CN107098964A - 一种肿瘤特异性重组水蛭素及其制备方法和用途 - Google Patents
一种肿瘤特异性重组水蛭素及其制备方法和用途 Download PDFInfo
- Publication number
- CN107098964A CN107098964A CN201710362102.1A CN201710362102A CN107098964A CN 107098964 A CN107098964 A CN 107098964A CN 201710362102 A CN201710362102 A CN 201710362102A CN 107098964 A CN107098964 A CN 107098964A
- Authority
- CN
- China
- Prior art keywords
- lepirudin
- ludon
- seq
- hirudin
- glu
- 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.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 138
- 229960004408 lepirudin Drugs 0.000 title claims abstract description 132
- OTQCKZUSUGYWBD-BRHMIFOHSA-N lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 title claims abstract 34
- 238000004519 manufacturing process Methods 0.000 title description 3
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 claims abstract description 91
- 108010007267 Hirudins Proteins 0.000 claims abstract description 70
- 102000007625 Hirudins Human genes 0.000 claims abstract description 69
- 229940006607 hirudin Drugs 0.000 claims abstract description 69
- 230000014509 gene expression Effects 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 36
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 claims abstract description 32
- 230000036039 immunity Effects 0.000 claims abstract description 32
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 claims abstract description 30
- 108010038807 Oligopeptides Proteins 0.000 claims abstract description 30
- 102000015636 Oligopeptides Human genes 0.000 claims abstract description 30
- 238000007710 freezing Methods 0.000 claims abstract description 22
- 108020001507 fusion proteins Proteins 0.000 claims abstract description 17
- 102000037865 fusion proteins Human genes 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 108010055460 bivalirudin Proteins 0.000 claims abstract description 4
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 claims abstract description 4
- 229960001500 bivalirudin Drugs 0.000 claims abstract description 4
- 238000012239 gene modification Methods 0.000 claims abstract description 3
- 230000005017 genetic modification Effects 0.000 claims abstract description 3
- 235000013617 genetically modified food Nutrition 0.000 claims abstract description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 74
- 210000004027 cell Anatomy 0.000 claims description 57
- 150000001413 amino acids Chemical class 0.000 claims description 45
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 26
- 230000029087 digestion Effects 0.000 claims description 17
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 16
- 230000003902 lesion Effects 0.000 claims description 15
- 230000001732 thrombotic effect Effects 0.000 claims description 15
- 241000545744 Hirudinea Species 0.000 claims description 14
- 108091008146 restriction endonucleases Proteins 0.000 claims description 14
- 239000000758 substrate Substances 0.000 claims description 14
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims description 13
- 239000012634 fragment Substances 0.000 claims description 12
- 238000001890 transfection Methods 0.000 claims description 12
- 239000003146 anticoagulant agent Substances 0.000 claims description 11
- 238000011191 terminal modification Methods 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 8
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 8
- 108060003951 Immunoglobulin Proteins 0.000 claims description 8
- 208000007536 Thrombosis Diseases 0.000 claims description 8
- 230000002785 anti-thrombosis Effects 0.000 claims description 8
- 238000001815 biotherapy Methods 0.000 claims description 8
- 230000002068 genetic effect Effects 0.000 claims description 8
- 102000018358 immunoglobulin Human genes 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 108010010968 hirudin HV2 Proteins 0.000 claims description 7
- 229920001184 polypeptide Polymers 0.000 claims description 7
- 241000894006 Bacteria Species 0.000 claims description 6
- 108091026890 Coding region Proteins 0.000 claims description 6
- 108010010961 hirudin HV3 Proteins 0.000 claims description 6
- 230000003248 secreting effect Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000013598 vector Substances 0.000 claims description 6
- 241000588724 Escherichia coli Species 0.000 claims description 5
- 230000010354 integration Effects 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 241000238631 Hexapoda Species 0.000 claims description 4
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 4
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 4
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 238000003780 insertion Methods 0.000 claims description 4
- 230000037431 insertion Effects 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 210000004962 mammalian cell Anatomy 0.000 claims description 4
- 210000000538 tail Anatomy 0.000 claims description 4
- 101000716729 Homo sapiens Kit ligand Proteins 0.000 claims description 3
- 102100020880 Kit ligand Human genes 0.000 claims description 3
- 230000002862 amidating effect Effects 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 3
- 230000036541 health Effects 0.000 claims description 3
- 230000006798 recombination Effects 0.000 claims description 3
- 238000005215 recombination Methods 0.000 claims description 3
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 claims description 2
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 claims description 2
- 241000235342 Saccharomycetes Species 0.000 claims description 2
- 101100305864 Alteromonas mediterranea (strain DSM 17117 / CIP 110805 / LMG 28347 / Deep ecotype) rph2 gene Proteins 0.000 claims 2
- 101000583616 Homo sapiens Polyhomeotic-like protein 2 Proteins 0.000 claims 2
- 101000583581 Homo sapiens Polyhomeotic-like protein 3 Proteins 0.000 claims 2
- 102100030903 Polyhomeotic-like protein 2 Human genes 0.000 claims 2
- 102100030905 Polyhomeotic-like protein 3 Human genes 0.000 claims 2
- 101100135363 Yarrowia lipolytica (strain CLIB 122 / E 150) RIM101 gene Proteins 0.000 claims 2
- 208000032843 Hemorrhage Diseases 0.000 abstract description 5
- 208000034158 bleeding Diseases 0.000 abstract description 4
- 230000000740 bleeding effect Effects 0.000 abstract description 4
- 238000007910 systemic administration Methods 0.000 abstract description 3
- 230000009885 systemic effect Effects 0.000 abstract description 3
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 abstract description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 abstract description 2
- 238000010276 construction Methods 0.000 abstract description 2
- 230000014508 negative regulation of coagulation Effects 0.000 abstract description 2
- 230000002537 thrombolytic effect Effects 0.000 abstract description 2
- FIBJDTSHOUXTKV-BRHMIFOHSA-N lepirudin Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)CNC2=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)C(C)C)[C@@H](C)O)[C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O FIBJDTSHOUXTKV-BRHMIFOHSA-N 0.000 description 103
- 230000000694 effects Effects 0.000 description 19
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical group NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 14
- 235000001014 amino acid Nutrition 0.000 description 12
- 108010070643 prolylglutamic acid Proteins 0.000 description 12
- 108010064235 lysylglycine Proteins 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 108700042769 prolyl-leucyl-glycine Proteins 0.000 description 10
- 108010073385 Fibrin Proteins 0.000 description 9
- 102000009123 Fibrin Human genes 0.000 description 9
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 9
- 229950003499 fibrin Drugs 0.000 description 9
- 108010050848 glycylleucine Proteins 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- GWIJZUVQVDJHDI-AVGNSLFASA-N Asp-Phe-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GWIJZUVQVDJHDI-AVGNSLFASA-N 0.000 description 8
- UXUSHQYYQCZWET-WDSKDSINSA-N Cys-Glu-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O UXUSHQYYQCZWET-WDSKDSINSA-N 0.000 description 8
- DZSICRGTVPDCRN-YUMQZZPRSA-N Cys-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CS)N DZSICRGTVPDCRN-YUMQZZPRSA-N 0.000 description 8
- OXFOKRAFNYSREH-BJDJZHNGSA-N Cys-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CS)N OXFOKRAFNYSREH-BJDJZHNGSA-N 0.000 description 8
- KVQOVQVGVKDZNW-GUBZILKMSA-N Gln-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KVQOVQVGVKDZNW-GUBZILKMSA-N 0.000 description 8
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 8
- OCDLPQDYTJPWNG-YUMQZZPRSA-N Gly-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN OCDLPQDYTJPWNG-YUMQZZPRSA-N 0.000 description 8
- BULIVUZUDBHKKZ-WDSKDSINSA-N Gly-Gln-Asn Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O BULIVUZUDBHKKZ-WDSKDSINSA-N 0.000 description 8
- DGTOKVBDZXJHNZ-WZLNRYEVSA-N Ile-Thr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N DGTOKVBDZXJHNZ-WZLNRYEVSA-N 0.000 description 8
- PPBKJAQJAUHZKX-SRVKXCTJSA-N Leu-Cys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC(C)C PPBKJAQJAUHZKX-SRVKXCTJSA-N 0.000 description 8
- FXGIMYRVJJEIIM-UWVGGRQHSA-N Pro-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FXGIMYRVJJEIIM-UWVGGRQHSA-N 0.000 description 8
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 8
- TYYBJUYSTWJHGO-ZKWXMUAHSA-N Ser-Asn-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TYYBJUYSTWJHGO-ZKWXMUAHSA-N 0.000 description 8
- 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 8
- 239000013612 plasmid Substances 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 210000004405 cytokine-induced killer cell Anatomy 0.000 description 7
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 6
- ZDJZEGYVKANKED-NRPADANISA-N Gln-Cys-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O ZDJZEGYVKANKED-NRPADANISA-N 0.000 description 6
- MYXNLWDWWOTERK-BHNWBGBOSA-N Gly-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN)O MYXNLWDWWOTERK-BHNWBGBOSA-N 0.000 description 6
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- AXFMEGAFCUULFV-BLFANLJRSA-N (2s)-2-[[(2s)-1-[(2s,3r)-2-amino-3-methylpentanoyl]pyrrolidine-2-carbonyl]amino]pentanedioic acid Chemical compound CC[C@@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AXFMEGAFCUULFV-BLFANLJRSA-N 0.000 description 4
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 4
- QGNXYDHVERJIAY-ACZMJKKPSA-N Asn-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N QGNXYDHVERJIAY-ACZMJKKPSA-N 0.000 description 4
- VJTWLBMESLDOMK-WDSKDSINSA-N Asn-Gln-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VJTWLBMESLDOMK-WDSKDSINSA-N 0.000 description 4
- FODVBOKTYKYRFJ-CIUDSAMLSA-N Asn-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N FODVBOKTYKYRFJ-CIUDSAMLSA-N 0.000 description 4
- AECPDLSSUMDUAA-ZKWXMUAHSA-N Asn-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N AECPDLSSUMDUAA-ZKWXMUAHSA-N 0.000 description 4
- DYBIDOHFRRUMLW-CIUDSAMLSA-N Cys-Leu-Cys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O DYBIDOHFRRUMLW-CIUDSAMLSA-N 0.000 description 4
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 4
- MXPBQDFWIMBACQ-ACZMJKKPSA-N Glu-Cys-Cys Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O MXPBQDFWIMBACQ-ACZMJKKPSA-N 0.000 description 4
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 4
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 4
- GXMXPCXXKVWOSM-KQXIARHKSA-N Glu-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N GXMXPCXXKVWOSM-KQXIARHKSA-N 0.000 description 4
- OHWJUIXZHVIXJJ-GUBZILKMSA-N Glu-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N OHWJUIXZHVIXJJ-GUBZILKMSA-N 0.000 description 4
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 4
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 4
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 4
- IALQAMYQJBZNSK-WHFBIAKZSA-N Gly-Ser-Asn Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O IALQAMYQJBZNSK-WHFBIAKZSA-N 0.000 description 4
- 101710154944 Hirudin variant-1 Proteins 0.000 description 4
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 4
- SPQWWEZBHXHUJN-KBIXCLLPSA-N Ile-Glu-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O SPQWWEZBHXHUJN-KBIXCLLPSA-N 0.000 description 4
- FZWVCYCYWCLQDH-NHCYSSNCSA-N Ile-Leu-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N FZWVCYCYWCLQDH-NHCYSSNCSA-N 0.000 description 4
- KWTVLKBOQATPHJ-SRVKXCTJSA-N Leu-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N KWTVLKBOQATPHJ-SRVKXCTJSA-N 0.000 description 4
- CCQLQKZTXZBXTN-NHCYSSNCSA-N Leu-Gly-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CCQLQKZTXZBXTN-NHCYSSNCSA-N 0.000 description 4
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 4
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 4
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 4
- CFVQPNSCQMKDPB-CIUDSAMLSA-N Lys-Cys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N CFVQPNSCQMKDPB-CIUDSAMLSA-N 0.000 description 4
- SVSQSPICRKBMSZ-SRVKXCTJSA-N Lys-Pro-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O SVSQSPICRKBMSZ-SRVKXCTJSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 4
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 4
- 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 4
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 4
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 4
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 4
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 4
- FKVNLUZHSFCNGY-RVMXOQNASA-N Pro-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 FKVNLUZHSFCNGY-RVMXOQNASA-N 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 4
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 4
- RJHJPZQOMKCSTP-CIUDSAMLSA-N Ser-His-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O RJHJPZQOMKCSTP-CIUDSAMLSA-N 0.000 description 4
- AQAMPXBRJJWPNI-JHEQGTHGSA-N Thr-Gly-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AQAMPXBRJJWPNI-JHEQGTHGSA-N 0.000 description 4
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 4
- YGKVNUAKYPGORG-AVGNSLFASA-N Tyr-Asp-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YGKVNUAKYPGORG-AVGNSLFASA-N 0.000 description 4
- 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 4
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 4
- 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 4
- YQYFYUSYEDNLSD-YEPSODPASA-N Val-Thr-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O YQYFYUSYEDNLSD-YEPSODPASA-N 0.000 description 4
- 108010005233 alanylglutamic acid Proteins 0.000 description 4
- 108010070783 alanyltyrosine Proteins 0.000 description 4
- 230000002429 anti-coagulating effect Effects 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 4
- 108010092854 aspartyllysine Proteins 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 108010073652 desirudin Proteins 0.000 description 4
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 4
- 108010010147 glycylglutamine Proteins 0.000 description 4
- 108010015792 glycyllysine Proteins 0.000 description 4
- 102000057593 human F8 Human genes 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 108010034529 leucyl-lysine Proteins 0.000 description 4
- 108010009298 lysylglutamic acid Proteins 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 229940047431 recombinate Drugs 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- MLCPTRRNICEKIS-FXQIFTODSA-N Glu-Asn-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MLCPTRRNICEKIS-FXQIFTODSA-N 0.000 description 3
- 101000702488 Rattus norvegicus High affinity cationic amino acid transporter 1 Proteins 0.000 description 3
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 3
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 238000009739 binding Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960000296 desirudin Drugs 0.000 description 3
- XYWBJDRHGNULKG-OUMQNGNKSA-N desirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 XYWBJDRHGNULKG-OUMQNGNKSA-N 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 2
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 2
- SEFVRKXJJPMVHQ-YUMQZZPRSA-N (2s)-2-[[2-[[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]butanedioic acid Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O SEFVRKXJJPMVHQ-YUMQZZPRSA-N 0.000 description 2
- QVWYCTGTGHDWFQ-AWEZNQCLSA-N (2s)-2-[[4-[2-chloroethyl(2-methylsulfonyloxyethyl)amino]benzoyl]amino]pentanedioic acid Chemical compound CS(=O)(=O)OCCN(CCCl)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QVWYCTGTGHDWFQ-AWEZNQCLSA-N 0.000 description 2
- RGNVSYKVCGAEHK-GUBZILKMSA-N (3s)-3-[[2-[[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O RGNVSYKVCGAEHK-GUBZILKMSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IMMKUCQIKKXKNP-DCAQKATOSA-N Ala-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCN=C(N)N IMMKUCQIKKXKNP-DCAQKATOSA-N 0.000 description 2
- WQVYAWIMAWTGMW-ZLUOBGJFSA-N Ala-Asp-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N WQVYAWIMAWTGMW-ZLUOBGJFSA-N 0.000 description 2
- WDIYWDJLXOCGRW-ACZMJKKPSA-N Ala-Asp-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WDIYWDJLXOCGRW-ACZMJKKPSA-N 0.000 description 2
- GWFSQQNGMPGBEF-GHCJXIJMSA-N Ala-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N GWFSQQNGMPGBEF-GHCJXIJMSA-N 0.000 description 2
- YSMPVONNIWLJML-FXQIFTODSA-N Ala-Asp-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(O)=O YSMPVONNIWLJML-FXQIFTODSA-N 0.000 description 2
- FBHOPGDGELNWRH-DRZSPHRISA-N Ala-Glu-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FBHOPGDGELNWRH-DRZSPHRISA-N 0.000 description 2
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 2
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 2
- SDZRIBWEVVRDQI-CIUDSAMLSA-N Ala-Lys-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O SDZRIBWEVVRDQI-CIUDSAMLSA-N 0.000 description 2
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 2
- 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 2
- 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 2
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 2
- OVVUNXXROOFSIM-SDDRHHMPSA-N Arg-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O OVVUNXXROOFSIM-SDDRHHMPSA-N 0.000 description 2
- LCBSSOCDWUTQQV-SDDRHHMPSA-N Arg-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LCBSSOCDWUTQQV-SDDRHHMPSA-N 0.000 description 2
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 2
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 2
- BHQQRVARKXWXPP-ACZMJKKPSA-N Asn-Asp-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N BHQQRVARKXWXPP-ACZMJKKPSA-N 0.000 description 2
- VWJFQGXPYOPXJH-ZLUOBGJFSA-N Asn-Cys-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)C(=O)N VWJFQGXPYOPXJH-ZLUOBGJFSA-N 0.000 description 2
- LUVODTFFSXVOAG-ACZMJKKPSA-N Asn-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N LUVODTFFSXVOAG-ACZMJKKPSA-N 0.000 description 2
- BZMWJLLUAKSIMH-FXQIFTODSA-N Asn-Glu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BZMWJLLUAKSIMH-FXQIFTODSA-N 0.000 description 2
- IICZCLFBILYRCU-WHFBIAKZSA-N Asn-Gly-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IICZCLFBILYRCU-WHFBIAKZSA-N 0.000 description 2
- 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 2
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 2
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 2
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 2
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 2
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 2
- BLQBMRNMBAYREH-UWJYBYFXSA-N Asp-Ala-Tyr Chemical compound N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O BLQBMRNMBAYREH-UWJYBYFXSA-N 0.000 description 2
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 2
- FMWHSNJMHUNLAG-FXQIFTODSA-N Asp-Cys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FMWHSNJMHUNLAG-FXQIFTODSA-N 0.000 description 2
- WJHYGGVCWREQMO-GHCJXIJMSA-N Asp-Cys-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WJHYGGVCWREQMO-GHCJXIJMSA-N 0.000 description 2
- DZQKLNLLWFQONU-LKXGYXEUSA-N Asp-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N)O DZQKLNLLWFQONU-LKXGYXEUSA-N 0.000 description 2
- VFUXXFVCYZPOQG-WDSKDSINSA-N Asp-Glu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VFUXXFVCYZPOQG-WDSKDSINSA-N 0.000 description 2
- KHBLRHKVXICFMY-GUBZILKMSA-N Asp-Glu-Lys Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O KHBLRHKVXICFMY-GUBZILKMSA-N 0.000 description 2
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 2
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 2
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 2
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 2
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-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](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 2
- GXIUDSXIUSTSLO-QXEWZRGKSA-N Asp-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N GXIUDSXIUSTSLO-QXEWZRGKSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 2
- QFMCHXSGIZPBKG-ZLUOBGJFSA-N Cys-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N QFMCHXSGIZPBKG-ZLUOBGJFSA-N 0.000 description 2
- CVOZXIPULQQFNY-ZLUOBGJFSA-N Cys-Ala-Cys Chemical compound C[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O CVOZXIPULQQFNY-ZLUOBGJFSA-N 0.000 description 2
- GRNOCLDFUNCIDW-ACZMJKKPSA-N Cys-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N GRNOCLDFUNCIDW-ACZMJKKPSA-N 0.000 description 2
- DCJNIJAWIRPPBB-CIUDSAMLSA-N Cys-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N DCJNIJAWIRPPBB-CIUDSAMLSA-N 0.000 description 2
- LYSHSHHDBVKJRN-JBDRJPRFSA-N Cys-Ile-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N LYSHSHHDBVKJRN-JBDRJPRFSA-N 0.000 description 2
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 2
- LHMSYHSAAJOEBL-CIUDSAMLSA-N Cys-Lys-Asn Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O LHMSYHSAAJOEBL-CIUDSAMLSA-N 0.000 description 2
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 2
- CHRCKSPMGYDLIA-SRVKXCTJSA-N Cys-Phe-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O CHRCKSPMGYDLIA-SRVKXCTJSA-N 0.000 description 2
- CNAMJJOZGXPDHW-IHRRRGAJSA-N Cys-Pro-Phe Chemical compound N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O CNAMJJOZGXPDHW-IHRRRGAJSA-N 0.000 description 2
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 2
- SAEVTQWAYDPXMU-KATARQTJSA-N Cys-Thr-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O SAEVTQWAYDPXMU-KATARQTJSA-N 0.000 description 2
- FNXOZWPPOJRBRE-XGEHTFHBSA-N Cys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CS)N)O FNXOZWPPOJRBRE-XGEHTFHBSA-N 0.000 description 2
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 108010020076 Cytochrome P-450 CYP2B1 Proteins 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 108010033174 Deoxycytidine kinase Proteins 0.000 description 2
- 102100029588 Deoxycytidine kinase Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 102100037362 Fibronectin Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- PRBLYKYHAJEABA-SRVKXCTJSA-N Gln-Arg-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O PRBLYKYHAJEABA-SRVKXCTJSA-N 0.000 description 2
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 2
- NSNUZSPSADIMJQ-WDSKDSINSA-N Gln-Gly-Asp Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NSNUZSPSADIMJQ-WDSKDSINSA-N 0.000 description 2
- CAXXTYYGFYTBPV-IUCAKERBSA-N Gln-Leu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CAXXTYYGFYTBPV-IUCAKERBSA-N 0.000 description 2
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 2
- PAOHIZNRJNIXQY-XQXXSGGOSA-N Gln-Thr-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O PAOHIZNRJNIXQY-XQXXSGGOSA-N 0.000 description 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 2
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 2
- CVPXINNKRTZBMO-CIUDSAMLSA-N Glu-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)CN=C(N)N CVPXINNKRTZBMO-CIUDSAMLSA-N 0.000 description 2
- RCCDHXSRMWCOOY-GUBZILKMSA-N Glu-Arg-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCCDHXSRMWCOOY-GUBZILKMSA-N 0.000 description 2
- RTOOAKXIJADOLL-GUBZILKMSA-N Glu-Asp-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N RTOOAKXIJADOLL-GUBZILKMSA-N 0.000 description 2
- ZXQPJYWZSFGWJB-AVGNSLFASA-N Glu-Cys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N ZXQPJYWZSFGWJB-AVGNSLFASA-N 0.000 description 2
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 2
- QQLBPVKLJBAXBS-FXQIFTODSA-N Glu-Glu-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QQLBPVKLJBAXBS-FXQIFTODSA-N 0.000 description 2
- KUTPGXNAAOQSPD-LPEHRKFASA-N Glu-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O KUTPGXNAAOQSPD-LPEHRKFASA-N 0.000 description 2
- VSRCAOIHMGCIJK-SRVKXCTJSA-N Glu-Leu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VSRCAOIHMGCIJK-SRVKXCTJSA-N 0.000 description 2
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 2
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 2
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 2
- ZIYGTCDTJJCDDP-JYJNAYRXSA-N Glu-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZIYGTCDTJJCDDP-JYJNAYRXSA-N 0.000 description 2
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 2
- LWYUQLZOIORFFJ-XKBZYTNZSA-N Glu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O LWYUQLZOIORFFJ-XKBZYTNZSA-N 0.000 description 2
- CQGBSALYGOXQPE-HTUGSXCWSA-N Glu-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O CQGBSALYGOXQPE-HTUGSXCWSA-N 0.000 description 2
- VHPVBPCCWVDGJL-IRIUXVKKSA-N Glu-Thr-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VHPVBPCCWVDGJL-IRIUXVKKSA-N 0.000 description 2
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 2
- LZEUDRYSAZAJIO-AUTRQRHGSA-N Glu-Val-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LZEUDRYSAZAJIO-AUTRQRHGSA-N 0.000 description 2
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 2
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 2
- SUDUYJOBLHQAMI-WHFBIAKZSA-N Gly-Asp-Cys Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(O)=O SUDUYJOBLHQAMI-WHFBIAKZSA-N 0.000 description 2
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 2
- NTOWAXLMQFKJPT-YUMQZZPRSA-N Gly-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN NTOWAXLMQFKJPT-YUMQZZPRSA-N 0.000 description 2
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 2
- LOEANKRDMMVOGZ-YUMQZZPRSA-N Gly-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O LOEANKRDMMVOGZ-YUMQZZPRSA-N 0.000 description 2
- QGDOOCIPHSSADO-STQMWFEESA-N Gly-Met-Phe Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGDOOCIPHSSADO-STQMWFEESA-N 0.000 description 2
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 2
- 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 2
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 2
- ABPRMMYHROQBLY-NKWVEPMBSA-N Gly-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)CN)C(=O)O ABPRMMYHROQBLY-NKWVEPMBSA-N 0.000 description 2
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 2
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 2
- YTKOTXRIWQHSAZ-GUBZILKMSA-N His-Glu-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N YTKOTXRIWQHSAZ-GUBZILKMSA-N 0.000 description 2
- OEROYDLRVAYIMQ-YUMQZZPRSA-N His-Gly-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O OEROYDLRVAYIMQ-YUMQZZPRSA-N 0.000 description 2
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 2
- CCUSLCQWVMWTIS-IXOXFDKPSA-N His-Thr-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O CCUSLCQWVMWTIS-IXOXFDKPSA-N 0.000 description 2
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 2
- 101000595925 Homo sapiens Plasminogen-like protein B Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 2
- PNTWNAXGBOZMBO-MNXVOIDGSA-N Ile-Lys-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PNTWNAXGBOZMBO-MNXVOIDGSA-N 0.000 description 2
- GVNNAHIRSDRIII-AJNGGQMLSA-N Ile-Lys-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N GVNNAHIRSDRIII-AJNGGQMLSA-N 0.000 description 2
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 2
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- BOFAFKVZQUMTID-AVGNSLFASA-N Leu-Gln-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N BOFAFKVZQUMTID-AVGNSLFASA-N 0.000 description 2
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 2
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 2
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 2
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 2
- PJWOOBTYQNNRBF-BZSNNMDCSA-N Leu-Phe-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)O)N PJWOOBTYQNNRBF-BZSNNMDCSA-N 0.000 description 2
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 2
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 2
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 2
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 2
- 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 2
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 2
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 2
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 2
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 2
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 2
- ZAWOJFFMBANLGE-CIUDSAMLSA-N Lys-Cys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N ZAWOJFFMBANLGE-CIUDSAMLSA-N 0.000 description 2
- GNLJXWBNLAIPEP-MELADBBJSA-N Lys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCCCN)N)C(=O)O GNLJXWBNLAIPEP-MELADBBJSA-N 0.000 description 2
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 2
- PINHPJWGVBKQII-SRVKXCTJSA-N Lys-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N PINHPJWGVBKQII-SRVKXCTJSA-N 0.000 description 2
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 0.000 description 2
- BXPHMHQHYHILBB-BZSNNMDCSA-N Lys-Lys-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BXPHMHQHYHILBB-BZSNNMDCSA-N 0.000 description 2
- MSSJJDVQTFTLIF-KBPBESRZSA-N Lys-Phe-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(O)=O MSSJJDVQTFTLIF-KBPBESRZSA-N 0.000 description 2
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 2
- LOGFVTREOLYCPF-RHYQMDGZSA-N Lys-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-RHYQMDGZSA-N 0.000 description 2
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 2
- LKDXINHHSWFFJC-SRVKXCTJSA-N Lys-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N LKDXINHHSWFFJC-SRVKXCTJSA-N 0.000 description 2
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 2
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 2
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 2
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- RNAGAJXCSPDPRK-KKUMJFAQSA-N Met-Glu-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 RNAGAJXCSPDPRK-KKUMJFAQSA-N 0.000 description 2
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 2
- VQILILSLEFDECU-GUBZILKMSA-N Met-Pro-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O VQILILSLEFDECU-GUBZILKMSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 240000007019 Oxalis corniculata Species 0.000 description 2
- CYZBFPYMSJGBRL-DRZSPHRISA-N Phe-Ala-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CYZBFPYMSJGBRL-DRZSPHRISA-N 0.000 description 2
- ULECEJGNDHWSKD-QEJZJMRPSA-N Phe-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 ULECEJGNDHWSKD-QEJZJMRPSA-N 0.000 description 2
- QCHNRQQVLJYDSI-DLOVCJGASA-N Phe-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 QCHNRQQVLJYDSI-DLOVCJGASA-N 0.000 description 2
- ALHULIGNEXGFRM-QWRGUYRKSA-N Phe-Cys-Gly Chemical compound OC(=O)CNC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=CC=C1 ALHULIGNEXGFRM-QWRGUYRKSA-N 0.000 description 2
- UMKYAYXCMYYNHI-AVGNSLFASA-N Phe-Gln-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N UMKYAYXCMYYNHI-AVGNSLFASA-N 0.000 description 2
- KYYMILWEGJYPQZ-IHRRRGAJSA-N Phe-Glu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KYYMILWEGJYPQZ-IHRRRGAJSA-N 0.000 description 2
- CSDMCMITJLKBAH-SOUVJXGZSA-N Phe-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O CSDMCMITJLKBAH-SOUVJXGZSA-N 0.000 description 2
- JEBWZLWTRPZQRX-QWRGUYRKSA-N Phe-Gly-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O JEBWZLWTRPZQRX-QWRGUYRKSA-N 0.000 description 2
- FXYXBEZMRACDDR-KKUMJFAQSA-N Phe-His-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(O)=O FXYXBEZMRACDDR-KKUMJFAQSA-N 0.000 description 2
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 2
- DNAXXTQSTKOHFO-QEJZJMRPSA-N Phe-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 DNAXXTQSTKOHFO-QEJZJMRPSA-N 0.000 description 2
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 2
- ZVRJWDUPIDMHDN-ULQDDVLXSA-N Phe-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 ZVRJWDUPIDMHDN-ULQDDVLXSA-N 0.000 description 2
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 2
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 2
- BTAIJUBAGLVFKQ-BVSLBCMMSA-N Phe-Trp-Val Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C(C)C)C(O)=O)C1=CC=CC=C1 BTAIJUBAGLVFKQ-BVSLBCMMSA-N 0.000 description 2
- 102100035195 Plasminogen-like protein B Human genes 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 2
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 2
- SUENWIFTSTWUKD-AVGNSLFASA-N Pro-Leu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SUENWIFTSTWUKD-AVGNSLFASA-N 0.000 description 2
- XQPHBAKJJJZOBX-SRVKXCTJSA-N Pro-Lys-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O XQPHBAKJJJZOBX-SRVKXCTJSA-N 0.000 description 2
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 2
- 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 2
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 2
- SRTCFKGBYBZRHA-ACZMJKKPSA-N Ser-Ala-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SRTCFKGBYBZRHA-ACZMJKKPSA-N 0.000 description 2
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 2
- FCRMLGJMPXCAHD-FXQIFTODSA-N Ser-Arg-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O FCRMLGJMPXCAHD-FXQIFTODSA-N 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 2
- RNMRYWZYFHHOEV-CIUDSAMLSA-N Ser-Gln-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RNMRYWZYFHHOEV-CIUDSAMLSA-N 0.000 description 2
- QKQDTEYDEIJPNK-GUBZILKMSA-N Ser-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CO QKQDTEYDEIJPNK-GUBZILKMSA-N 0.000 description 2
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 2
- 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 2
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 2
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 2
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 2
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 2
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 2
- GYUUYCIXELGTJS-MEYUZBJRSA-N Thr-Phe-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O GYUUYCIXELGTJS-MEYUZBJRSA-N 0.000 description 2
- WNQJTLATMXYSEL-OEAJRASXSA-N Thr-Phe-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WNQJTLATMXYSEL-OEAJRASXSA-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
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 2
- REJRKTOJTCPDPO-IRIUXVKKSA-N Thr-Tyr-Glu 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](CCC(O)=O)C(O)=O REJRKTOJTCPDPO-IRIUXVKKSA-N 0.000 description 2
- KVEWWQRTAVMOFT-KJEVXHAQSA-N Thr-Tyr-Val 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](C(C)C)C(O)=O KVEWWQRTAVMOFT-KJEVXHAQSA-N 0.000 description 2
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 2
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 102000006601 Thymidine Kinase Human genes 0.000 description 2
- 108020004440 Thymidine kinase Proteins 0.000 description 2
- BIJDDZBDSJLWJY-PJODQICGSA-N Trp-Ala-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O BIJDDZBDSJLWJY-PJODQICGSA-N 0.000 description 2
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 2
- RWAYYYOZMHMEGD-XIRDDKMYSA-N Trp-Leu-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 RWAYYYOZMHMEGD-XIRDDKMYSA-N 0.000 description 2
- IEESWNWYUOETOT-BVSLBCMMSA-N Trp-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(O)=O IEESWNWYUOETOT-BVSLBCMMSA-N 0.000 description 2
- IELISNUVHBKYBX-XDTLVQLUSA-N Tyr-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 IELISNUVHBKYBX-XDTLVQLUSA-N 0.000 description 2
- ZWZOCUWOXSDYFZ-CQDKDKBSSA-N Tyr-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 ZWZOCUWOXSDYFZ-CQDKDKBSSA-N 0.000 description 2
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 2
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- CLEGSEJVGBYZBJ-MEYUZBJRSA-N Tyr-Thr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 CLEGSEJVGBYZBJ-MEYUZBJRSA-N 0.000 description 2
- LTFLDDDGWOVIHY-NAKRPEOUSA-N Val-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N LTFLDDDGWOVIHY-NAKRPEOUSA-N 0.000 description 2
- ZMDCGGKHRKNWKD-LAEOZQHASA-N Val-Asn-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZMDCGGKHRKNWKD-LAEOZQHASA-N 0.000 description 2
- VLOYGOZDPGYWFO-LAEOZQHASA-N Val-Asp-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VLOYGOZDPGYWFO-LAEOZQHASA-N 0.000 description 2
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 2
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 2
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 2
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 2
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 2
- ZRSZTKTVPNSUNA-IHRRRGAJSA-N Val-Lys-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(O)=O ZRSZTKTVPNSUNA-IHRRRGAJSA-N 0.000 description 2
- YDVDTCJGBBJGRT-GUBZILKMSA-N Val-Met-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N YDVDTCJGBBJGRT-GUBZILKMSA-N 0.000 description 2
- WMRWZYSRQUORHJ-YDHLFZDLSA-N Val-Phe-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N WMRWZYSRQUORHJ-YDHLFZDLSA-N 0.000 description 2
- LTTQCQRTSHJPPL-ZKWXMUAHSA-N Val-Ser-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N LTTQCQRTSHJPPL-ZKWXMUAHSA-N 0.000 description 2
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 2
- DLRZGNXCXUGIDG-KKHAAJSZSA-N Val-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O DLRZGNXCXUGIDG-KKHAAJSZSA-N 0.000 description 2
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 2
- 108010031318 Vitronectin Proteins 0.000 description 2
- 102100035140 Vitronectin Human genes 0.000 description 2
- 108010011164 acein 1 Proteins 0.000 description 2
- 108010078114 alanyl-tryptophyl-alanine Proteins 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 108010027371 asparaginyl-leucyl-prolyl-arginine Proteins 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 108010047857 aspartylglycine Proteins 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 108010004073 cysteinylcysteine Proteins 0.000 description 2
- 108010016616 cysteinylglycine Proteins 0.000 description 2
- 108010069495 cysteinyltyrosine Proteins 0.000 description 2
- 108010018719 cytochrome P-450 CYP4B1 Proteins 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 210000003038 endothelium Anatomy 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 2
- 108010040856 glutamyl-cysteinyl-alanine Proteins 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 108010027338 isoleucylcysteine Proteins 0.000 description 2
- KLNGALQMFAURPH-NOQNJSOHSA-N kinetensin (1-8) Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 KLNGALQMFAURPH-NOQNJSOHSA-N 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- 108010091871 leucylmethionine Proteins 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 2
- 108010012581 phenylalanylglutamate Proteins 0.000 description 2
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 108010077112 prolyl-proline Proteins 0.000 description 2
- 108010015796 prolylisoleucine Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960001967 tacrolimus Drugs 0.000 description 2
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 2
- 108010047303 von Willebrand Factor Proteins 0.000 description 2
- 102100036537 von Willebrand factor Human genes 0.000 description 2
- 229960001134 von willebrand factor Drugs 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- UQQHOWKTDKKTHO-ICQCTTRCSA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-5-(6-methoxypurin-9-yl)oxolane-3,4-diol Chemical compound C1=NC=2C(OC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O UQQHOWKTDKKTHO-ICQCTTRCSA-N 0.000 description 1
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 description 1
- 101150025032 13 gene Proteins 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- HKCXKNGHGLCFHK-UHFFFAOYSA-N 2-methoxy-7h-purine Chemical compound COC1=NC=C2NC=NC2=N1 HKCXKNGHGLCFHK-UHFFFAOYSA-N 0.000 description 1
- CNJLMVZFWLNOEP-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[4.1.0]heptan-5-one Chemical compound O=C1C(C)CCC2C(C)(C)C12 CNJLMVZFWLNOEP-UHFFFAOYSA-N 0.000 description 1
- PZUPAGRIHCRVKN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]-5-[3,4,5-trihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-[(3,4,5-trihydroxyoxan-2-yl)oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound OCC1OC(O)C(O)C(O)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(COC4C(C(O)C(O)CO4)O)O3)O)C(COC3C(C(O)C(O)CO3)O)O2)O)C(COC2C(C(O)C(O)CO2)O)O1 PZUPAGRIHCRVKN-UHFFFAOYSA-N 0.000 description 1
- STACJSVFHSEZJV-GHCJXIJMSA-N Ala-Asn-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STACJSVFHSEZJV-GHCJXIJMSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 1
- ATYWBXGNXZYZGI-ACZMJKKPSA-N Asp-Asn-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O ATYWBXGNXZYZGI-ACZMJKKPSA-N 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Chinese gallotannin Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- WKKKNGNJDGATNS-QEJZJMRPSA-N Cys-Trp-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O WKKKNGNJDGATNS-QEJZJMRPSA-N 0.000 description 1
- VRJZMZGGAKVSIQ-SRVKXCTJSA-N Cys-Tyr-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VRJZMZGGAKVSIQ-SRVKXCTJSA-N 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 102100027419 Cytochrome P450 4B1 Human genes 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- UPEZCKBFRMILAV-JNEQICEOSA-N Ecdysone Natural products O=C1[C@H]2[C@@](C)([C@@H]3C([C@@]4(O)[C@@](C)([C@H]([C@H]([C@@H](O)CCC(O)(C)C)C)CC4)CC3)=C1)C[C@H](O)[C@H](O)C2 UPEZCKBFRMILAV-JNEQICEOSA-N 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 1
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-N 0.000 description 1
- UUTGYDAKPISJAO-JYJNAYRXSA-N Glu-Tyr-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 UUTGYDAKPISJAO-JYJNAYRXSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 1
- KGVHCTWYMPWEGN-FSPLSTOPSA-N Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CN KGVHCTWYMPWEGN-FSPLSTOPSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 101710154919 Hirudin variant-2 Proteins 0.000 description 1
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 description 1
- 101000624947 Homo sapiens Nesprin-1 Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- YBJWJQQBWRARLT-KBIXCLLPSA-N Ile-Gln-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O YBJWJQQBWRARLT-KBIXCLLPSA-N 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZMYHJISLFYTQGK-FXQIFTODSA-N Met-Asp-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ZMYHJISLFYTQGK-FXQIFTODSA-N 0.000 description 1
- AETNZPKUUYYYEK-CIUDSAMLSA-N Met-Glu-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O AETNZPKUUYYYEK-CIUDSAMLSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100023306 Nesprin-1 Human genes 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- GXDPQJUBLBZKDY-IAVJCBSLSA-N Phe-Ile-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GXDPQJUBLBZKDY-IAVJCBSLSA-N 0.000 description 1
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 description 1
- 101710132082 Pyrimidine/purine nucleoside phosphorylase Proteins 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- VFWQQZMRKFOGLE-ZLUOBGJFSA-N Ser-Ser-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O VFWQQZMRKFOGLE-ZLUOBGJFSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 101000915480 Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4) Zinc metalloprotease ZmpC Proteins 0.000 description 1
- 102100025292 Stress-induced-phosphoprotein 1 Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- RCEHMXVEMNXRIW-IRIUXVKKSA-N Thr-Gln-Tyr Chemical compound C[C@H]([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)O RCEHMXVEMNXRIW-IRIUXVKKSA-N 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 102100031372 Thymidine phosphorylase Human genes 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- DWJQKEZKLQCHKO-SRVKXCTJSA-N Tyr-Asn-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)O DWJQKEZKLQCHKO-SRVKXCTJSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- UPEZCKBFRMILAV-UHFFFAOYSA-N alpha-Ecdysone Natural products C1C(O)C(O)CC2(C)C(CCC3(C(C(C(O)CCC(C)(C)O)C)CCC33O)C)C3=CC(=O)C21 UPEZCKBFRMILAV-UHFFFAOYSA-N 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- YUENFNPLGJCNRB-UHFFFAOYSA-N anthracen-1-amine Chemical class C1=CC=C2C=C3C(N)=CC=CC3=CC2=C1 YUENFNPLGJCNRB-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000005098 blood-cerebrospinal fluid barrier Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000001112 coagulating effect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- UPEZCKBFRMILAV-JMZLNJERSA-N ecdysone Chemical compound C1[C@@H](O)[C@@H](O)C[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@@H]([C@H](O)CCC(C)(C)O)C)CC[C@]33O)C)C3=CC(=O)[C@@H]21 UPEZCKBFRMILAV-JMZLNJERSA-N 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006052 feed supplement Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 108010062699 gamma-Glutamyl Hydrolase Proteins 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000012637 gene transfection Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 108010034892 glycyl-arginyl-glycyl-aspartyl-serine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 108010002230 lepirudin Proteins 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229940087875 leukine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 108010091901 purine phosphoribosyltransferase Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229940030915 refludan Drugs 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 235000001508 sulfur Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000003582 thrombocytopenic effect Effects 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明公开了一种肿瘤特异性重组水蛭素,所述重组水蛭素的N末端含有可被基质金属蛋白酶9(MMP9)识别并裂解的寡肽序列PLGI,用于重组的水蛭素为水蛭素异构体、水蛭素突变体、截短的水蛭肽、基因修饰的水蛭素或水蛭素融合蛋白。相应地,本发明还提供了肿瘤特异性重组水蛭素的制备方法及其在制备防治肿瘤的药物中的应用,还提供了表达肿瘤特异性重组水蛭素的过继免疫细胞的制备方法和用途。本发明的重组水蛭素,使水蛭素抗凝活性进行肿瘤靶向性释放,营造不易形成血栓的微环境,甚至溶解已形成的微小栓子以达到抗凝、溶栓、防止肿瘤细胞转移的功能,这就克服了野生型水蛭素全身用药引起***性出血的风险。
Description
技术领域
本发明涉及生物治疗与生物医药领域,特别涉及一种肿瘤特异性重组水蛭素及其制备方法和用途。
背景技术
水蛭素是迄今发现的活性最强的天然凝血酶特异性抑制剂,最初从医用水蛭唾液腺中分离得到,由65~66个氨基酸组成,可直接与凝血酶以l:l(摩尔比)的方式结合形成非共价复合物,从而使凝血酶失去裂解纤维蛋白原的能力,抑制血栓的形成。天然水蛭素存在十种以上变体,主要有简称为HV1、HV2、HV3三种同源性很高的异构体(Hirudin Variant)。
目前,国外已有两个重组水蛭素产品被批准上市:1.Desirudin(商品名:Revasc,瑞士Novartis产品),2.Lepirudin(商品名:Refludan,英国Pharmion及美国BerlexLaboratories产品)。两者结构上仅在N-端存在微小差异,Desirudin为Val1-Val2,而Lepirudin为Leu1-Tyr2。Desirudin用于手术时深度静脉血栓(DVT)的预防与治疗,Lepirudin用于肝素诱导的血小板减少性疾病患者的抗凝治疗。此外,水蛭素在防治不稳定性心绞痛、弥散性血管内凝血、脑血栓、血栓静脉炎及冠状动脉血栓等方面都具有巨大的潜在临床应用价值。
在多种恶性肿瘤患者中存在着血液高凝状态,如肺癌、乳腺癌、胃癌、胰腺癌等。恶性肿瘤患者血液中的高凝状态,不仅能促进体内血栓形成,而且与肿瘤生长、侵袭以及转移明显相关。凝血功能变化可引起肿瘤细胞表型和活性改变,促进肿瘤细胞与血小板、内皮细胞、纤维结合蛋白(Fibrinectin)以及Von Willebrand factor(vWF)的黏附,从而使肿瘤细胞在局部增殖、浸润甚至向其他部位转移。血栓性疾病是恶性肿瘤患者第二大致死因素,仅次于肿瘤转移。对血栓形成高危肿瘤患者及早进行药物性干预,对于延长患者生存期、降低死亡率有重要意义。研究表明,水蛭素在肿瘤治疗中也能发挥作用。重组水蛭素通过其抗凝作用,抑制纤维蛋白的形成,能防止肿瘤细胞与血纤维蛋白或血小板凝集,使NK细胞或其他细胞毒效应细胞的活性得以发挥。已证明水蛭素治疗可发挥疗效的肿瘤有纤维肉瘤、骨肉瘤、血管肉瘤、黑素瘤和白血病等。水蛭素还可配合化疗和放疗,通过促进肿瘤中的血流、改善乏氧状态而增强疗效。
动物试验和临床研究表明,静脉或皮下注射水蛭素均无明显毒副作用,半致死剂量远大于治疗所需剂量,机体易接受,免疫性弱,不影响血小板、纤维蛋白原水平和血红蛋白含量,不易通过血脑脊液屏障。无论急性、亚急性的毒性试验,水蛭素对呼吸、血压、心率均不影响。水蛭素在体内无降解,以活性成分经肾脏***。
水蛭素作为一种高效、直接、特异的凝血酶抑制剂,具有很强的抗凝、抗血栓以及抗炎等多种药理活性。与肝素等传统的抗凝药物相比,其治疗剂量小、疗效高、不会引起过敏反应。水蛭素有抗原性,但其抗体没有害,反而延长消除半衰期,是一种少见的正效果抗体。因此水蛭素的应用将会不断得到开拓和推广,重组水蛭素将会成为新一代的抗凝、抗栓和抗肿瘤新药。但是,水蛭素又可导致凝血相关参数,如活化部分凝血活酶时间(APTT)、凝血酶时间(TT)和凝血酶原时间(PT)等明显升高,从而可能引起全身或***性出血风险。临床上,作为一个理想的抗凝药物,在全身用药条件下,应当具有明确的抗凝、抗栓效果,但又不引起出血副作用,尤其是在以***为目的的临床应用时,其理想的工作状态为靶向性的在肿瘤局部发挥抗凝、抗栓、抗肿瘤作用,从而使临床用药安全性提高。在肿瘤治疗领域,如何进一步减少水蛭素的副作用,增加其肿瘤治疗靶向性是值得探讨的问题。
发明内容
本发明的目的是提供一种肿瘤特异性重组水蛭素及表达肿瘤特异性重组水蛭素的过继免疫细胞,至少能够解决上述问题之一。
本发明思想的指导原则的关键是构建水蛭素衍生物,使水蛭素抗凝活性进行肿瘤靶向性释放,即在正常条件下,该水蛭素衍生物无抗凝活性,而当位于肿瘤位置时,该水蛭素衍生物的抗凝活性才在肿瘤局部释放,营造不易形成血栓的微环境,甚至溶解已形成的微小栓子以达到抗凝、溶栓、防止肿瘤细胞转移的功能。这就克服了野生型水蛭素全身用药引起***性出血的风险。
基质金属蛋白酶(MMPs)是一类以无活性酶原形式分泌的Zn2+依赖性肽链内切酶家族,是构成胞外基质降解最重要的蛋白水解***。MMP9即基质金属蛋白酶9,是其家族的重要成员。能够降解肿瘤微环境中的多种蛋白胶原,促进肿瘤侵袭。大量的实验研究表明,MMP9在癌细胞的快速增殖、侵袭及转移的过程中起到很重要的作用。MMP9通过以下方式促进肿瘤浸润及转移:降解ECM的分子物质;调节细胞的黏附性;配合其他酶类降解血管基底膜和血管周围基质。这是血管树生长的重要条件,只有通过降解过程,内皮细胞才能迁移入周围组织,并逐渐形成血管树,促进肿瘤细胞的转移和侵袭。MMP9酶与底物作用后可使明胶中Gly-Ile之间的肽键断裂。
水蛭素是由65~66个氨基酸组成的单链多肽,其N末端可以与凝血酶催化活性位点结合,具有抗凝活性,C末端与凝血酶的底物识别位点结合,对凝血酶有很强的特异性亲和作用。本发明设计了一个封闭水蛭素N末端的措施,以达到降低该水蛭素衍生物的抗凝活性的目的,同时还具有肿瘤靶向寻的功能。当该水蛭素衍生物位于肿瘤微环境使时,利用肿瘤微环境中富含MMP9酶特点,使该水蛭素衍生物N末端被封闭的水蛭素重新回复为水蛭素原形,在肿瘤局部发挥特异性靶向抗凝作用,从而成为一类新型、安全、有效的肿瘤靶向性抗凝、抗癌剂。
为实现上述目的,根据本发明的一个方面,提供了一种肿瘤特异性重组水蛭素,重组水蛭素的N末端含有可被MMP9识别并裂解的寡肽序列,用于重组的水蛭素为水蛭素异构体、水蛭素突变体、截短的水蛭肽、基因修饰的水蛭素或水蛭素融合蛋白。
进一步的,寡肽序列为可被MMP9识别并裂解的短肽,其结构特征为XnGI,Xn代表任意数量的任意氨基酸。
重组水蛭素是在水蛭素异构体HV2或HV3的N末端修饰有寡肽PLG,与水蛭素异构体HV2或HV3的N末端序列I共同组成MMP9识别并酶切的底物肽序列PLGI,重组水蛭素PLG-HV2氨基酸序列为:SEQ ID NO.1,基因序列为:SEQ ID NO.2,重组水蛭素PLG-HV3氨基酸序列为:SEQ ID NO.3,基因序列为:SEQ ID NO.4;
或者,所述重组水蛭素,是人白蛋白与N末端氨基酸是I的水蛭素异构体HV2或HV3通过寡肽PLG连接而成的融合蛋白HPH2,或HPH3,HPH2氨基酸序列为:SEQ ID NO.17,基因序列为:SEQ ID NO.18,HPH3氨基酸序列为:SEQ ID NO.19,基因序列为:SEQ ID NO.20;
或者,所述重组水蛭素,是人嵌合免疫球蛋白Fc段与N末端氨基酸是I的水蛭素异构体HV2或HV3通过寡肽PLG连接而成的融合蛋白FPH2,或FPH3,人嵌合免疫球蛋白Fc段包含人IgG4铰链区、Fc段序列和IgM尾片序列,FPH2氨基酸序列为:SEQ ID NO.21,基因序列为:SEQ ID NO.22,FPH3氨基酸序列为:SEQ ID NO.23,基因序列为:SEQ ID NO.24。
肿瘤细胞能够营造肿瘤微环境,通过分析肿瘤微环境的特点,可以找到肿瘤靶向性的靶标。研究表明αvβ3在多种肿瘤细胞如肺癌、乳腺癌、***癌、膀胱癌、胶质母细胞瘤及浸润性黑色素瘤等表面高表达。在肿瘤组织新生血管内皮细胞中强烈表达,在成熟的血管内皮细胞和绝大多数正常组织中αvβ3的表达水平很低。在肿瘤组织中,肿瘤细胞分泌的生长因子使上皮细胞活化,其中整合素αvβ3的表达水平很高,这使得αvβ3成为肿瘤靶向治疗的一个理想位点。与正常组织血管***相比,肿瘤组织大量表达αvβ3,αvβ3在肿瘤组织新生毛细血管***中的表达水平比正常组织高出很多。整合素αvβ3能识别细胞外基质蛋白,与其特异性结合,介导肿瘤细胞的粘附与迁移,在肿瘤的生长、浸润、转移尤其是血管生成中发挥重要作用。αvβ3能够与多种含有RGD序列的蛋白结合,例如玻璃体结合蛋白、纤维结合蛋白、纤维蛋白素原、凝血酶敏感素及一些模拟RGD序列的内源性蛋白。一些设计的抗体或小分子量的αvβ3拮抗剂,在体内模型中能抑制血管内皮细胞与玻璃体结合蛋白之间的粘附,肿瘤的血管发生明显减少。
在以往研究中,RGD序列常被作为靶向药物的载体,将药物靶向到表达整合素αvβ3的肿瘤血管***去。RGD序列是作为纤维结合蛋白与细胞的结合位点被发现的,其基本识别位点由Arg-Gly-Asp三个氨基酸组成。在RGD衍生物中,c(RGDfK)常被作为药物的载体,因为赖氨酸残基K是最理想的能够同其他化学物质发生偶联反应的基团。人们运用噬菌体技术发现了另外一种能和αvβ3特异性结合的RGD配体:含两个二硫键的RGD序列(ACDCRGDCFCG),人们称其为RGD4C。其结合能力是含一个二硫键RGD序列的20倍,是通常线性RGD序列的200倍。RGD4C的缺点是能够形成不同的环状结构,如果形成了附加的单环和二环结构,则其结合能力降低10倍。二者相比,c(RGDfK)稳定性较好而且容易与其他化学基团发生偶联,更适合作为化学偶联的载体。而RGD4C则适合作为运用重组技术设计的靶向药物载体。
进一步的,重组水蛭素,是靶向整合素αvβ3的多肽RGD4C与N末端氨基酸是I的水蛭素异构体HV2或HV3通过Linker和寡肽PLG连接而成的融合蛋白RPH2,或RPH3,RPH2氨基酸序列为:SEQ ID NO.13,基因序列为:SEQ ID NO.14,RPH3氨基酸序列为:SEQ ID NO.15,基因序列为:SEQ ID NO.16。
目前已经了解,水蛭素分子的N末端是其核心部分,含三对二硫键(Cys6-Cys14,Cys16-Cys28,Cys32-Cys39),使N末端肽链绕迭成密集形核心环肽结构,与凝血酶的催化活性位点结合;而C末端为一无规则伸展的链状结构,其中Gln49~Gly54有空间和疏水作用,而Asp55~Pro60富含酸性氨基酸,带有负电荷,易与凝血酶碱性的底物识别位点结合。HV1/HV2的Ser32-Asp33-Gly34-Glu35(SDGE)或HV3的Ser32-Asn33-Gly34-Lys35(SNGK)为一突出于β-折叠间的Loop结构,构象自由,对活性无明显作用。根据水蛭素的以上特性,将野生型水蛭素(HV2/HV3)肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Met35(RGDM)。RGD序列由精氨酸、甘氨酸和天冬氨酸组成,存在于多种细胞外基质中,可与整合素αvβ3特异性结合。经过RGDS或RGDM修饰的重组水蛭素可以更好的靶向肿瘤微环境的整合素αvβ3,通过MMP9蛋白酶将水蛭素释放出来,发挥抗凝、抗栓和抗肿瘤作用。
进一步的,所述重组水蛭素,是将野生型水蛭素HV2或HV3肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Ser35,再在其N末端修饰PLG寡肽,所述重组水蛭素PLG-HV2-RGDS氨基酸序列为:SEQ ID NO.5,基因序列为:SEQ ID NO.6,重组水蛭素PLG-HV3-RGDS氨基酸序列为:SEQ ID NO.7,基因序列为:SEQ ID NO.8;
或者,所述重组水蛭素,是将野生型水蛭素HV2或HV3肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Met35,再在其N末端修饰PLGL寡肽,所述重组水蛭素PLG-HV2-RGDM氨基酸序列为:SEQ ID NO.9,基因序列为:SEQ ID NO.10,重组水蛭素PLG-HV3-RGDM氨基酸序列为:SEQ ID NO.11,基因序列为:SEQ ID NO.12。
相应地,本发明还提供了上述肿瘤特异性重组水蛭素的制备方法,包括以下步骤:化学合成上述肿瘤特异性重组水蛭素基因片段,在其N末端连接信号肽序列,并在重组编码基因的两端添加限制性酶切位点,将重组编码基因***基因载体中制备重组载体,用该重组载体转化或转染宿主细胞,培养宿主细胞,并从中回收和纯化该肿瘤特异性重组水蛭素,宿主细胞为大肠杆菌、乳酸菌、酵母菌、昆虫细胞或哺乳动物细胞。
相应地,本发明还提供了上述的肿瘤特异性重组水蛭素在制备抗凝、抗血栓、防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物、保健品和功能性食品中的应用。
相应地,本发明还提供了表达上述肿瘤特异性重组水蛭素的过继免疫细胞制备方法,体外培养人源免疫细胞,将人源分泌型信号肽编码基因与上述的肿瘤特异性重组水蛭素的编码基因相连,并在重组编码基因的两端添加限制性酶切位点,将编码基因***载体中制备成重组基因载体,转染免疫细胞,获得表达肿瘤特异性重组水蛭素的过继免疫细胞。
进一步的,人源分泌型信号肽为人酰胺化酶信号肽,氨基酸序列为:SEQ IDNO.25,基因序列为:SEQ ID NO.26。
进一步的,免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种,所述免疫细胞为人源免疫细胞。
进一步的,过继免疫细胞的膜表面表达有靶标分子,靶标分子通过跨膜序列定位在细胞膜表面。
进一步的,靶标分子为CD19的全长或其截短片段,或CD20的全长或其截短片段。
进一步的,靶标分子及跨膜段的结构为:GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段,其氨基酸序列为:SEQ ID NO.27,基因序列为SEQ ID NO.28。
以过继免疫细胞为载体,在肿瘤患者体内持续稳定表达肿瘤特异性重组水蛭素,发挥“微型细胞药厂”的作用,既将细胞过继免疫治疗技术与肿瘤靶向性重组水蛭素的防栓抗癌功能整合,更好的发挥抗肿瘤作用,又可通过在体内长期稳定表达肿瘤特异性重组水蛭素,避免反复注射肿瘤特异性重组水蛭素引起潜在的过敏反应。
相应地,本发明还提供了上述表达肿瘤特异性重组水蛭素的过继免疫细胞的应用,用于抗凝、抗血栓、防治肿瘤的生物治疗,尤其是防治伴有高凝状态和/或血栓的肿瘤患者的生物治疗。
本发明的有益效果为:本发明的肿瘤特异性重组水蛭素的N末端含有可被MMP9识别并酶切的短肽,可以封闭水蛭素N末端的凝血酶催化活性位点,以达到降低该水蛭素衍生物的抗凝活性、减少出血副作用的目的,同时还具有肿瘤靶向寻的功能。当该水蛭素衍生物位于肿瘤微环境使时,利用肿瘤微环境中的富含MMP9酶特点,特异性切除该水蛭素衍生物N末端的封闭肽,使被封闭的水蛭素重新回复为水蛭素原形,在肿瘤局部发挥特异性抗凝作用,从而成为一类新型、安全、有效的肿瘤靶向性抗凝、抗栓和抗癌剂。本发明更进一步的提供了表达肿瘤特异性重组水蛭素的免疫细胞,通过以过继免疫细胞为载体,在体内持续表达肿瘤特异性重组水蛭素,可解决水蛭素半衰期短的弊端,无需短时间内反复给药,可避免反复给药引起过敏或诱导抗体产生,更加适合需要长期抗凝、抗栓的肿瘤患者。表达肿瘤特异性重组水蛭素的过继免疫细胞可靶向肿瘤局部表达,改善肿瘤患者高凝状态,溶解微血栓,防止肿瘤转移,促进免疫细胞进入肿瘤内部发挥杀伤功能,可单独应用或临床配合化/放疗使用。
具体实施方式
下面对本发明作进一步说明。
本发明的肿瘤特异性重组水蛭素的的N末端含有可被MMP9识别并裂解的寡肽序列,,用于重组的水蛭素为水蛭素异构体、水蛭素突变体、截短的水蛭肽或水蛭素融合蛋白。寡肽序列为可被MMP9识别并酶切的短肽,其结构特征为XnGI,Xn代表任意数量的任意氨基酸。
天然水蛭素有多种异构体,其中三种主要异构体分别为Hirudin variant 1(HV1)、Hirudin variant 2(HV2)、Hirudin variant 3(HV3)。
HV2和HV3的N末端氨基酸为I,MMP9的生理底物序列为GI,酶切后断裂点位为G↓I。在HV2或HV3的N末端连接上PLG短肽,或其它XXXG型具有同等功效的短肽,与HV2或HV3的N末端的I共同组成MMP9的底物序列,当被MMP9自G和I之间裂解后,可完整释放水蛭素的抗凝活性。
进一步的,重组水蛭素的末端还连接有用于靶向整合素αvβ3的多肽,该多肽包含RGD序列。则可使上述水蛭素衍生物更好的靶向肿瘤微环境的整合素αvβ3。具体的RGD序列为RGD4C序列。当RGD4C导向载体与肿瘤细胞表面αvβ3结合后,通过MMP9将水蛭素原形释放出来,发挥抗凝、抗栓和抗肿瘤作用。
相应地,本发明还提供了上述肿瘤特异性重组水蛭素的制备方法,包括以下步骤:化学合成上述肿瘤特异性重组水蛭素基因片段,在其N末端连接信号肽,并在重组编码基因的两端添加限制性酶切位点,将重组编码基因***基因载体中制备重组载体,,用该重组载体转化或转染宿主细胞,培养宿主细胞,并从中回收和纯化该肿瘤特异性重组水蛭素,宿主细胞为大肠杆菌、乳酸菌、酵母、昆虫细胞或哺乳动物细胞。
用于重组的载体优选的为真核表达载体,优选的为pPIC9K。宿主细胞优选的为甲醇营养型酵母菌株GS115。
相应地,本发明还提供了上述的肿瘤特异性重组水蛭素在制备抗凝、抗血栓、防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物、保健品和功能性食品中的应用。
相应地,本发明还提供了表达上述肿瘤特异性重组水蛭素的过继免疫细胞制备方法,将人源分泌型信号肽编码基因与上述的肿瘤特异性重组水蛭素的编码基因相连,制备成重组基因载体,转染免疫细胞,获得表达肿瘤特异性重组水蛭素的过继免疫细胞。
该过继免疫细胞的膜表面表达有靶标分子,靶标分子通过跨膜序列定位在细胞膜表面,肿瘤特异性重组水蛭素直接表达或通过偶联诱导表达***进行诱导表达。靶标分子为CD19的全长或其截短片段,或CD20的全长或其截短片段。
本发明表达肿瘤特异性重组水蛭素的过继免疫细胞,肿瘤特异性重组水蛭素可以组成性表达,也可以偶联诱导表达***进行诱导表达。偶联诱导表达***可以是四环素诱导表达***、蜕皮激素(ecdysone)诱导表达***、他克莫司(tacrolimus,FK506)/雷帕霉素(rapamycin)诱导***或RU486诱导***。免疫细胞可以是αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种,免疫细胞为人源免疫细胞。
表达肿瘤特异性重组水蛭素的过继免疫细胞还表达***基因/前药***。***基因/前药***为单纯疱疹病毒1型胸腺嘧啶激酶/戊环鸟苷(HSV-tk/GCV)***、带状疱疹病毒胸腺嘧啶激酶/阿糖甲氧基嘌呤(VZV-tk/Ara-M)***、胞嘧啶脱氨酶/5氟胞嘧啶(CD/5FC)***、细胞色素P450微粒体酶CYP2B1/环磷酰胺(CYP2B1/CPA)***;细胞色素P450CYP4B1/氨基蒽(CYP4B1/2AA)***、脱氧胞苷激酶/阿糖胞苷(dCK/Ara-C)***、乌苷-黄嘌呤磷酸核糖基转移酶/6-硫黄嘌呤(gpt/6TX)***、硝基还原酶/CB1954(NTR/CB1954)***、嘌呤核苷磷酸化酶/6-甲基嘌呤脱氧核苷(PNP/6-MeP-dR)***、胸腺嘧啶磷酸化酶/5’-脱氧-5-氟尿嘧啶(TP/5’-DFUR)***、羧基肽酶G2/CMDA***(CPG2/CMDA)、羧酸酯酶/CPT-11(CE/CPT-11)***中的一种。
上述的表达肿瘤特异性重组水蛭素的过继免疫细胞的制备方法,包括以下步骤:制备编码肿瘤特异性重组水蛭素和膜型分子靶标的基因载体,基因载体中包括(信号肽序列-肿瘤特异性重组水蛭素序列)和(信号肽序列-靶标分子序列-Linker-跨膜段序列)两段基因序列;将上述编码肿瘤特异性重组水蛭素和靶标分子的基因载体通过基因工程技术转染免疫细胞。
基因工程技术为公知技术,所用基因转染***包括慢病毒转染***、逆转录病毒转染***、腺病毒转染***、腺相关病毒转染***、睡美人转座子转染***、质粒电转染***。优选的,采用睡美人转座子转染***或电转染***。以瞬时表达载体,将肿瘤特异性重组水蛭素基因导入过继免疫细胞,可使其外源基因表达量可控,避免过量表达的风险。
编码肿瘤特异性重组水蛭素和膜型分子靶标的基因载体的结构为:信号肽-肿瘤特异性重组水蛭素-IRES-信号肽-靶标分子-Linker-跨膜段,或者,信号肽-靶标分子-Linker-跨膜段-P2A-信号肽-肿瘤特异性重组水蛭素。
相应地,本发明还提供了上述表达肿瘤特异性重组水蛭素的过继免疫细胞的应用,用于抗凝、抗血栓、防治肿瘤的生物治疗,尤其是防治伴有高凝状态和/或血栓的肿瘤患者的生物治疗。
下面结合具体实施方式对本发明作进一步详细的说明。
实施例1
本实施例中重组水蛭素是在水蛭素异构体HV2的N末端修饰有寡肽PLG,与水蛭素异构体HV2的N末端序列I共同组成MMP9识别并裂解的底物肽序列PLGI,肿瘤特异性重组水蛭素PLG-HV2,氨基酸序列为:SEQ ID NO.1,基因序列为:SEQ ID NO.2。
其中,PLGI可被其它MMP9识别并酶切底物肽序列替换,其共同特点为包含有GI序列,以保证经MMP9识别并酶切后,释放的水蛭素N末端的氨基酸为I。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例2
本实施例中重组水蛭素是在水蛭素异构体HV3的N末端修饰有寡肽PLG,与水蛭素异构体HV3的N末端序列I共同组成MMP9识别并酶切的底物肽序列PLGI,重组水蛭素PLG-HV3,氨基酸序列为:SEQ ID NO.3,基因序列为:SEQ ID NO.4。
其中,PLGI可被其它MMP9识别并酶切底物肽序列替换,其共同特点为包含有GI序列,以保证经MMP9酶切后,释放的水蛭素N末端的氨基酸为I。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例3
本实施例中重组水蛭素,是将野生型水蛭素HV2肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Ser35,再在其N末端修饰PLG寡肽,重组水蛭素PLG-HV2-RGDS氨基酸序列为:SEQ ID NO.5,基因序列为:SEQ ID NO.6。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例4
本实施例中用于重组的水蛭素为水蛭素突变体,是将野生型水蛭素HV3肽链的Ser32-Asn33-Gly34-Lys35替换为Arg32-Gly33-Asp34-Ser35,再在其N末端修饰PLG寡肽,重组水蛭素的结构为:PLG-HV3-RGDS,氨基酸序列为:SEQ ID NO.7,基因序列为:SEQ IDNO.8。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例5
本实施例中重组水蛭素,是将野生型水蛭素HV2肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Met35,再在其N末端修饰PLGL寡肽,重组水蛭素PLG-HV2-RGDM氨基酸序列为:SEQ ID NO.9,基因序列为:SEQ ID NO.10。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例6
本实施例中用于重组的水蛭素为水蛭素突变体,是将野生型水蛭素HV3肽链的Ser32-Asn33-Gly34-Lys35替换为Arg32-Gly33-Asp34-Met35(RGDM),重组水蛭素PLG-HV3-RGDM,氨基酸序列为:SEQ ID NO.11,基因序列为:SEQ ID NO.12。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例7
本实施例的重组水蛭素,是靶向整合素αvβ3的多肽RGD4C与N末端氨基酸是I的水蛭素异构体HV2通过Linker和寡肽PLG连接而成的融合蛋白RPH2(RGD4C-PLG-HV2),重组水蛭素的结构为:RGD4C-Linker1-MMP9酶切位点-HV2,氨基酸序列为:SEQ ID NO.13基因序列为:SEQ ID NO.14。
其中,RGD4C可被其它包含RGD序列的可靶向结合αvβ3的短肽序列替换。PLGI可被其它MMP9识别并酶切底物肽序列替换,其共同特点为包含有GI序列,以保证经MMP9酶切后,释放的水蛭素N末端的氨基酸为I;Linker1的长度为2~15个氨基酸。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例8
本实施例的重组水蛭素,是靶向整合素αvβ3的多肽RGD4C与N末端氨基酸是I的水蛭素异构体HV3通过Linker和寡肽PLG连接而成的融合蛋白RPH3(RGD4C-PLG-HV3),重组水蛭素的结构为:RGD4C-Linker1-MMP9酶切位点-HV3,氨基酸序列为:SEQ ID NO.15,基因序列为:SEQ ID NO.16。
其中,RGD4C可被其它包含RGD序列的可靶向结合αvβ3的短肽序列替换。PLGI可被其它MMP9识别并酶切底物肽序列替换,其共同特点为包含有GI序列,以保证经MMP9酶切后,释放的水蛭素N末端的氨基酸为I。Linker1的长度为2~15个氨基酸。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例9
本实施方式的重组水蛭素是人白蛋白与N末端氨基酸是I的水蛭素异构体HV2通过寡肽PLG连接而成的融合蛋白HPH2(HSA-PLG-HV2),HPH2氨基酸序列为:SEQ ID NO.17,基因序列为:SEQ ID NO.18
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例10
本实施方式的重组水蛭素是人白蛋白与N末端氨基酸是I的水蛭素异构体HV3通过寡肽PLG连接而成的融合蛋白HPH3(HSA-PLG-HV3),HPH3氨基酸序列为:SEQ ID NO.19,基因序列为:SEQ ID NO.20。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例11
本实施方式的重组水蛭素,是人嵌合免疫球蛋白Fc段与N末端氨基酸是I的水蛭素异构体HV2通过寡肽PLG连接而成的融合蛋白FPH2(Fc-PLG-HV2),人嵌合免疫球蛋白Fc段包含人IgG4铰链区、Fc段序列和IgM尾片序列,FPH2氨基酸序列为:SEQ ID NO.21,基因序列为:SEQ ID NO.22。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例12
本实施方式的重组水蛭素,是人嵌合免疫球蛋白Fc段与N末端氨基酸是I的水蛭素异构体HV3通过寡肽PLG连接而成的融合蛋白FPH3(Fc-PLG-HV3),人嵌合免疫球蛋白Fc段包含人IgG4铰链区、Fc段序列和IgM尾片序列,FPH3氨基酸序列为:SEQ ID NO.23,基因序列为:SEQ ID NO.24。
该肿瘤特异性重组水蛭素在制备防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物中的应用。
实施例13
本实施例的肿瘤特异性重组水蛭素的制备方法,包括以下步骤:化学合成上述实施例1~12任一的肿瘤特异性重组水蛭素基因片段,并将其连接成编码基因,将编码基因***载体中制备重组载体,用该重组载体转化或转染宿主细胞,宿主细胞为大肠杆菌、乳酸菌、酵母、昆虫细胞或哺乳动物细胞,培养宿主细胞,之后离心收集上清液,经超滤浓缩、凝胶过滤、离子交换三步法纯化获得肿瘤特异性重组水蛭素。
本实施例用于重组的载体优选的为真核表达载体,采用pPIC9K。宿主细胞为甲醇营养型酵母菌株GS115。
宿主细胞GS115的发酵方法为:用低盐培养基扩增工程菌,诱导前用含微量元素的甘油溶液进行补料,培养增殖后,用含微量元素的甲醇溶液进行诱导表达,发酵参数为:温度30℃、氧容量控制在35±5%、pH=5、搅拌速度与DO连动。
实施例14
表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法是将人源分泌型信号肽编码基因与上述实施例1~12任一的肿瘤特异性重组水蛭素的编码基因相连,制备成重组基因载体,转染免疫细胞,获得表达肿瘤特异性重组水蛭素的过继免疫细胞。
过继免疫细胞的膜表面表达有靶标分子,靶标分子通过跨膜序列定位在细胞膜表面。该过继免疫细胞的膜表面表达有靶标分子,靶标分子通过跨膜序列定位在细胞膜表面。靶标分子为CD19的全长或其截短片段,或CD20的全长或其截短片段。
本实施例的表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法包括步骤S1~S3,具体如下。
S1、体外培养人源CIK细胞,包括步骤A的外周血单个核细胞(PBMC)采集和步骤B的CIK细胞培养。
A、外周血单个核细胞的采集具有以下步骤:
A1、自患者体内抽取外周血50-100ml;
A2、淋巴细胞分离液密度梯度离心法进一步纯化PBMC;
A3、无血清培养液洗涤2次,获得纯度在90%以上的PBMC。
B、CIK细胞的培养:
B1、将PBMC按1~2×106/ml的浓度悬浮于无血清培养液中,加入1,000U/ml的重组人IFN-γ,37℃,5%CO2培养箱中培养;
B2、24h后加入50ng/ml的CD3单克隆抗体和300U/ml的重组人IL-2,刺激CIK细胞的生长和增殖;
注:此时也可同时加入100U/ml的重组人IL-1α。
B3、每3天半量换液或扩瓶一次,并补加重组人IL-2 300U/ml;
B4、在培养的第14d,收获CIK细胞。
其中,细胞培养基中还可添加5%~20%的自体血清。
S2、制备重组基因载体.
本实施列采用肿瘤特异性重组水蛭素RPH2(RGD4C-PGR-HV2)基因序列,融合蛋白RPH2的氨基酸序列为:SEQ ID NO.13,基因序列为:SEQ ID NO.14。依照肿瘤特异性重组水蛭素RPH2的基因序列,在其N末端添加人酰胺化酶信号肽序列,其氨基酸序列为:SEQ IDNO.25,基因序列为SEQ ID NO.26。化学合成基因片段,将其连接成重组编码基因,N端添加NheⅠ限制性酶切位点,C端添加EcoRⅠ限制性酶切位点。
本实施列采用靶标分子结构为:GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段,其氨基酸序列为:SEQ ID NO.27,基因序列为SEQ ID NO.28。化学合成基因片段,N端添加BamHⅠ限制性酶切位点,C端添加NotⅠ限制性酶切位点。
应用基因工程技术制备编码肿瘤特异性重组水蛭素和膜型分子靶标的基因载体,将信号肽序列-肿瘤特异性重组水蛭素序列和信号肽序列-靶标分子序列-Linker-跨膜段序列两段基因分别克隆入pIRES质粒的两个克隆位点。所用基因工程技术为公知技术,简述如下:
按照已有的方法建立标准的限制性内切酶消化体系,然后利用NheⅠ和EcoRⅠ处理pIRES质粒,回收大片段;利用相同的限制性内切酶NheⅠ和EcoRⅠ处理并回收重组肿瘤特异性水蛭素RPH基因片段,然后与上述酶切好的载体pIRES大片段相连,构建出重组肿瘤特异性水蛭素表达质粒pIRES-RPH;转化大肠杆菌DH5α后,筛选出阳性克隆并扩增。
纯化pIRES-RPH2质粒,然后利用BamHⅠ和NotⅠ处理pIRES-RPH2质粒,回收大片段;利用相同的限制性内切酶BamHⅠ和NotⅠ处理并回收重组GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段基因片段,然后与上述酶切好的pIRES-RPH2载体大片段相连,构建出同时表达重组肿瘤特异性水蛭素和膜型分子靶标CD20的双表达质粒pIRES-RPH2/CD20。转化大肠杆菌DH5α后,筛选出阳性克隆并扩增,纯化pIRES-RPH2/CD20质粒。
S3、纯化经步骤S2得到的pIRES-RPH2/CD20重组质粒,用该重组载体以质粒电转染方法转染步骤S1得到的CIK细胞,之后进行细胞培养36h以上,得到表达重组水蛭素的CIK细胞,经流式细胞仪检测获得转染率,根据临床需要计算所需阳性细胞数量,回输肿瘤患者。
该表达肿瘤特异性重组水蛭素的CIK细胞,用于抗凝、抗血栓、防治肿瘤的生物治疗,尤其是防治伴有高凝状态和/或血栓的肿瘤患者的生物治疗。
以上所述的仅是本发明的一些实施方式。对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
序 列 表
<110>何向锋
<120>一种肿瘤特异性重组水蛭素及其制备方法和用途
<160>28
<210>1
<211>68
<212>PRT
<213>人工序列
<400>1
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu Gly Ser Asn Gly Glu Glu Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Asn Gly Asp Phe Glu
50 55 60
Glu Ile Pro Glu Glu Tyr Leu Gln
65
<210>2
<211>207
<212>DNA
<213>人工序列
<400>2
cccttaggta ttacttacac tgattgtaca gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgcggtaa aggcaataag tgcatattgg gttctaatgg agaggaaaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataataacgg cgatttcgaa 180
gaaattccag aagaatattt acaatga 207
<210>3
<211>70
<212>PRT
<213>人工序列
<400>3
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Ile Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu Gly Ser Asn Gly Lys Asp Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Gln Gly Asp Phe Glu
50 55 60
Pro Ile Pro Glu Asp Ala Tyr Asp Glu Lys
65 70
<210>4
<211>213
<212>DNA
<213>人工序列
<400>4
cccttaggta ttacttacac tgattgtata gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgtggtaa aggcaataag tgcatattgg gttctaatgg aaaggacaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataatcaagg cgatttcgaa 180
ccaattccag aagacgctta tgatgaaaaa tga 213
<210>5
<211>68
<212> PRT
<213>人工序列
<400>5
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu Gly Arg Gly Asp Ser Glu Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Asn Gly Asp Phe Glu
50 55 60
Glu Ile Pro Glu Glu Tyr Leu Gln
65
<210>6
<211>207
<212> DNA
<213>人工序列
<400>6
cccttaggta ttacttacac tgattgtaca gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgcggtaa aggcaataag tgcatattgg gtcgcggaga ttctgaaaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataataacgg cgatttcgaa 180
gaaattccag aagaatattt acaatga 207
<210>7
<211>70
<212> PRT
<213>人工序列
<400>7
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Ile Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu GlyArg Gly Asp Ser Asp Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Gln Gly Asp Phe Glu
50 55 60
Pro Ile Pro Glu Asp Ala Tyr Asp Glu Lys
65 70
<210>8
<211>213
<212> DNA
<213>人工序列
<400>8
cccttaggta ttacttacac tgattgtata gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgtggtaa aggcaataag tgcatattgg gtcgcggaga ttctgacaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataatcaagg cgatttcgaa 180
ccaattccag aagacgctta tgatgaaaaa tga 213
<210>9
<211>68
<212> PRT
<213>人工序列
<400>9
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu Gly Arg Gly Asp Met Glu Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Asn Gly Asp Phe Glu
50 55 60
Glu Ile Pro Glu Glu Tyr Leu Gln
65
<210>10
<211>207
<212> DNA
<213>人工序列
<400>10
cccttaggta ttacttacac tgattgtaca gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgcggtaa aggcaataag tgcatattgg gtcgcggaga tatggaaaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataataacgg cgatttcgaa 180
gaaattccag aagaatattt acaatga 207
<210>11
<211>70
<212> PRT
<213>人工序列
<400>11
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Ile Glu Ser Gly Gln Asn
5 10 15
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
20 25 30
Cys Ile Leu Gly Arg Gly Asp Met Asp Asn Gln Cys Val Thr Gly
35 40 45
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Gln Gly Asp Phe Glu
50 55 60
Pro Ile Pro Glu Asp Ala Tyr Asp Glu Lys
65 70
<210>12
<211>213
<212> DNA
<213>人工序列
<400>12
cccttaggta ttacttacac tgattgtata gaatcgggtc aaaatttgtg cctctgcgag 60
ggaagcaatg tttgtggtaa aggcaataag tgcatattgg gtcgcggaga tatggacaac 120
caatgtgtca ctggcgaagg tacaccgaag cctcaaagcc ataatcaagg cgatttcgaa 180
ccaattccag aagacgctta tgatgaaaaa tga 213
<210>13
<211>109
<212> PRT
<213>人工序列
<400>13
Met Glu Phe Trp Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys
5 10 15
Gly Val Gln Cys Ala Cys Asp CysArg Gly Asp Cys Phe Cys Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Pro Leu Gly Ile
35 40 45
Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn Leu Cys Leu Cys
50 55 60
Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys Cys Ile Leu Gly
65 70 75
Ser Asn Gly Glu Glu Asn Gln Cys Val Thr Gly Glu Gly Thr Pro
80 85 90
Lys Pro Gln Ser His Asn Asn Gly Asp Phe Glu Glu Ile Pro Glu
95 100 105
Glu Tyr Leu Gln
<210>14
<211>330
<212> DNA
<213>人工序列
<400>14
atggagtttt ggctgagctg ggttttcctt gttgctattt taaaaggtgt ccagtgtgca 60
tgtgattgta ggggagattg tttttgtggt agcggtggcg gtggctctgg tggtggtggc 120
agccccttag gtattactta cactgattgt acagaatcgg gtcaaaattt gtgcctctgc 180
gagggaagca atgtttgcgg taaaggcaat aagtgcatat tgggttctaa tggagaggaa 240
aaccaatgtg tcactggcga aggtacaccg aagcctcaaa gccataataa cggcgatttc 300
gaagaaattc cagaagaata tttacaatga 330
<210>15
<211>111
<212> PRT
<213>人工序列
<400>15
Met Glu Phe Trp Leu Ser Trp Val Phe Leu Val Ala Ile Leu Lys
5 10 15
Gly Val Gln Cys Ala Cys Asp CysArg Gly Asp Cys Phe Cys Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Pro Leu Gly Ile
35 40 45
Thr Tyr Thr Asp Cys Ile Glu Ser Gly Gln Asn Leu Cys Leu Cys
50 55 60
Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys Cys Ile Leu Gly
65 70 75
Ser Asn Gly Lys Asp Asn Gln Cys Val Thr Gly Glu Gly Thr Pro
80 85 90
Lys Pro Gln Ser His Asn Gln Gly Asp Phe Glu Pro Ile Pro Glu
95 100 105
Asp Ala Tyr Asp Glu Lys
110
<210>16
<211>336
<212> DNA
<213>人工序列
<400>16
atggagtttt ggctgagctg ggttttcctt gttgctattt taaaaggtgt ccagtgtgca 60
tgtgattgta ggggagattg tttttgtggt agcggtggcg gtggctctgg tggtggtggc 120
agccccttag gtattactta cactgattgt atagaatcgg gtcaaaattt gtgcctctgc 180
gagggaagca atgtttgtgg taaaggcaat aagtgcatat tgggttctaa tggaaaggac 240
aaccaatgtg tcactggcga aggtacaccg aagcctcaaa gccataatca aggcgatttc 300
gaaccaatc cagaagacgc ttatgatgaa aaatga 336
<210>17
<211>653
<212> PRT
<213>人工序列
<400>17
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly
5 10 15
Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr
20 25 30
Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu
35 40 45
Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
50 55 60
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys
65 70 75
Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys
80 85 90
Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His
95 100 105
Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
110 115 120
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
125 130 135
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
140 145 150
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe
155 160 175
Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
180 185 190
Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys
195 200 205
Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala
210 215 220
Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys
225 230 235
Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
240 245 250
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp
255 260 265
Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser
270 275 280
Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu
285 290 295
Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
300 305 310
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val
315 320 325
Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe
330 335 340
Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu
345 350 355
Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
360 365 370
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp
375 380 385
Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
390 395 400
Asn Cys Glu Leu Phe Lys Gln Leu Gly Glu Tyr Lys Phe Gln Asn
405 410 415
Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
420 425 430
Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser
435 440 445
Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu
450 455 450
Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu
455 460 465
Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu
485 490 495
Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His
500 505 510
Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
515 520 525
Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
530 535 540
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val
545 550 555
Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
560 565 570
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
575 580 585
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Thr Glu Ser Gly Gln Asn
590 595 600
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
605 610 615
Cys Ile Leu Gly Ser Asn Gly Glu Glu Asn Gln Cys Val Thr Gly
620 625 630
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Asn Gly Asp Phe Glu
635 640 645
Glu Ile Pro Glu Glu Tyr Leu Gln
650
<210>18
<211>336
<212> DNA
<213>人工序列
<400>18
gatgcacaca agagtgaggt tgctcatcgg tttaaagatt tgggagaaga aaatttcaaa 60
gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120
aaattagtga atgaagtaac tgaatttgca aaaacatgtg tagctgatga gtcagctgaa 180
aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240
cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300
tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360
gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420
gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480
tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540
aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaaatgt 600
gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtggc tcgcctgagc 660
cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720
gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780
gccaagtata tctgtgaaaa tcaggattcg atctccagta aactgaagga atgctgtgaa 840
aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900
gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960
gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020
tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactcta gagaagtgc 1080
tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140
gtggaagagc ctcagaattt aatcaaacaa aactgtgagc tttttaagca gcttggagag 1200
tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260
ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320
cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380
tgtgtgttgc atgagaaaac gccagtaagt gacagagtca caaaatgctg cacagagtcc 1440
ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500
gagtttaatg ctgaaacatt caccttccat gcagatatatg cacactttct gagaaggag 1560
agacaaatca agaaacaaac tgcacttgtt gagcttgtga aacacaagcc caaggcaaca 1620
aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680
gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc tgcaagtcaa 1740
gctgccttag gcttaccctt aggtattact tacactgatt gtacagaatc gggtcaaaat 1800
ttgtgcctctg cgagggaa gcaatgtttgc ggtaaaggca ataagtgcat attgggttct 1860
aatggagagg aaaaccaatg tgtcactggc gaaggtacac cgaagcctcaa agccataat 1920
aacggcgatt tcgaagaaat tccagaagaa tatttacaat ga 1962
<210>19
<211>655
<212> PRT
<213>人工序列
<400>19
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly
5 10 15
Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr
20 25 30
Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu
35 40 45
Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
50 55 60
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys
65 70 75
Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys
80 85 90
Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His
95 100 105
Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
110 115 120
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
125 130 135
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
140 145 150
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe
155 160 165
Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
170 175 180
Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys
185 190 195
Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala
200 205 210
Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys
215 220 225
Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp
245 250 255
Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser
260 265 270
Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu
275 280 285
Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
290 295 300
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val
305 310 315
Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe
320 325 330
Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu
335 340 345
Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
350 355 360
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp
365 370 375
Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
380 385 390
Asn Cys Glu Leu Phe Lys Gln Leu Gly Glu Tyr Lys Phe Gln Asn
405 410 415
Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
420 425 430
Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser
435 440 445
Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu
450 455 450
Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu
455 460 465
Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu
485 490 495
Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His
500 505 510
Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
515 520 525
Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
530 535 540
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val
545 550 555
Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
560 565 570
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
575 580 585
Pro Leu Gly Ile Thr Tyr Thr Asp Cys Ile Glu Ser Gly Gln Asn
590 595 600
Leu Cys Leu Cys Glu Gly Ser Asn Val Cys Gly Lys Gly Asn Lys
605 610 615
Cys Ile Leu Gly Ser Asn Gly Lys Asp Asn Gln Cys Val Thr Gly
620 625 630
Glu Gly Thr Pro Lys Pro Gln Ser His Asn Gln Gly Asp Phe Glu
635 640 645
Pro Ile Pro Glu Asp Ala Tyr Asp Glu Lys
650
<210>20
<211>336
<212> DNA
<213>人工序列
<400>20
gatgcacaca agagtgaggt tgctcatcgg tttaaagatt tgggagaaga aaatttcaaa 60
gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120
aaattagtga atgaagtaac tgaatttgca aaaacatgtg tagctgatga gtcagctgaa 180
aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240
cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300
tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360
gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420
gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480
tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540
aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaaatgt 600
gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtggc tcgcctgagc 660
cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720
gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780
gccaagtata tctgtgaaaa tcaggattcg atctccagta aactgaagga atgctgtgaa 840
aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900
gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960
gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020
tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactcta gagaagtgc 1080
tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140
gtggaagagc ctcagaattt aatcaaacaa aactgtgagc tttttaagca gcttggagag 1200
tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260
ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320
cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380
tgtgtgttgc atgagaaaac gccagtaagt gacagagtca caaaatgctg cacagagtcc 1440
ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500
gagtttaatg ctgaaacatt caccttccat gcagatatatg cacactttct gagaaggag 1560
agacaaatca agaaacaaac tgcacttgtt gagcttgtga aacacaagcc caaggcaaca 1620
aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680
gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc tgcaagtcaa 1740
gctgccttag gcttaccctt aggtattact tacactgatt gtatagaatc gggtcaaaat 1800
ttgtgcctct gcgagggaag caatgtttgt ggtaaaggca ataagtgcat attgggttct 1860
aatggaaagg acaaccaatg tgtcactggc gaaggtacac cgaagcctca aagccataat 1920
caaggcgatt tcgaaccaat tccagaagac gcttatgatg aaaaatga 1968
<210>21
<211>313
<212> PRT
<213>人工序列
<400>21
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
5 10 15
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
65 70 75
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
80 85 90
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
95 100 105
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
110 115 120
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
125 130 135
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
140 145 150
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
155 160 165
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
170 175 180
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
185 190 195
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
200 205 200
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
215 220 225
Ser Leu Gly Lys Pro Thr Leu Tyr Asn Val Ser Leu Val Met Ser
230 235 240
Asp Thr Ala Gly Thr Pro Leu Gly Ile Thr Tyr Thr Asp Cys Thr
245 250 255
Glu Ser Gly Gln Asn Leu Cys Leu Cys Glu Gly Ser Asn Val Cys
260 265 270
Gly Lys Gly Asn Lys Cys Ile Leu Gly Ser Asn Gly Glu Glu Asn
275 280 285
Gln Cys Val Thr Gly Glu Gly Thr Pro Lys Pro Gln Ser His Asn
290 295 300
Asn Gly Asp Phe Glu Glu Ile Pro Glu Glu Tyr Leu Gln
300 310
<210>22
<211>942
<212> DNA
<213>人工序列
<400>22
gaatctaagt acggccctcc ctgcccaccc tgtcctgctc cagagtttct gggcggaccc 60
tccgtgttcc tgttcccccc aaagcccaag gacaccctga tgatctcccg gacccccgaa 120
gtgacctgcg tggtggtgga cgtgtcccag gaagatcccg aggtccagtt caattggtac 180
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttcaactcc 240
acctaccggg tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagag 300
tacaagtgca aggtctccaa caagggcctg ccctccagca tcgaaaagac catctccaag 360
gccaagggcc agccccgcga gcctcaggtg tacacactgc cccctagcca agaagagatg 420
accaagaacc aggtgtccct gacatgcctg gtgaagggct tctacccctc cgatatcgcc 480
gtggaatggg agtccaacgg ccagcccgag aacaactaca agaccacccc ccctgtgctg 540
gactccgacg gctccttctt cctgtactct cggctgaccg tggacaagtc ccggtggcag 600
gaaggcaacg tcttctcctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 660
aagtctctga gcctgtccct gggcaagccc accctgtaca acgtgtccct ggtcatgtcc 720
gacacagctg gcaccccctt aggtattact tacactgatt gtacagaatc gggtcaaaat 780
ttgtgcctct gcgagggaag caatgtttgc ggtaaaggca ataagtgcat attgggttct 840
aatggagagg aaaaccaatg tgtcactggc gaaggtacac cgaagcctca aagccataat 900
aacggcgatt tcgaagaaat tccagaaga atatttacaat ga 942
<210>23
<211>315
<212> PRT
<213>人工序列
<400>23
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
5 10 15
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
20 25 30
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
65 70 75
Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
80 85 90
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
95 100 105
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
110 115 120
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
125 130 135
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
140 145 150
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
155 160 165
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
170 175 180
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
185 190 195
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
200 205 200
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
215 220 225
Ser Leu Gly Lys Pro Thr Leu Tyr Asn Val Ser Leu Val Met Ser
230 235 240
Asp Thr Ala Gly Thr Pro Leu Gly Ile Thr Tyr Thr Asp Cys Ile
245 250 255
Glu Ser Gly Gln Asn Leu Cys Leu Cys Glu Gly Ser Asn Val Cys
260 265 270
Gly Lys Gly Asn Lys Cys Ile Leu Gly Ser Asn Gly Lys Asp Asn
275 280 285
Gln Cys Val Thr Gly Glu Gly Thr Pro Lys Pro Gln Ser His Asn
290 295 300
Gln Gly Asp Phe Glu Pro Ile Pro Glu Asp Ala Tyr Asp Glu Lys
305 310 315
<210>24
<211>948
<212> DNA
<213>人工序列
<400>24
gaatctaagt acggccctcc ctgcccaccc tgtcctgctc cagagtttct gggcggaccc 60
tccgtgttcc tgttcccccc aaagcccaag gacaccctga tgatctcccg gacccccgaa 120
gtgacctgcg tggtggtgga cgtgtcccag gaagatcccg aggtccagtt caattggtac 180
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gttcaactcc 240
acctaccggg tggtgtctgt gctgaccgtg ctgcaccagg actggctgaa cggcaaagag 300
tacaagtgca aggtctccaa caagggcctg ccctccagca tcgaaaagac catctccaag 360
gccaagggcc agccccgcga gcctcaggtg tacacactgc cccctagcca agaagagatg 420
accaagaacc aggtgtccct gacatgcctg gtgaagggct tctacccctc cgatatcgcc 480
gtggaatggg agtccaacgg ccagcccgag aacaactaca agaccacccc ccctgtgctg 540
gactccgacg gctccttctt cctgtactct cggctgaccg tggacaagtc ccggtggcag 600
gaaggcaacg tcttctcctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 660
aagtctctga gcctgtccct gggcaagccc accctgtaca acgtgtccct ggtcatgtcc 720
gacacagctg gcaccccctt aggtattact tacactgatt gtatagaatc gggtcaaaat 780
ttgtgcctct gcgagggaag caatgtttgt ggtaaaggca ataagtgcat attgggttct 840
aatggaaagg acaaccaatg tgtcactggc gaaggtacac cgaagcctca aagccataat 900
caaggcgatt tcgaaccaat tccagaagac gcttatgatg aaaaatga 948
<210>25
<211>20
<212> PRT
<213>人工序列
<400>25
Met Ala Gly Arg Val Pro Ser Leu Leu Val Leu Leu Val Phe Pro
5 10 15
Ser Ser Cys Leu Ala
20
<210>26
<211>60
<212> DNA
<213>人工序列
<400>26
atggctggcc gcgtccctag cctgctagtt ctccttgttt ttccaagcag ctgtttggct 60
<210>27
<211>83
<212> PRT
<213>人工序列
<400>27
Met Val Leu Ala Gln Gly Leu Leu Ser Met Ala Leu Leu Ala Leu
5 10 15
Cys Trp Glu Arg Ser Leu Ala Asn Ile Tyr Asn Cys Glu Pro Ala
20 25 30
Asn Pro Ser Glu Lys Asn Ser Pro Ser Thr Gln Tyr Cys Tyr Ser
35 40 45
Ile Gln Ser Gly Gly Ser Gly Gly Pro Phe Trp Val Leu Val Val
50 55 60
Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala
65 70 75
Phe Ile Ile Phe Trp Val Arg Ser
80
<210>28
<211>252
<212> DNA
<213>人工序列
<400>28
atggtgctgg cccaggggct gctctccatg gccctgctgg ccctgtgctg ggagcgcagc 60
ctggcaaaca tatacaactg tgaaccagct aatccctctg agaaaaactc cccatctacc 120
caatactgtt acagcataca atctggcgga agcggaggcc ccttttgggt gctggtggtg 180
gttggtggag tcctggcttg ctatagcttg ctagtaacag tggcctttat tattttctgg 240
gtgaggagtt aa 252
Claims (12)
1.一种肿瘤特异性重组水蛭素,其特征在于,所述重组水蛭素的N末端含有可被MMP9识别并裂解的寡肽序列,用于重组的水蛭素为水蛭素异构体、水蛭素突变体、水蛭素嵌合体、截短的水蛭肽、基因修饰的水蛭素或水蛭素融合蛋白。
2.根据权利要求1所述的肿瘤特异性重组水蛭素,其特征在于,所述寡肽序列为可被MMP9识别并裂解的短肽,其结构特征为XnGI,Xn代表任意数量的任意氨基酸。
3.根据权利要求1所述的肿瘤特异性重组水蛭素,其特征在于,所述重组水蛭素是在水蛭素异构体HV2或HV3的N末端修饰有寡肽PLG,与水蛭素异构体HV2或HV3的N末端的异亮氨酸共同组成MMP9识别并酶切的底物肽序列PLGI,重组水蛭素PLG-HV2氨基酸序列为:SEQ IDNO.1,基因序列为:SEQ ID NO.2,重组水蛭素PLG-HV3氨基酸序列为:SEQ ID NO.3,基因序列为:SEQ ID NO.4;
或者,所述重组水蛭素,是将野生型水蛭素HV2或HV3肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Ser35,再在其N末端修饰PLG寡肽,所述重组水蛭素PLG-HV2-RGDS氨基酸序列为:SEQ ID NO.5,基因序列为:SEQ ID NO.6,重组水蛭素PLG-HV3-RGDS氨基酸序列为:SEQ ID NO.7,基因序列为:SEQ ID NO.8;
或者,所述重组水蛭素,是将野生型水蛭素HV2或HV3肽链的Ser32-Asn33-Gly34-Glu35替换为Arg32-Gly33-Asp34-Met35,再在其N末端修饰PLG寡肽,所述重组水蛭素PLG-HV2-RGDM氨基酸序列为:SEQ ID NO.9,基因序列为:SEQ ID NO.10,重组水蛭素PLG-HV3-RGDM氨基酸序列为:SEQ ID NO.11,基因序列为:SEQ ID NO.12;
或者,所述重组水蛭素,是靶向整合素αvβ3的多肽RGD4C与N末端氨基酸是I的水蛭素异构体HV2或HV3通过Linker和寡肽PLG连接而成的融合蛋白RPH2,或RPH3,RPH2氨基酸序列为:SEQ ID NO.13,基因序列为:SEQ ID NO.14,RPH3氨基酸序列为:SEQ ID NO.15,基因序列为:SEQ ID NO.16;
或者,所述重组水蛭素,是人白蛋白与N末端氨基酸是I的水蛭素异构体HV2或HV3通过寡肽PLG连接而成的融合蛋白HPH2,或HPH3,HPH2氨基酸序列为:SEQ ID NO.17,基因序列为:SEQ ID NO.18,HPH3氨基酸序列为:SEQ ID NO.19,基因序列为:SEQ ID NO.20;
或者,所述重组水蛭素,是人嵌合免疫球蛋白Fc段与N末端氨基酸是I的水蛭素异构体HV2或HV3通过寡肽PLG连接而成的融合蛋白FPH2,或FPH3,人嵌合免疫球蛋白Fc段包含人IgG4铰链区、Fc段序列和IgM尾片序列,FPH2氨基酸序列为:SEQ ID NO.21,基因序列为:SEQID NO.22,FPH3氨基酸序列为:SEQ ID NO.23,基因序列为:SEQ ID NO.24。
4.肿瘤特异性重组水蛭素的制备方法,其特征在于,包括以下步骤:化学合成权利要求1~3任一项的肿瘤特异性重组水蛭素基因片段,在其N末端连接信号肽序列,并在重组编码基因的两端添加限制性酶切位点,将编码基因***载体中制备重组载体,用该重组载体转化或转染宿主细胞,培养宿主细胞,并从中回收和纯化该肿瘤特异性重组水蛭素,宿主细胞为大肠杆菌、乳酸菌、酵母菌、昆虫细胞或哺乳动物细胞。
5.权利要求1~3任一项所述的肿瘤特异性重组水蛭素在制备抗凝、抗血栓、防治肿瘤的药物中的应用,尤其是防治肿瘤伴发高凝状态和血栓性病变的药物、保健品和功能性食品中的应用。
6.表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法,其特征在于,体外培养人源免疫细胞,将人源分泌型信号肽编码基因与权利要求1~3任一项的肿瘤特异性重组水蛭素的编码基因相连,并在重组编码基因的两端添加限制性酶切位点,将编码基因***载体中制备成重组基因载体,转染免疫细胞,获得表达肿瘤特异性重组水蛭素的过继免疫细胞。
7.根据权利要求6所述的表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法,其特征在于,所述人源分泌型信号肽为人酰胺化酶信号肽,氨基酸序列为:SEQ ID NO.25,基因序列为:SEQ ID NO.26。
8.根据权利要求6所述的表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法,其特征在于,所述免疫细胞为αβT、γδT、NKT、NK、DC、CIK、CAR-T、CAR-NK、TCR-T中的一种或多种,所述免疫细胞为人源免疫细胞。
9.根据权利要求6所述的表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法,其特征在于,所述过继免疫细胞的膜表面表达有靶标分子,靶标分子通过跨膜序列定位在细胞膜表面。
10.根据权利要求9所述的表达水蛭素的过继免疫细胞,其特征在于,所述靶标分子为CD19的全长或其截短片段,或CD20的全长或其截短片段。
11.根据权利要求10所述的表达肿瘤特异性重组水蛭素的过继免疫细胞制备方法,其特征在于,所述靶标分子及跨膜段的结构为:GM-CSFR信号肽-ΔCD20-Linker2-CD28跨膜段,其氨基酸序列为:SEQ ID NO.27,基因序列为SEQ ID NO.28。
12.权利要求6所述的表达肿瘤特异性重组水蛭素的过继免疫细胞,用于抗凝、抗血栓、防治肿瘤的生物治疗,尤其是防治伴有高凝状态和/或血栓的肿瘤患者的生物治疗。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710362102.1A CN107098964A (zh) | 2017-05-19 | 2017-05-19 | 一种肿瘤特异性重组水蛭素及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710362102.1A CN107098964A (zh) | 2017-05-19 | 2017-05-19 | 一种肿瘤特异性重组水蛭素及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107098964A true CN107098964A (zh) | 2017-08-29 |
Family
ID=59669304
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710362102.1A Pending CN107098964A (zh) | 2017-05-19 | 2017-05-19 | 一种肿瘤特异性重组水蛭素及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107098964A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115572329A (zh) * | 2021-06-21 | 2023-01-06 | 王大勇 | 一组活性增强代谢较慢的菲牛蛭基因重组水蛭素及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1371994A (zh) * | 2001-02-20 | 2002-10-02 | 王革 | 用酵母分泌表达重组水蛭素 |
CN1428173A (zh) * | 2001-12-25 | 2003-07-09 | 重庆富进生物医药有限公司 | 重组水蛭素口服肠溶缓释制剂 |
CN102153646A (zh) * | 2010-12-31 | 2011-08-17 | 中国药科大学 | 新型双作用靶点重组水蛭素突变体的优化设计与应用 |
-
2017
- 2017-05-19 CN CN201710362102.1A patent/CN107098964A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1371994A (zh) * | 2001-02-20 | 2002-10-02 | 王革 | 用酵母分泌表达重组水蛭素 |
CN1428173A (zh) * | 2001-12-25 | 2003-07-09 | 重庆富进生物医药有限公司 | 重组水蛭素口服肠溶缓释制剂 |
CN102153646A (zh) * | 2010-12-31 | 2011-08-17 | 中国药科大学 | 新型双作用靶点重组水蛭素突变体的优化设计与应用 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115572329A (zh) * | 2021-06-21 | 2023-01-06 | 王大勇 | 一组活性增强代谢较慢的菲牛蛭基因重组水蛭素及其制备方法 |
CN115572329B (zh) * | 2021-06-21 | 2024-02-06 | 王大勇 | 一组活性增强代谢较慢的菲牛蛭基因重组水蛭素及其制备方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20190216898A1 (en) | Interleukin Combination and Use Thereof | |
CN108135968A (zh) | 嵌合多肽组装体及其制备和使用方法 | |
CN107709356A (zh) | 用于肿瘤特异性活化的掩蔽嵌合抗原受体t细胞 | |
KR20190019220A (ko) | 항-전이성 요법에서 axl 신호전달의 저해 | |
CN102470156A (zh) | 选择性作用于αvβ3整合素并缀合人血清白蛋白(HSA)变体的多肽及其药学用途 | |
CN107034235A (zh) | 联合靶向pd‑1及egfr的嵌合性抗原t细胞肿瘤免疫方法 | |
CN109576217A (zh) | 调节干细胞的免疫调节作用的方法 | |
CZ302303B6 (cs) | Homodimerní fúzní protein vykazující inhibicní aktivitu na angiogenezi, zpusob jeho produkce, molekula DNA a replikovatelný expresní vektor | |
CN105722860A (zh) | 白介素-2融合蛋白及其应用 | |
ES2799153T3 (es) | Alfa 1 antitripsina para uso en la preparación de un sujeto para trasplante | |
WO2019214757A1 (es) | Proteínas de fusión compuestas por una muteina de interleucina-2 e interferon tipo 1 | |
CN105722982A (zh) | 白介素-4受体结合融合蛋白及其应用 | |
CN1643140A (zh) | 生长因子和蛋白酶的组合 | |
CN108300699A (zh) | 修饰的nk细胞及其用途 | |
CN105531284A (zh) | 细胞穿透肽和包含其的缀合物 | |
US20240207316A1 (en) | Chimeric receptor for improving killing activity of immune cells and application thereof | |
CN104394880A (zh) | 用于调节toso活性的方法和组合物 | |
CN108341881A (zh) | 带安全开关的嵌合抗原受体及其表达基因、其修饰的nk细胞及应用 | |
TW201609793A (zh) | 去整合蛋白變異體及其醫藥用途 | |
CN113416260A (zh) | 靶向Claudin18.2的特异性嵌合抗原受体细胞及其制备方法和应用 | |
WO2017071173A1 (zh) | 经il-12/cd62l融合蛋白改造的肿瘤治疗剂及其制法和用途 | |
EA037256B1 (ru) | Химерный белок мочевого трипсинового ингибитора (мти), содержащий домен мти и fc-домен igg1 | |
US20050063948A1 (en) | Methods for targeting interleukin-12 to malignant endothelium | |
CN108395480A (zh) | 嵌合抗原受体及其基因和重组表达载体、carher2-nkt细胞及其制备方法和应用 | |
CN111499766B (zh) | 针对慢性淋巴细胞白血病的免疫效应细胞、其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20180807 Address after: 211100 568 dragon sleeping Avenue, Jiangning District, Nanjing, Jiangsu (Jiangning Gao Xinyuan) Applicant after: New key (Nanjing) Biotechnology Co., Ltd. Address before: 226000 7 yuan 205, Chen Yuan District, Chongchuan District, Nantong, Jiangsu Applicant before: He Xiangfeng |
|
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170829 |