047 0.043 0.041 0.038 0.066 0.164 30118 0.122 0.216 0.126 0.12 0.11 0.125 0.696 0.923 30119 0.023 0.028 0.031 0.028 0.023 0.024 0.23 0.426 30120 0.025 0.024 0.027 0.025 0.039 0.027 0.03 0.024 30121 0.03 0.033 0.033 0.029 0.052 0.034 0.037 0.032 30122 0.029 0.031 0.056 0.03 0.052 0.033 0.035 0.03 30123 0.085 0.081 0.076 0.075 0.087 0.071 0.094 0.137 30124 0.022 0.084 0.022 0.022 0.023 0.022 0.193 0.391 30125 0.095 0.128 0.091 0.089 0.172 0.159 0.47 0.708 17805 0.038 0.051 0.039 0.033 0.09 0.154 0.738 1.169 13059 0.011 0.011 0.012 0.012 0.014 0.012 0.229 0.681 Chimp1 0.095 0.38 0.276 0.126 0.098 0.095 0.099 0.805 Chimp2 0.026 0.234 0.143 0.035 0.036 0.038 0.354 0.822 Chimp3 0.018 0.017 0.02 0.022 0.023 0.019 0.141 0.353 -
TABLE 4 E2 antigens Sample peptide HVR I C1-a C1-b HVR II C2-a C2-b C3 C3′ C3″ V4 C4 C4-a C4-b C4-c recE2h No sample 0.006 0.009 0.011 0.015 0.007 0.006 0.01 0.01 0.01 0.01 0.01 0.01 0.007 0.007 0.009 0.032 30108 0.036 0.747 0.848 0.969 0.032 0.033 0.03 0.04 0.02 0.02 0.03 0.03 0.041 0.026 0.031 0.988 30109 0.027 0.849 0.93 1.053 0.027 0.032 0.03 0.03 0.02 0.02 0.03 0.02 0.038 0.023 0.026 1.079 30110 0.018 0.026 0.021 0.044 0.019 0.024 0.02 0.02 0.02 0.02 0.02 0.03 0.023 0.026 0.056 0.11 30111 0.017 0.02 0.021 0.088 0.018 0.02 0.02 0.02 0.01 0.02 0.02 0.03 0.022 0.028 0.07 0.137 30112 0.037 0.092 0.052 0.177 0.044 0.048 0.04 0.04 0.04 0.04 0.04 0.05 0.043 0.562 0.053 0.947 30113 0.045 0.104 0.054 0.276 0.051 0.047 0.05 0.03 0.04 0.04 0.04 0.05 0.054 0.633 0.07 1.003 30114 0.045 0.112 0.075 0.726 0.046 0.041 0.05 0.05 0.03 0.04 0.04 0.06 0.054 0.646 0.067 1.065 30115 0.022 0.982 0.034 0.064 0.025 0.025 0.02 0.03 0.02 0.03 0.03 0.02 0.03 0.097 0.031 0.413 30116 0.015 0.023 0.02 0.04 0.017 0.02 0.02 0.02 0.02 0.02 0.02 0.03 0.023 0.022 0.046 0.084 30117 0.04 0.087 0.048 0.119 0.037 0.044 0.05 0.05 0.03 0.04 0.04 0.04 0.041 0.547 0.049 0.935 30118 0.112 0.213 0.122 0.119 0.119 0.121 0.12 0.12 0.11 0.05 0.11 0.1 0.117 0.105 0.2 0.289 30119 0.03 0.954 1.012 1.128 0.026 0.029 0.03 0.03 0.02 0.02 0.03 0.03 0.035 0.026 0.03 1.123 30120 0.031 0.427 0.208 0.208 0.03 0.033 0.03 0.04 0.03 0.03 0.03 0.03 0.033 0.032 0.032 0.577 30121 0.033 0.734 0.463 0.398 0.037 0.042 0.04 0.05 0.04 0.03 0.04 0.03 0.04 0.034 0.037 0.963 30122 0.03 0.661 0.413 0.365 0.043 0.034 0.03 0.04 0.04 0.03 0.03 0.03 0.038 0.03 0.034 0.907 30123 0.079 0.11 0.576 0.789 0.09 0.108 0.09 0.08 0.08 0.06 0.07 0.06 0.091 0.078 0.077 0.916 30124 0.02 0.939 0.041 0.065 0.028 0.237 0.04 0.04 0.02 0.03 0.02 0.02 0.038 0.108 0.049 0.4 30125 0.096 0.133 0.103 0.096 0.097 0.115 0.15 0.14 0.09 0.09 0.09 0.1 0.1 0.092 0.183 0.227 17805 0.042 0.255 0.074 0.078 0.071 0.045 0.06 0.06 0.05 0.04 0.06 0.04 0.163 0.043 0.831 0.881 13059 0.013 0.47 0.02 0.019 0.018 0.022 0.02 0.03 0.02 0.01 0.01 0.02 0.36 0.052 0.904 0.944 Chimp1 0.102 0.103 0.116 0.118 0.23 0.109 0.12 0.19 0.17 0.19 0.1 0.1 0.087 0.098 0.095 0.581 Chimp2 0.028 0.181 0.267 0.261 0.056 0.032 0.03 0.04 0.04 0.04 0.04 0.04 0.188 0.035 0.033 1.008 Chimp3 0.058 0.035 0.162 0.086 0.026 0.062 0.02 0.03 0.04 0.02 0.03 0.03 0.023 0.02 0.026 1.327 -
TABLE 5 HCV E1 peptides Sample PCR Genotype V1V2 V2V3 V3V4 V4V5 HR/SA V5C4 C4V6 E1s Patient 1 14/8/90 pos 3a 0.014 0.03 0.06 0.034 0.037 0.048 0.045 0.051 01/06/91 0.03 0.032 0.064 0.041 0.041 0.051 0.048 0.045 20/9/91 neg 0.06 0.064 0.064 0.037 0.039 0.05 0.398 0.045 13/3/92 0.034 0.041 0.037 0.034 0.037 0.046 0.044 0.04 04/09/92 neg 0.037 0.041 0.039 0.037 0.037 0.052 0.048 0.043 24/9/93 0.048 0.051 0.05 0.046 0.052 0.048 0.047 0.042 20/10/94 neg 0.045 0.048 0.398 0.044 0.048 0.047 0.045 0.041 23/10/95 0.051 0.045 0.045 0.04 0.043 0.042 0.041 0.051 10/12/96 pos? 0.037 0.041 0.033 0.034 0.035 0.039 0.038 0.045 Patient 2 15/2/90 0.106 0.103 0.104 0.108 0.104 0.949 0.872 1.03 03/05/90 pos 1a 0.103 0.109 0.106 0.104 0.108 0.828 0.859 1.04 04/12/90 0.096 0.103 0.105 0.103 0.095 0.737 0.848 1.218 23/9/91 0.063 0.078 0.078 0.067 0.072 0.318 0.354 0.66 14/4/92 0.099 0.106 0.099 0.1 0.096 0.219 0.255 0.491 18/12/92 0.104 0.106 0.102 0.105 0.101 0.222 0.249 0.448 26/3/93 0.089 0.095 0.09 0.085 0.082 0.168 0.194 0.357 30/9/93 neg 0.092 0.081 0.089 0.09 0.088 0.17 0.18 0.35 17/6/94 pos 1a 0.084 0.09 0.096 0.599 0.095 0.154 0.166 0.32 18/12/95 0.072 0.077 0.077 0.077 0.081 0.111 0.121 0.206 23/12/96 neg 0.065 0.078 0.074 0.073 0.078 0.106 0.108 0.199 Patient 3 15/04/93 0.005 0.006 0.005 0.004 0.006 0.005 0.006 0.007 06/09/94 pos 3a 0.007 0.008 0.007 0.008 0.007 0.006 0.006 0.009 30/10/95 neg 0.007 0.01 0.009 0.009 0.009 0.008 0.007 0.011 18/11/96 pos? 1b 0.012 0.012 0.012 0.011 0.01 0.009 0.009 0.012 Patient 4 12/04/91 pos 1a 0.006 0.007 0.006 0.006 0.007 0.006 0.006 0.01 23/09/91 neg 0.01 0.01 0.008 0.009 0.009 0.006 0.008 0.013 27/07/92 neg 0.007 0.009 0.007 0.008 0.007 0.006 0.007 0.01 11/06/93 neg 0.009 0.011 0.009 0.01 0.009 0.007 0.006 0.011 29/11/96 pos 1a 0.007 0.01 0.008 0.007 0.007 0.005 0.006 0.008 Patient 5 18/09/92 pos 0.017 0.01 0.008 0.007 0.008 0.178 0.196 0.537 17/12/93 neg 0.012 0.014 0.011 0.01 0.011 0.039 0.04 0.231 15/11/96 neg 0.012 0.014 0.012 0.01 0.01 0.026 0.017 0.116 Patient 6 10/05/90 pos 0.311 0.006 0.007 0.005 0.006 0.004 0.01 0.544 11/10/91 neg 0.284 0.007 0.007 0.006 0.007 0.006 0.013 0.605 Patient 7 10/10/91 pos 1b 0.009 0.01 0.009 0.008 0.008 0.008 0.01 0.043 18/12/92 neg 0.01 0.011 0.011 0.009 0.009 0.008 0.011 0.043 28/06/93 neg 0.006 0.006 0.007 0.006 0.007 0.005 0.008 0.021 10/03/97 pos 1b 0.008 0.008 0.007 0.008 0.007 0.006 0.008 0.012 Patient 8 19/08/91 neg 0.008 0.009 0.008 0.008 0.008 0.006 0.008 0.009 17/07/95 pos 1b 0.01 0.009 0.009 0.009 0.006 0.007 0.007 0.018 09/10/95 pos 1b 0.007 0.007 0.008 0.005 0.006 0.007 0.007 0.009 15/12/95 neg 0.008 0.009 0.008 0.009 0.008 0.007 0.007 0.011 04/03/96 neg 0.009 0.011 0.01 0.011 0.009 0.008 0.007 0.01 02/09/96 neg 0.01 0.011 0.011 0.01 0.01 0.008 0.008 0.013 Patient 9 26/08/91 pos 1b/2ac 0.044 0.015 0.022 0.023 0.028 0.031 0.034 0.115 21/12/93 neg 0.033 0.017 0.021 0.027 0.022 0.025 0.023 0.048 20/12/94 pos 1b 0.023 0.016 0.015 0.028 0.019 0.028 0.034 0.077 21/12/95 pos 1b 0.019 0.029 0.024 0.027 0.027 0.031 0.034 0.048 Patient 10 27/04/92 pos 1b 0.128 0.024 0.02 0.023 0.026 0.118 0.449 0.68 01/06/93 neg 0.107 0.03 0.029 0.027 0.026 0.098 0.385 0.667 Patient 11 09/11/90 neg 0.018 0.019 0.012 0.013 0.015 0.087 0.141 0.591 12/07/91 pos 1b 0.023 0.023 0.016 0.02 0.018 0.073 0.1 0.466 28/05/93 pos 0.008 0.009 0.009 0.005 0.008 0.123 0.173 0.495 20/01/95 neg 0.011 0.009 0.008 0.007 0.007 0.026 0.047 0.187 08/01/96 neg 0.012 0.013 0.01 0.009 0.009 0.025 0.031 0.21 07/02/97 neg 0.019 0.019 0.014 0.014 0.013 0.027 0.051 0.203 Patient 12 11/05/92 pos 1b 0.017 0.013 0.011 0.014 0.015 0.227 0.173 0.425 26/02/93 neg 0.022 0.014 0.013 0.013 0.014 0.178 0.264 0.417 12/08/93 pos 1b 0.016 0.016 0.016 0.014 0.015 0.29 0.387 0.63 Patient 13 07/01/91 pos 1b 0.027 0.017 0.021 0.026 0.026 0.04 0.074 0.062 19/08/91 neg 0.018 0.018 0.015 0.013 0.012 0.021 0.009 0.043 21/08/92 pos 0.015 0.012 0.015 0.014 0.017 0.015 0.021 0.023 06/08/93 neg 0.019 0.018 0.016 0.021 0.016 0.01 0.011 0.02 06/03/95 pos 1b 0.027 0.026 0.018 0.015 0.018 0.02 0.023 0.028 12/04/96 neg 0.03 0.017 0.018 0.036 0.021 0.027 0.027 0.022 Patient 14 22/11/94 pos 1b 0.016 0.011 0.013 0.013 0.026 0.318 0.437 0.461 11/10/95 pos 0.024 0.014 0.014 0.018 0.019 0.039 0.061 0.059 15/02/96 neg 0.032 0.022 0.021 0.023 0.016 0.031 0.041 0.102 Patient 15 04/12/90 pos 1b 0.003 0.005 0.005 0.004 0.005 0.005 0.005 0.019 29/11/90 neg 0.005 0.005 0.005 0.006 0.005 0.008 0.006 0.011 09/10/92 pos 1b 0.006 0.008 0.007 0.007 0.007 0.006 0.005 0.012 25/03/96 neg 0.006 0.008 0.007 0.006 0.006 0.004 0.007 0.012 Patient 16 16/12/91 pos 3a 0.003 0.004 0.006 0.004 0.004 0.08 0.102 0.435 04/10/93 neg 0.006 0.007 0.007 0.006 0.008 0.028 0.033 0.253 12/09/94 neg 0.004 0.008 0.006 0.005 0.005 0.034 0.038 0.197 09/09/96 neg 0.004 0.008 0.007 0.006 0.005 0.008 0.013 0.08 Patient 17 24/04/97 pos 1b 0.076 0.006 0.008 0.004 0.009 0.203 0.327 1.196 Patient 18 08/01/97 neg 0.006 0.007 0.007 0.007 0.006 0.006 0.008 0.009 Blank 0.006 0.009 0.009 0.006 0.006 0.007 0.006 0.009 -
TABLE 6 Sample# Blank E1 V1V2 20188 68 74 20189 77 73 20251 170 150 20252 490 1319 20253 92 70 20254 50 55 20255 81 88 20256 56 62 20266 119 134 20271 77 78 20272 61 69 21010 129 135 21011 159 161 21012 120 93 21286 108 105 -
-
1 41 1 35 PRT Hepatitis C virus 1 Tyr Gln Val Arg Asn Ser Thr Gly Leu Tyr His Val Thr Asn Asp Cys 1 5 10 15 Pro Asn Ser Ser Ile Val Tyr Glu Ala Ala Asp Ala Ile Leu His Thr 20 25 30 Pro Gly Cys 35 2 35 PRT Hepatitis C virus 2 Tyr Glu Val Arg Asn Val Ser Gly Ile Tyr His Val Thr Asn Asp Cys 1 5 10 15 Ser Asn Ser Ser Ile Val Tyr Glu Ala Ala Asp Met Ile Met His Thr 20 25 30 Pro Gly Cys 35 3 35 PRT Hepatitis C virus 3 Val Glu Val Lys Asn Asn Ser Asn Ser Tyr Met Ala Thr Asn Asp Cys 1 5 10 15 Ser Asn Ser Ser Ile Ile Trp Gln Leu Glu Gly Ala Val Leu His Thr 20 25 30 Pro Gly Cys 35 4 35 PRT Hepatitis C virus 4 Val Glu Val Lys Asn Thr Ser Thr Ser Tyr Met Val Thr Asn Asp Cys 1 5 10 15 Ser Asn Ser Ser Ile Val Trp Gln Leu Glu Gly Ala Val Leu His Thr 20 25 30 Pro Gly Cys 35 5 35 PRT Hepatitis C virus 5 Leu Glu Trp Arg Asn Thr Ser Gly Leu Tyr Val Leu Thr Asn Asp Cys 1 5 10 15 Ser Asn Ser Ser Ile Val Tyr Glu Ala Asp Asp Val Ile Leu His Thr 20 25 30 Pro Gly Cys 35 6 24 PRT Hepatitis C virus 6 Leu Thr Asn Asp Cys Ser Asn Ser Ser Ile Val Tyr Glu Ala Asp Asp 1 5 10 15 Val Ile Leu His Thr Pro Gly Cys 20 7 35 PRT Hepatitis C virus 7 Ile Asn Tyr Arg Asn Val Ser Gly Ile Tyr His Val Thr Asn Asp Cys 1 5 10 15 Pro Asn Ser Ser Ile Val Tyr Glu Ala Asp His His Ile Leu His Leu 20 25 30 Pro Gly Cys 35 8 35 PRT Hepatitis C virus 8 Val Pro Tyr Arg Asn Ala Ser Gly Ile Tyr His Ile Thr Asn Asp Cys 1 5 10 15 Pro Asn Ser Ser Ile Val Tyr Glu Ala Asp Asn Leu Ile Leu His Ala 20 25 30 Pro Gly Cys 35 9 35 PRT Hepatitis C virus 9 Leu Thr Tyr Gly Asn Ser Ser Gly Leu Tyr His Leu Thr Asn Asp Cys 1 5 10 15 Ser Asn Ser Ser Ile Val Leu Glu Ala Asp Ala Met Ile Leu His Leu 20 25 30 Pro Gly Cys 35 10 29 PRT Hepatitis C virus 10 Ile Val Tyr Glu Ala Ala Asp Met Ile Met His Thr Pro Gly Cys Val 1 5 10 15 Pro Cys Val Arg Glu Asn Asn Ser Ser Arg Cys Trp Val 20 25 11 34 PRT Hepatitis C virus 11 Val Arg Glu Asn Asn Ser Ser Arg Cys Trp Val Ala Leu Thr Pro Thr 1 5 10 15 Leu Ala Ala Arg Asn Ala Ser Val Pro Thr Thr Thr Ile Arg Arg His 20 25 30 Val Asp 12 36 PRT Hepatitis C virus 12 Pro Cys Val Arg Glu Asn Asn Ser Ser Arg Cys Trp Val Ala Leu Thr 1 5 10 15 Pro Thr Leu Ala Ala Arg Asn Ala Ser Val Pro Thr Thr Thr Ile Arg 20 25 30 Arg His Val Asp 35 13 30 PRT Hepatitis C virus 13 His Val Asp Leu Leu Val Gly Ala Ala Ala Phe Cys Ser Ala Met Tyr 1 5 10 15 Val Gly Asp Leu Cys Gly Ser Val Phe Leu Val Ser Gln Leu 20 25 30 14 40 PRT Hepatitis C virus 14 Ser Gln Leu Phe Thr Ile Ser Pro Arg Arg His Glu Thr Val Gln Asp 1 5 10 15 Cys Asn Cys Ser Ile Tyr Pro Gly His Ile Thr Gly His Arg Met Ala 20 25 30 Trp Asp Met Met Met Asn Trp Ser 35 40 15 34 PRT Hepatitis C virus 15 Ser Ile Tyr Pro Gly His Ile Thr Gly His Arg Met Ala Trp Asp Met 1 5 10 15 Met Met Asn Trp Ser Pro Thr Thr Ala Leu Val Val Ser Gln Leu Leu 20 25 30 Arg Ile 16 41 PRT Hepatitis C virus 16 Pro Gln Ala Val Val Asp Met Val Ala Gly Ala His Trp Gly Val Leu 1 5 10 15 Ala Gly Leu Ala Tyr Tyr Ser Met Val Gly Asn Trp Ala Lys Val Leu 20 25 30 Val Val Met Leu Leu Phe Ala Gly Val 35 40 17 32 PRT Hepatitis C virus 17 His Thr Arg Val Ser Gly Gly Ala Ala Ala Ser Asn Thr Arg Gly Leu 1 5 10 15 Val Ser Leu Phe Ser Pro Gly Ser Ala Gln Lys Ile Gln Leu Val Asn 20 25 30 18 35 PRT Hepatitis C virus 18 Leu Val Asn Thr Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn 1 5 10 15 Cys Asn Asp Ser Leu Gln Thr Gly Phe Phe Ala Ala Leu Phe Tyr Lys 20 25 30 His Lys Phe 35 19 38 PRT Hepatitis C virus 19 Asn Asp Ser Leu Gln Thr Gly Phe Phe Ala Ala Leu Phe Tyr Lys His 1 5 10 15 Lys Phe Asn Ser Ser Gly Cys Pro Glu Arg Leu Ala Ser Cys Arg Ser 20 25 30 Ile Asp Lys Phe Ala Gln 35 20 28 PRT Hepatitis C virus 20 Arg Ser Ile Asp Lys Phe Ala Gln Gly Trp Gly Pro Leu Thr Tyr Thr 1 5 10 15 Glu Pro Asn Ser Ser Asp Gln Arg Pro Tyr Cys Trp 20 25 21 34 PRT Hepatitis C virus 21 Ser Asp Gln Arg Pro Tyr Cys Trp His Tyr Ala Pro Arg Pro Cys Gly 1 5 10 15 Ile Val Pro Ala Ser Gln Val Cys Gly Pro Val Tyr Cys Phe Thr Pro 20 25 30 Ser Pro 22 31 PRT Hepatitis C virus 22 Ser Gln Val Cys Gly Pro Val Tyr Cys Phe Thr Pro Ser Pro Val Val 1 5 10 15 Val Gly Thr Thr Asp Arg Phe Gly Val Pro Thr Tyr Asn Trp Gly 20 25 30 23 44 PRT Hepatitis C virus 23 Gly Val Pro Thr Tyr Asn Trp Gly Ala Asn Asp Ser Asp Val Leu Ile 1 5 10 15 Leu Asn Asn Thr Arg Pro Pro Arg Gly Asn Trp Phe Gly Cys Thr Trp 20 25 30 Met Asn Gly Thr Gly Phe Thr Lys Thr Cys Gly Gly 35 40 24 36 PRT Hepatitis C virus 24 Ala Asn Asp Ser Asp Val Leu Ile Leu Asn Asn Thr Arg Pro Pro Arg 1 5 10 15 Gly Asn Trp Phe Gly Cys Thr Trp Met Asn Gly Thr Gly Phe Thr Lys 20 25 30 Thr Cys Gly Gly 35 25 25 PRT Hepatitis C virus 25 Thr Arg Pro Pro Arg Gly Asn Trp Phe Gly Cys Thr Trp Met Asn Gly 1 5 10 15 Thr Gly Phe Thr Lys Thr Cys Gly Gly 20 25 26 30 PRT Hepatitis C virus 26 Thr Lys Thr Cys Gly Gly Pro Pro Cys Asn Ile Gly Gly Ala Gly Asn 1 5 10 15 Asn Thr Leu Thr Cys Pro Thr Asp Cys Phe Arg Lys His Pro 20 25 30 27 45 PRT Hepatitis C virus 27 Thr Asp Cys Phe Arg Lys His Pro Glu Ala Thr Tyr Ala Arg Cys Gly 1 5 10 15 Ser Gly Pro Trp Leu Thr Pro Arg Cys Met Val His Tyr Pro Tyr Arg 20 25 30 Leu Trp His Tyr Pro Cys Thr Val Asn Phe Thr Ile Phe 35 40 45 28 33 PRT Hepatitis C virus 28 Ala Arg Cys Gly Ser Gly Pro Trp Leu Thr Pro Arg Cys Met Val His 1 5 10 15 Tyr Pro Tyr Arg Leu Trp His Tyr Pro Cys Thr Val Asn Phe Thr Ile 20 25 30 Phe 29 25 PRT Hepatitis C virus 29 Leu Thr Pro Arg Cys Met Val His Tyr Pro Tyr Arg Leu Trp His Tyr 1 5 10 15 Pro Cys Thr Val Asn Phe Thr Ile Phe 20 25 30 28 PRT Hepatitis C virus 30 Thr Val Asn Phe Thr Ile Phe Lys Val Arg Met Tyr Val Gly Gly Val 1 5 10 15 Glu His Arg Phe Glu Ala Ala Cys Asn Trp Thr Arg 20 25 31 33 PRT Hepatitis C virus 31 Glu Ala Ala Cys Asn Trp Thr Arg Gly Glu Arg Cys Asp Leu Glu Asp 1 5 10 15 Arg Asp Arg Ser Glu Leu Ser Pro Leu Leu Leu Ser Thr Thr Glu Trp 20 25 30 Gln 32 36 PRT Hepatitis C virus 32 Gln Trp Gln Ile Leu Pro Cys Ser Phe Thr Thr Leu Pro Ala Leu Ser 1 5 10 15 Thr Gly Leu Ile His Leu His Gln Asn Ile Val Asp Val Gln Tyr Leu 20 25 30 Tyr Gly Val Gly 35 33 42 PRT Hepatitis C virus 33 Gly Val Gly Ser Ala Val Val Ser Leu Val Ile Lys Trp Glu Tyr Val 1 5 10 15 Leu Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Ile Cys Ala Cys Leu 20 25 30 Trp Met Met Leu Leu Ile Ala Gln Ala Glu 35 40 34 34 PRT Hepatitis C virus 34 Asn Thr Arg Gly Leu Val Ser Leu Phe Ser Pro Gly Ser Ala Gln Lys 1 5 10 15 Ile Gln Leu Val Asn Thr Asn Gly Ser Trp His Ile Asn Arg Thr Ala 20 25 30 Leu Asn 35 31 PRT Hepatitis C virus 35 Asp Arg Ser Glu Leu Ser Pro Leu Leu Leu Ser Thr Thr Glu Trp Gln 1 5 10 15 Ile Leu Pro Cys Ser Phe Thr Thr Leu Pro Ala Leu Ser Thr Gly 20 25 30 36 20 PRT Hepatitis C virus 36 Val Gly Thr Thr Asp Arg Phe Gly Val Pro Thr Tyr Asn Trp Gly Ala 1 5 10 15 Asn Asp Ser Asp 20 37 40 PRT Hepatitis C virus 37 Val Ala Leu Thr Pro Thr Leu Ala Ala Arg Asn Ala Ser Val Pro Thr 1 5 10 15 Thr Thr Ile Arg Arg His Val Asp Ser Gln Leu Phe Thr Ile Ser Pro 20 25 30 Arg Arg His Glu Thr Val Gln Asp 35 40 38 36 PRT Hepatitis C virus 38 Thr His Ala Cys Arg Ala Asn Gly Gln Tyr Phe Leu Thr Asn Cys Cys 1 5 10 15 Ala Pro Glu Asp Ile Gly Phe Cys Leu Glu Gly Gly Cys Leu Val Ala 20 25 30 Leu Gly Gly Lys 35 39 16 PRT Hepatitis C virus 39 Ser Gln Leu Phe Thr Ile Ser Pro Arg Arg His Glu Thr Val Gln Asp 1 5 10 15 40 35 PRT Hepatitis C virus 40 Leu Ile Asn Thr Asn Gly Ser Trp His Ile Asn Arg Thr Ala Leu Asn 1 5 10 15 Cys Asn Asp Ser Leu His Thr Gly Phe Leu Ala Ser Leu Phe Tyr Thr 20 25 30 His Ser Phe 35 41 30 PRT Hepatitis C virus 41 Arg Ser Ile Glu Ala Phe Arg Val Gly Trp Gly Ala Leu Gln Tyr Glu 1 5 10 15 Asp Asn Val Thr Asn Pro Glu Asp Met Arg Pro Tyr Cys Trp 20 25 30
Claims (22)
1. A peptide of more than 20 contiguous amino acids derived from the envelope region of HCV-related viruses which binds and recognizes anti-HCV-related virus antibodies.
2. A peptide which binds and recognizes an anti-HCV antibody or an anti-HGV antibody present in a sample of body fluid and which is chosen from the group consisting of the sequences as represented in SEQ D NOs 1 to 38.
3. A functionally equivalent variant or fragment of a peptide according to claim 2 .
4. A peptide according to claims 2 or 3, wherein said anti-HCV antibody present in a sample of body fluid is an anti-HCV-E1 or anti-HCV-E2 antibody.
5. A peptide according to of claims 2 or 3, wherein said anti-HGV antibody present in a sample of body fluid is an anti-HGV-E1 or anti-HGV-E2 antibody.
6. A peptide according to any of claims 1 to 5 , wherein said peptide is synthesized chemically.
7. A peptide according to any of claims 1 to 5 , wherein said peptide is synthesized using recombinant DNA techniques.
8. A peptide according to any of claims 1 to 7 , wherein said peptide is biotinylated or contains cysteine bridges.
9. A combination of peptides according to any of claims 1 to 8 .
10. A method for diagnosing exposure to or infection by HCV-related viruses comprising:
contacting anti-HCV-related virus antibodies within a sample of body fluid with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
determining the binding of anti-HCV-related virus antibodies within a sample of body fluid with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 .
11. An assay kit for detecting the presence of anti-HCV-related virus antibodies within a sample of body fluid comprising:
possibly a solid support,
a peptide according to any of claims 1 to 8 or a combination of peptides according to claim 9 ,
appropriate markers which allow to determine the complexes formed between anti-HCV-related virus antibodies within a sample of body fluid with a peptide according to any of claims 1 to 8 or a combination of peptides according to claim 9 .
12. A bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising:
contacting anti-HCV-related virus antibodies with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
determining the binding of anti-HCV-related virus antibodies with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
adding a modulator or a combination of modulators to the contacted anti-HCV-related virus antibodies and a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
determining the modulation of binding of anti-HCV-related virus antibodies with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 .
13. A bioassay for identifying compounds which modulate the interaction between a peptide and an anti-HCV-related virus antibody, said bioassay comprising:
determining the binding of anti-HCV-related virus antibodies with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
contacting a modulator with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
adding anti-HCV-related virus antibodies to the contacted modulator with the peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 ,
determining the modulation of binding between anti-HCV-related virus antibodies with a peptide according to any of claims 1 to 8 or with a combination of peptides according to claim 9 .
14. A method for producing a modulator as defined by claims 12 or 13.
15. A modulator for the interaction between a peptide and an anti-HCV-related virus antibody, wherein said modulator was identified by the method according to claims 12 or 13.
16. A composition containing a modulator or a combination of modulators wherein said modulator or combination of modulators was identified by the method according to claims 12 or 13.
17. A composition comprising a peptide according to any of claims 1 to 8 or a combination of peptides according to claim 9 .
18. A plasmid vector comprising a nucleotide sequence encoding a polypeptide according to any of claims 1 to 5 or a modulator according to any of claims 12 to 16 , operably linked to transcription regulatory elements.
19. A composition according to any of claims 16 to 18 for vaccinating humans against infection with HCV-related virus or any mutated strain thereof.
20. A composition according to any of claims 16 to 18 for therapeutically treating humans against infection with HCV-related virus or any mutated strain thereof.
21. An antibody, more particularly a monoclonal antibody, characterized in that it specifically recognizes an HCV-related virus peptide according to any of claims 1 to 9 .
22. A method to immunize humans against infection with HCV-related virus or any mutated stain thereof, comprising the use of a peptide according to any of claims 1 to 8 or a combination of peptides according to claim 9.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/685,435 US20040126754A1 (en) | 1997-11-06 | 2003-10-16 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
US11/248,300 US20060078932A1 (en) | 1997-11-06 | 2005-10-13 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97870179 | 1997-11-06 | ||
EP97870179.5 | 1997-11-06 | ||
PCT/EP1998/007105 WO1999024466A2 (en) | 1997-11-06 | 1998-11-06 | Multi-mer peptides derived from hepatitis c virus envelope proteins for diagnostic use and vaccination purposes |
US09/566,266 US6855318B1 (en) | 1997-11-06 | 2000-05-05 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
US10/685,435 US20040126754A1 (en) | 1997-11-06 | 2003-10-16 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/566,266 Division US6855318B1 (en) | 1997-11-06 | 2000-05-05 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/248,300 Division US20060078932A1 (en) | 1997-11-06 | 2005-10-13 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040126754A1 true US20040126754A1 (en) | 2004-07-01 |
Family
ID=8231063
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/566,266 Expired - Fee Related US6855318B1 (en) | 1997-11-06 | 2000-05-05 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
US10/685,435 Abandoned US20040126754A1 (en) | 1997-11-06 | 2003-10-16 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
US11/248,300 Abandoned US20060078932A1 (en) | 1997-11-06 | 2005-10-13 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/566,266 Expired - Fee Related US6855318B1 (en) | 1997-11-06 | 2000-05-05 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/248,300 Abandoned US20060078932A1 (en) | 1997-11-06 | 2005-10-13 | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes |
Country Status (8)
Country | Link |
---|---|
US (3) | US6855318B1 (en) |
EP (1) | EP1028972B1 (en) |
JP (1) | JP2001522599A (en) |
AT (1) | ATE482974T1 (en) |
AU (1) | AU752131C (en) |
CA (1) | CA2305847A1 (en) |
DE (1) | DE69841919D1 (en) |
WO (1) | WO1999024466A2 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SK13142003A3 (en) | 2001-04-24 | 2004-11-03 | Innogenetics Nv | Core-glycosylated HCV envelope proteins |
AU2003295427A1 (en) * | 2002-11-08 | 2004-06-03 | The Administrators Of The Tulane Educational Fund | Flaviviris fusion inhibitors |
CA2539789A1 (en) * | 2003-09-22 | 2005-03-31 | Green Peptide Co., Ltd. | Peptide originating in hepatitis c virus |
PT2125889E (en) | 2007-02-21 | 2014-04-15 | Univ Massachusetts | Human antibodies against hepatitis c virus (hcv) uses thereof |
US20100104555A1 (en) * | 2008-10-24 | 2010-04-29 | The Scripps Research Institute | HCV neutralizing epitopes |
WO2011100508A2 (en) * | 2010-02-12 | 2011-08-18 | Arizona Board Of Regents For And On Behalf Of Arizona State University | Methods and compositions related to glycoprotein-immunoglobulin fusions |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5670153A (en) * | 1991-09-13 | 1997-09-23 | Chiron Corporation | Immunoreactive polypeptide compositions |
US5747239A (en) * | 1990-02-16 | 1998-05-05 | United Biomedical, Inc. | Synthetic peptides specific for the detection of antibodies to HCV, diagnosis of HCV infection and preventions thereof as vaccines |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU638304B2 (en) * | 1989-12-22 | 1993-06-24 | Abbott Laboratories | Hepatitis c assay |
CA2047792C (en) * | 1990-07-26 | 2002-07-02 | Chang Y. Wang | Synthetic peptides specific for the detection of antibodies to hcv, diagnosis of hcv infection and prevention thereof as vaccines |
IT1249684B (en) * | 1991-07-19 | 1995-03-09 | Sorin Biomedica Spa | HEPATITIS VIRUS PROTEIN ENV EPITOPES |
WO1993006488A1 (en) * | 1991-09-16 | 1993-04-01 | Genelabs Technologies, Inc. | Peptide based hepatitis c virus immunoassays |
WO1993006247A1 (en) * | 1991-09-16 | 1993-04-01 | Abbott Laboratories | Hepatitis c assay |
SG77551A1 (en) | 1992-03-06 | 2005-04-28 | Innogenetics Nv | Process for the determination of peptides corresponding to immunologically important epitopes and their use in a process for determination of antibodies or biotinylated peptides corresponding to immunologically important epitopes, a process for preparing |
KR100312534B1 (en) * | 1993-04-28 | 2002-05-13 | 성재갑 | Immunoblot kit for simultaneous detecting antibodies to hepatitis c virus and hepatitis b virus and immunoblot analysis |
ATE290592T1 (en) * | 1993-11-04 | 2005-03-15 | Innogenetics Nv | HUMAN T CELL IMMUNODOMINANT EPITOPES OF THE C-HEPATITIS VIRUS |
WO1995032291A2 (en) * | 1994-05-20 | 1995-11-30 | Genelabs Technologies, Inc. | Hepatitis g virus and molecular cloning thereof |
ES2174957T5 (en) * | 1994-07-29 | 2006-12-16 | Innogenetics N.V. | PURIFIED PROTEINS OF HEPATITIS C VIRUS WRAPPING FOR DIAGNOSTIC AND THERAPEUTIC USE. |
-
1998
- 1998-11-06 EP EP98959858A patent/EP1028972B1/en not_active Expired - Lifetime
- 1998-11-06 DE DE69841919T patent/DE69841919D1/en not_active Expired - Lifetime
- 1998-11-06 CA CA002305847A patent/CA2305847A1/en not_active Abandoned
- 1998-11-06 WO PCT/EP1998/007105 patent/WO1999024466A2/en active IP Right Grant
- 1998-11-06 AT AT98959858T patent/ATE482974T1/en not_active IP Right Cessation
- 1998-11-06 AU AU15609/99A patent/AU752131C/en not_active Ceased
- 1998-11-06 JP JP2000520474A patent/JP2001522599A/en active Pending
-
2000
- 2000-05-05 US US09/566,266 patent/US6855318B1/en not_active Expired - Fee Related
-
2003
- 2003-10-16 US US10/685,435 patent/US20040126754A1/en not_active Abandoned
-
2005
- 2005-10-13 US US11/248,300 patent/US20060078932A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5747239A (en) * | 1990-02-16 | 1998-05-05 | United Biomedical, Inc. | Synthetic peptides specific for the detection of antibodies to HCV, diagnosis of HCV infection and preventions thereof as vaccines |
US5670153A (en) * | 1991-09-13 | 1997-09-23 | Chiron Corporation | Immunoreactive polypeptide compositions |
Also Published As
Publication number | Publication date |
---|---|
EP1028972A2 (en) | 2000-08-23 |
WO1999024466A2 (en) | 1999-05-20 |
AU752131C (en) | 2003-12-04 |
AU1560999A (en) | 1999-05-31 |
JP2001522599A (en) | 2001-11-20 |
US20060078932A1 (en) | 2006-04-13 |
ATE482974T1 (en) | 2010-10-15 |
AU752131B2 (en) | 2002-09-05 |
EP1028972B1 (en) | 2010-09-29 |
DE69841919D1 (en) | 2010-11-11 |
CA2305847A1 (en) | 1999-05-20 |
US6855318B1 (en) | 2005-02-15 |
WO1999024466A3 (en) | 1999-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0804584B1 (en) | Sequences of hepatitis c virus genotype 7 and their use as prophylactic, therapeutic and diagnostic agents | |
Ishii et al. | High titers of antibodies inhibiting the binding of envelope to human cells correlate with natural resolution of chronic hepatitis C | |
KR930008092B1 (en) | Peptides for the detection, diagnosis and prevention of hepatitis c. | |
US6762024B2 (en) | Sequences of hepatitis C virus genotypes and their use as therapeutic and diagnostic agents | |
AU765940B2 (en) | Particles of HCV envelope proteins: use for vaccination | |
US7282341B2 (en) | Assay for the diagnosis of flaviviral infection using antibodies with high affinity for NS1 protein of flavivirus in hexameric form | |
CA2331368C (en) | Nucleic acid vaccines for prevention of flavivirus infection | |
US20060078932A1 (en) | Multi-mer peptides derived from hepatitis C virus envelope proteins for diagnostic use and vaccination purposes | |
PL175360B1 (en) | Nucleic acid molecule and composition for detecting hepatitis c viral infections | |
US6670114B1 (en) | Host derived proteins binding HCV: medical, diagnostic and purification use | |
Ferroni et al. | Identification of four epitopes in hepatitis C virus core protein | |
EP1002092B1 (en) | Mimotopes of hypervariable region 1 of the e2 glycoprotein of hcv and uses thereof | |
JPH09500784A (en) | Linear and branched peptides useful for the diagnosis and detection of non-A, non-B hepatitis | |
Ahmed et al. | Murine humoral immune response against recombinant structural proteins of hepatitis C virus distinct from those of patients | |
Cardoso et al. | The serology of hepatitis C virus (HCV) infection: antibody crossreaction in the hypervariable region 1 | |
KR20020089371A (en) | Purified hepatitis c virus envelope proteins for diagnostic and therapeutic use | |
KR20230140889A (en) | p62 protein fragment derived from African swine fever virus as recombinant antigen, and uses thereof | |
KR20200142459A (en) | p104 protein fragment derived from African swine fever virus as recombinant antigen, and uses thereof | |
AU2012201067A1 (en) | Compositions of HSP60 peptides and viral antigens for vaccination and diagnosis | |
WO2002043754A1 (en) | Proteins binding hcv and their medical, diagnostic and purification use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |