IE67124B1 - A synthetic vaccine against foot and mouth disease and a process for the preparation thereof - Google Patents
A synthetic vaccine against foot and mouth disease and a process for the preparation thereofInfo
- Publication number
- IE67124B1 IE67124B1 IE129689A IE129689A IE67124B1 IE 67124 B1 IE67124 B1 IE 67124B1 IE 129689 A IE129689 A IE 129689A IE 129689 A IE129689 A IE 129689A IE 67124 B1 IE67124 B1 IE 67124B1
- Authority
- IE
- Ireland
- Prior art keywords
- synthetic vaccine
- membrane
- mouth disease
- foot
- vaccine
- Prior art date
Links
- 229940126577 synthetic vaccine Drugs 0.000 title claims abstract description 20
- 241000710198 Foot-and-mouth disease virus Species 0.000 title claims abstract description 17
- 208000007212 Foot-and-Mouth Disease Diseases 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000004873 anchoring Methods 0.000 claims abstract description 27
- 229960005486 vaccine Drugs 0.000 claims abstract description 18
- 230000021615 conjugation Effects 0.000 claims abstract description 7
- 241000700605 Viruses Species 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 101900061472 Foot-and-mouth disease virus Capsid protein VP1 Proteins 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 229960005030 other vaccine in atc Drugs 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 abstract description 6
- 102000004169 proteins and genes Human genes 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 239000012528 membrane Substances 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 108010028921 Lipopeptides Proteins 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- YNJBLTDKTMKEET-ZLUOBGJFSA-N Cys-Ser-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O YNJBLTDKTMKEET-ZLUOBGJFSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 101150052863 THY1 gene Proteins 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940028617 conventional vaccine Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229940028435 intralipid Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- KKNIUBFRGPFELP-UHFFFAOYSA-N secretolin Chemical compound N=1C=CNC=1CC(N)C(=O)NC(CO)C(=O)NC(CC(O)=O)C(=O)NCC(=O)NC(C(C)O)C(=O)NC(C(=O)NC(C(=O)NC(CO)C(=O)NC(CCC(O)=O)C(=O)NC(CC(C)C)C(=O)NC(CO)C(=O)NC(CCCNC(N)=N)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NC(CC(O)=O)C(=O)NC(CO)C(=O)NC(C)C(=O)NC(CCCNC(N)=N)C(=O)NC(CC(C)C)C(=O)NC(CCC(N)=O)C(=O)NC(CCCNC(N)=N)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(N)=O)C(=O)NCC(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(O)=O)C(C)O)CC1=CC=CC=C1 KKNIUBFRGPFELP-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/32011—Picornaviridae
- C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
- C12N2770/32122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
A synthetic vaccine against foot and mouth disease is produced by conjugation of at least one membrane anchoring compound with at least one partial sequence of a protein of foot and mouth disease virus. The said vaccine has the advantage that it can be stored for a very long time even without cooling and that, by reason of its high activity, it generates adequate protection against foot and mouth disease even after a single administration.
Description
Description The present invention relates to a vaccine against foot and mouth disease and a process for the preparation thereof.
Foot and mouth disease tFMD) causes great losses in r cattle breeding, despite vaccines which have now been available for a long time. One reason for the occurrence of foot and mouth disease at present is the unreliability of classical vaccines which contain killed or inactivated FW viruses: the inactivation of the virus is occasionally incomplete so that 'post-vaccination' outbreaks of FMD may occur (cf. Bohm, Strohmaier, Tierarztl. umschau 39, 3 - 8 (1984)). This danger does not exist with synthetic FMD vaccines because in the latter only partial sequences of certain viral proteins, which do not have the function of an intact virus, are used.
Although synthetic FMD vaccines already exist (cf. European Patent Application 0,204,480) they are still in need of improvement« It has now been found that particularly effective FMD vaccines can be prepared using membrane-anchoring compounds and certain partial sequences of the FMD virus. Although the preparation of synthetic vaccines is mentioned in German Offenlegungsschrift DE 3,546,150 Al as one of many possible uses of membrane aachor/active substance conjugates, it was not to be expected that the conjugates of membrane-anchoring compounds and partial sequences of the FMD virus (membrane anchor/active substance conjugates) would exhibit the exceptional activity which has been found on administration of relatively small amounts of vaccine. * Furthermore, the said vaccines are distinguished, surprisingly, by providing aa adequate protection even after a single administration of the vaccine. Moreover, they have the advantage by comparison with conventional vaccines that virtually unlimited storage without cooling is possible.
Accordingly, the invention relates to a synthetic veccma which is active against foot and mouth disease and comprises a conjugate of a membrane-anchoring compound and a partial sequence of th® foot and mouth disease virus which are linked together covalently, where the membrane-anchoring compound has a structure from the formula© below R -CO-O-CHp R -0-CH2 R -0-C0-CH2 R'-CO-O-CH* R'-O-bi* R'-O-CO-CH* Wn (cn2)a A A 1 | ^H2 (ch2)m R-C©-NH-CK*~CO-X R5'-C0~HH-CH*-C0-X R’’-CO-NH-CH*-CO-X I. II. III.
R -NK-CO-CH R'-NH-CO-CH* Wn A (CK )m R~CO-NH-eH -CO-X R -C0-CH3 R’-CO-CH* Wn A (CH?)m R’’-CO~NH-CHS-CO~X B I Λ (CH?) I ξ Π1 R’’-NH-CO-CH -CO-X IV.
V.
VI, R,-CH. ι PL-CH' c I (CH.) ι s. n A (CH.) ι c ul R-CO-NH~CH*-CO-X j VII. in which A can he sulfur, oxygen, disulfide (-S-S-), me thy 1 ene (- CSt2 -) or - NK -; n = 0 to 5, os 1 or 2j G* is an asymmetric carbon atom with the R or S configuration, R, Rf and R™ are identical or different and is hydrogen or an alkyl, alkenyl or alkynyl group which has 7 to 25 carbon atoms and which can be substituted by hydroxyl, amino, oxo, acyl, alkyl or cycloalkyl groups, B ia formula VI can have the meaning of each of the -(CH2)„(substituted alkyl) radicals listed in formulae I~V, and Rn and R2 are identical or different and have the same meanings as R, R* aad R but can also be -OR, -O-COR, COOR, NKCOR or -CQNHR, where X is ra chain of 1 to 10 amino acids to which the partial sequence of the virus is bonded» Membrane-anchoring compounds are compounds which can be introduced into biological or artificial membranes.
Further explanations of membrane-anchoring compounds are to ba found in the German Offenlegungsschrift 3,546,150 already quoted and in G. Jung et al» ia Peptides, Structure and Function, V.J. Hruby and D.H. Rich, pages 179 to 182, Pierce Chem. Co. Rockford, Illinois, (1983)» Examples of the membrane-anchoring compound, to be particularly emphasised are: N termini occuring in bacterial lipoprotein, such as, for example: Y-Ser-Ser-Ser-Asn, Y-Ile-Leu-Leu-Ala, Y-Ala-AsaAsn-Gla, Y-Asn-Ser-Asa-Ser, Ύ-Gly-Ala-Met-Ser, Y-Gln-AlaAsn-Tyr, Y-Gla-Val-Asn-Asn, ¥~Asp-Asa-Ser~Ser, where Y can be one of the radicals listed under formula I to VII. These lipopentapeptides can also be used in shortened form (lipodi, lipotri or lipotetrapeptid.es) as membraneanchoring compound. Very particularly preferred is 2ϊpalmitoyl-S- (2,3-(bispalmitoyloxy)propyl]-cysteinylseryl-seriae (Pass^Cys-Ser-Ser), N-palmitoyl-S-[2,3-(bispalmitoyloxy)propyl]-cysteinyl-seryl-glyciae and N-palmitoyl-S-[2,3-(bispalmitoyloxy)propyl]-cysteinylalanyl-D-isoglutamine. Examples of other preferred membrane-anchoring compounds are to be found in German Offenlegungsschrift 3,546,150.
Many different partial sequences can be employed as the partial sequences of the PMD virus which are bonded to the membrane-anchoring compound. The following partial sequences are preferreds Partial sequence -(134-154) -(135-154) -(134-158) - -(134-160) « -(141-160) 81 -(141-158) -(200-213) " -(200-210) 85 -(161-180) it being possible to use the sequences of all known serotypes and subtypes. Examples of serotypes which may be indicated in this connection are: Serotype A: A5 Westerwald 134 NKYSTGGP--RRGDMGSAAARAAKQLP 161 180 ASFNYGAIRAITIHELLVRM 200 213 RHKQKIIAPARQLL 160 Serotype C: 134 Cx Qberbayera TTY TAST 161 160 --RGDLAHLTAT RAGHLP A12 USA 134 160 NKYSASGSG-VRGDFGSLAPRvARQLP 161 180 ASFHYGAIKAETIHELLVRM 200 212 RHSCQKIIAPGKQL 180 TSFNFGAUKASTITGLLVAM 200 213 RHKQPLVAPAKQLL 134 ISO CRYNRNAVPKn.RGDLQVLAQKVARTLP CRYSRHAVPNLRGDLQVLAQKVARTLP RRYSRNAVPNVRGDLQALGQKARTLP CLYSDARVSNVRGDLQVLAQKAERAL CRYGNVAVTNVRGDLQVLAQKAERALP 200 213 RHKQKIVAPVKQTL 161 180 TS FNYGAIKATRVTSLLYRM Serotype O: Ox Kaufbeuren Ox li&ugaxsa O2 Norrf,andy O Wuppertal 0 Israel 0χ Kaufbeuren 0Σ Kaufbeuren Particularly suitable synthetic vaccines are those which comprise a Mixture of peptides from various sero- and/or subtypes of the foot and mouth disease virus, each of which is covalently bonded to the membx'ane-anchoring compound(s).
Particularly preferred synthetic vaccines are those which comprise a mixture of sequences VPl 134-150 of serotypes O, A and C, bonded to the membrane-anchoring compound Mpalmi toyl - S - [2,3 - (bispalmi toyloxy) propyl] cysteinyl - seryl serine.
When the sequence 134-154 froxn serotype G and the sequence 134-155 from serotype A are used, the latter can, as long .'as it contains C-terainaX lysine, be linked covalently via the e-amino group to the membrane-anchoring compound.
Particularly suitable synthetic vaccines according to the invention have proven to be those which contain the partial sequence of PHD virus VP 1 (135-154).
Additionally particularly preferred is a vaccine comprising N-palmifcovX-S- [2,3- (bi spalmitoyloxy) propyl] cysteinyl-seryl-seryl-VP 1 (135-154), i.e. the compound of the formula below.
QS Tha membrane-anchoring compounds can, in principle, be in the form of R,S or R,R diastereomers or of a mixture of diastereomers. However, it has emerged that the vaccines which contain a R,R-diastereomeric membrane-anchoring compound have particularly high activity.
Tha invention additionally relates to a process for the preparation of a synthetic vaccine, which comprises bonding partial sequences of the FHD virus to the membrane-anchoring compound by a conjugation reaction.
Tha conjugation reaction can be, for example, a condensation, addition, substitution, oxidation or disulfide formation. Preferred conjugation methods are i indicated in Example 1. Further conjugation methods are described in German Offealegungsschrift 3,546,150 which has already been cited.
The preparation of the membrane-anchoring compounds is likewise described in detail in the last-mentioned German Offenlegungsschrift.
The separation of the diastereomers, which is necessary where appropriate, can also be carried out by a variety of methods as described, for example, in Hoppe-Seyler's Z. Physiolog. Chem. 364 (1983) 593. A preferred separation process is described in Example 2. ’ The partial sequences of the particular PMD proteins can be constructed in a variety of ways known from the literature, cf., for example, Wunsch et al. in HoubenWeyl, vol. 15/1,2, Stuttgart, Thieme-Verlag or Wunsch in Angew. Chem. 83 (1971), 773, Ξ. Gross and J. Meienhofer (editors), The Peptides, vol. 1 (1979), 2 (1979), 3 (1981) and 5 (1983), Academic Press, New York, or German Offenlegungsschrift 3,546,150. A preferred process for the preparation of a partial sequence and of a conjugate is explained in more detail in Example 3.
The invention additionally relates to pharmaceutical or veterinary medicinal formulations which contain a conjugate of membrane-anchoring compound and partial sequence of a FMD virus. Besides a solvent, there is normally no additional need fox' additional auxiliaries and carriers or adjuvants for the formulations according to the invention. However, in some cases, it may be worthwhile to add such auxiliaries and/or carriers as well as, where appropriate, adjuvants to the formulations according to the invention. The relevant substances are mixed and dispensed by processes known to those skilled in the art.
The amount of vaccine necessary for reliable immunisation of an animal depends on the species, on the membraneanchoring compound(s) and on the partial sequence(s) of v the FMD virus and should be determined empirically in the individual case. For example, sufficient for reliable immunisation of a guinea pig against FMD virus serotype O-jK is a single administration of about 100 - 500 gg of vaccine according to the invention, without further auxiliaries or carriers.
Tha invention additionally relates to the us® of tha described vaccine for raising antibodies In mammals.
Example 1 Conjugation of peptides/proteins with PasagCys-Ser-Ser-OSu or PasstjCys-Ser-Ser-OH 1. Peptides and proteins soluble in DMF /xmol of peptide/protein are dissolved in 0.5-1 ml of DMF, and 8 gaol (9.2 mg) of solid Psm3Cys-Ser~ Ser-OSu are added. A homogeneous solution is obtained by gentle heating and sonication, and 4 /zmol of organic base (N-ethylmorpholine) are added. After stirring for 12 h, 1 - 2 ml of chloroform: methanol (1:1) sre added, and the mixture is cooled in an ice bath for 2 h.
The sediment is taken up with 1 ml of cold chloroform: methanol (1:1) washed in tert«butanol/water (3 si) (sonicate if necessary) and freese-dried. 2. Peptides and proteins soluble in water μηοΐ of peptide/protein are dissolved in 0.8 ml of water, and 4 gmol (4.5 mg) Pam3Cys-Ser-Ser-OH are added. The mixture is thoroughly sonicated until an emulsion is produced and a pH of 5.0 to 5.5 is set up. After 5 mg of SDC (1-3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride) dissolved in 100 μΐ of K20 has been added the mixture is stirred at room temperature for 18 h and then dialyzed twice against 1 1 of distilled H20 each time. The contents of the dialysis tube are freeze-dried.
Example 2 Separation of the diastereomers of M-paladLfcoyl-S- (2,3(bispalaoitoyloaey)propyl] -cysteine tert.-butyl ester (PasagCys-OBufc) : ’ 2 g of PcUn3Cys-03u are dissolved in 10 ml of mobile 1 phase, dichloromethane/ethyl acetate (20:1), and loaded onto a column (length 120 ca, diameter 4 ca) packed with MN silica gel 60, 0.063-0.2 mm/70 - 230 mesh ASTM. At a drop rate of 2 drops/sec, 350 fix-actions each of 10 ml are collected, and sn aliquot of each fraction is checked for Pam3Cys-OBu'c after chromatography on silica gel 60 plates in dichloromethane/ethyl acetate (20 si) and staining with chlorine/TDM reagent.
Fractions 280 - 315 contain the R,R diastereomer, frac15 tions 316 - 335 contain a mixture of R,R and R,S, and fractions 336 - 354 contain the R,S diastereomer of Pam3Cys-OBufc. After the solvent has been evaporated off in a rotary evaporator and the residue has been taken up in warm tert.-butanol and freeze-dried, 600 mg of R,S-, 370 mg of a mixture of R,R- and R,S-, and 540 mg of R,SPam3Cys=OBu£ ar® obtained.
Example 3 Synthesis of N-palmitoyl-Ξ- [2,3- (hispahsaitcsyloxy) propyl] cysteinyl-seryl-seryl-V5> 1 (135-154) The VP 1 peptide sequence of FMD virus serotype ΟχΚ was synthesised by solid-phase peptide synthesis. Pmoe-amino acids were used. The following side-chain protective v groups were used: Lys(Boc), His(Fmoc), Arg(Mtr), Ser(tBu), Asp(OtBu), Tyr(tBu). Starting from 1 g of (p30 bensoyloxybenzyl alcohol) - resin loaded with FmoeLys(Boc)-OH, (0.47 mmol/g), the following synthesis cycles were performed: N-Activation with 55 % piperidine in N-methylpyrrolidone (lx 2 min, 1 x 5 min) , preactivation of Fmoe-A-A-OH (1.5 mmol) in N-methylpyrrolidona (6 ml) with diisopropylcarbodiimide (1.5 mmol) and 1-hydroxybenzotriazole (1.5 mmol) with subsequent coupling for 1.5 h. Washing with N-ethylmorpholine (5 % in N-methylpyrrolidone) was followed by repetition of the preactivation and coupling. The blocking of unreacted amino groups was carried out with acetic anhydride (2.5 mmol) and diisopropylamine (1.2 mmol) in N-methylpyrrolidone. After each step the peptide-resin was washed several times with N-methylpyrrolidone, dichloromethane and again with N-methylpyrrolidone.
After the resin-bound FMD virus sequence had been synthesized, a part of the peptide was obtained by cleavage with trifluoroacetic acid and checked by HPLC, MS, amino acid analysis, chiral phase analysis and sequence analysis. The bonding of 2 serine residues to the resin-bound peptide was followed by coupling of the tripalmitoyl-Sglycerylcysteine. After 4 hours 1 equivalent of N-methylmorpholine was added, and after another hour the lipopeptide-resin was washed. The lipopeptide was separated from the resin using 2 ml of trifluoroacetic acid (containing 100 gl of thioanisole) within 4 1/2 hours. The filtrate was evaporated, the residue was taken up with acetic acid, and the solution was added to cold ether. The precipitated lipopeptide was washed 3 x with ether. Further purification was achieved by recrystallisation from trifluoroethanol/chloroform in the ratio 1:3 with cold acetone and a few drops of water. The lipopeptide was freeze-dried from tert. -butanol/water in the ratio 3 :1.
BxajspXe 4 Activity test: Guinea pigs with a weight of 450 to 500 g chosen at random wars inoculated intramuscularly or subcutaneously. 0.5 mg of the freeze-dried, vaccine CN-palmitoyl-S[(2R,R) - 2,3 - (bispalxaitoyloxy)propyl) -cysteinyl-serylseryl-VPI(135-154) was emulsified in 500 μΐ of a 1:3. mixture of 0.05 M phosphate buffer and Intralipid(Kabi -? Vitrum, Sweden) . The mixture was sonicated for 10 s. Pour animals were infected with FMD virus by subcutaneous injaction into the left rear paw of at least 500 guinea pigs units of a virulent 0.,K PMD virus 21 days after the inoculation. Control animals were injected with the membrane-anchoring compound or phosphate buffer in place of the vaccine. A high titer of neutralising antibodies log10SN50 of 0.36 was found in all the inoculated animals.
The control animals had no antibody titer (blank 0.17).
The titer of neutralizing antibodies was determined as the logarithm of the serum dilution necessary to neutralize 50 % of ths virus cells in a monolayer of 3HK (baby hamster kidney) cells. It was possible to detect antibodies in the inoculated animals by means of an anfci2 0 peptide ELISA (A492) , which was not possible for the noninoculated animals. Inoculated animals showed no secondary lesions, whereas all the non-inoculated animals showed the complete picture of foot and mouth disease infection.
Claims (13)
1. A synthetic vaccine which is active against foot and mouth disease and comprises a conjugate of a membrane-anchoring compound and a partial sequence of the foot and mouth disease virus which are linked together covalently, where the membrane-anchoring compound has a structure from the formulae below R -CG~0-CH 2 R’-CO-O-CS* A 2 } * R-CO-NH-CH*-CO-j R -O-CH 2 R'-O-CH* Wn A (0Η 2 )^ R”-CO-HH~fcH*~CO~Z R -0-C0-CH 2 R'-O-CO-CH* Wn W* R-CO-NH-CH*~CO-X I. II. Ill. ο is R'-NH-CO-CH* Wn A ( CH.) 1 2'm r-co-nh~c:-:*-co~v R -C0-CH 2 R'-CO-CH* Wn (¢3,) 2. 'a A (CH.) I &· Μ» R-CO-NH-CH~~CO-X R-NH-C0-CH*-C0-X IV. VI. . R 1 -CH 2 R.-CH* (CH,) 2'n R-CO-NH-CH*-CO~X VII. in. which A caa be sulfur, oxygen, disulfide (-S-S-), methylene (-CH 2 -) or -HH-; n = 0 to 5, m ~ 1 or 2; C* is an asymmetric carbon atom with the R or S configuration, R, R' and R s * are identical or different and is hydrogen or an alkyl, alkenyl or alkynyl group which has 7 to 25 carbon atoms and which can be substituted by hydroxyl, amino, oxo, acyl, alkyl or cycloalkyl groups, B in formula Vl can have the meaning of each of the - (C« 2 ) a - (substituted alkyl) radicals listed in formulae I-V, and R x and R, are identical or different and have the same meanings as R, R' and R 1 but can also be -OR, -O-COR, -COOR, NHCOR or -COKIHR, where I is s chain of up to 10 amino acids to which the partial sequence of the virus is bonded.
2. A synthetic vaccine as claimed in claim 1, wherein the partial sequence of the foot and mouth disease virus which is bonded to the membrane-anchoring compound is selected from the group comprising sequence-(134-154) m -(135-154) BS -(134-158) » -(134-160) tB -(141-160) -(141-158) w -(200-213) « -(200-210) “ -(161-180), or the C~ terminal amidated or alkylamidated forms thereof, it being possible to use the sequences of < all known serotypes and subtypes. * A synthetic vaccine as claimed in claim 1 or 2, wherein the partial sequence of the foot and mouth disease virus VP 1 (135-154) is bonded to the membrane-anchoring compound. * 5 ,ϊ <
3. 4. A synthetic vaccine as claimed in one or more of claims 1 - 3, which comprises a mixture of peptides from various sero- and/or subtypes of the foot and mouth disease virus, each of which is covalently bonded to the membrane-anchoring compound or membrane-anchoring compounds.
4. 5. A synthetic vaccine as claimed in one or more of claims 1-4, which comprises a mixture of sequences VP1 134-160 of serotypes O, A or C bonded to the membrane-anchoring compound N-palmitoyl~S-[2,3(bispalmitoyloxy)propyl]-cysteinyl-seryl-serine. S. A synthetic vaccine as claimed in one or more of claims 1-5, which vaccine comprises N-palmitoyl-S(2,3- (bispalmitoyloxy) propyl] cysteinyl-seryl-seryl VP 1 (135-154), it being possible for the membraneanchoring compound to be in the form of the R,S or R,R diastercomer or of a mixture of diaetereomers.
5. 7. A synthetic vaccine as claimed in one or more of claims 1 to 6, wherein the membrane-anchoring compound is in the form of the R,R diastereomer.
6. 8 . A process for the preparation of a synthetic vaccine as claimed in one or mors of claims 1-7, which comprises the partial sequences of the foot and mouth disease virus which have been prepared in a manner known per se being bonded to the membraneanchoring compound by a conjugation reaction.
7. 9. A pharmaceutical or veterinary medicinal formulation, which contains a synthetic vaccine as claimed in one or more of claims 1 - 8, where appropriate in addition to customary auxiliaries and/or carriers, adjuvants and/or other vaccines.
8. 10. The use of a synthetic vaccine as claimed in one or more of claims 1-9 for raising antibodies against foot and mouth disease viruses in mammals.
9. 11. A synthetic vaccine according to claim 1, substantially as hereinbefore described.
10. 12. A process according to claim 8, for the preparation 5 of a synthetic vaccine, substantially as hereinbefore described and exemplified.
11. 13. A synthetic vaccine whenever prepared by a process θ claimed in a preceding claim.
12. 14. A pharmaceutical or veterinary medical formulation according to claim 9, substantially as hereinbefore described .
13. 15. Use according to claim 10, substantially as hereinbefore described .
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3813821A DE3813821A1 (en) | 1988-04-22 | 1988-04-22 | SYNTHETIC VACCINE AGAINST MOUTH AND CLAUS DISEASE AND METHOD FOR THEIR PRODUCTION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE891296L IE891296L (en) | 1989-10-22 |
| IE67124B1 true IE67124B1 (en) | 1996-03-06 |
Family
ID=6352780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE129689A IE67124B1 (en) | 1988-04-22 | 1989-04-21 | A synthetic vaccine against foot and mouth disease and a process for the preparation thereof |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0338437B1 (en) |
| JP (1) | JP2837866B2 (en) |
| AR (1) | AR243081A1 (en) |
| AT (1) | ATE118507T1 (en) |
| AU (1) | AU619826B2 (en) |
| CA (1) | CA1333563C (en) |
| DE (2) | DE3813821A1 (en) |
| DK (1) | DK175629B1 (en) |
| ES (1) | ES2068215T3 (en) |
| GR (1) | GR3015358T3 (en) |
| IE (1) | IE67124B1 (en) |
| NZ (1) | NZ228824A (en) |
| PT (1) | PT90333B (en) |
| RU (1) | RU1836102C (en) |
| ZA (1) | ZA892954B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6024964A (en) * | 1985-06-24 | 2000-02-15 | Hoechst Aktiengesellschaft | Membrane anchor/active compound conjugate, its preparation and its uses |
| US6074650A (en) * | 1985-06-24 | 2000-06-13 | Hoechst Aktiengesellschaft | Membrane anchor/active compound conjugate, its preparation and its uses |
| DE3937412A1 (en) * | 1989-11-10 | 1991-05-16 | Hoechst Ag | SYNTHETIC VACCINE FOR THE SPECIFIC INDUCTION OF CYTOTOXIC T-LYMPHOZYTES |
| GB9915074D0 (en) * | 1999-06-28 | 1999-08-25 | Cortecs Plc | Ligand-binding composition |
| KR101853513B1 (en) * | 2010-03-23 | 2018-04-30 | 노파르티스 아게 | Compounds (cystein based lipopeptides) and compositions as tlr2 agonists used for treating infections, inflammations, respiratory diseases etc. |
| CN105555756B (en) | 2013-06-28 | 2018-12-07 | 奥克兰联合服务有限公司 | Amino acid conjugate and peptide conjugate and conjugation methods |
| BR112017013574A2 (en) | 2014-12-23 | 2018-03-06 | Verdon Daniel | amino acid and peptide conjugates and uses thereof |
| JP7161404B2 (en) | 2016-02-26 | 2022-10-26 | オークランド ユニサービシーズ リミティド | Amino acid and peptide conjugates and conjugation methods |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5849321A (en) * | 1981-06-16 | 1983-03-23 | ジエネンテツク・インコ−ポレイテツド | Foot-and-mouth disease vaccine |
| ZA831854B (en) * | 1982-03-26 | 1984-01-25 | Biogen Nv | Small peptides with the specificity of foot and mouth disease viral antigens |
| CA1247080A (en) * | 1983-03-08 | 1988-12-20 | Commonwealth Serum Laboratories Commission | Antigenically active amino acid sequences |
| AU573574B2 (en) * | 1983-03-08 | 1988-06-16 | Chiron Mimotopes Pty Ltd | Immunogenic deteminants of foot and mouth disease virus |
| JPS59500719A (en) * | 1983-04-06 | 1984-04-26 | ビトル ジエイムズ エル | Synthetic picornavirus antigen |
| EP0142193A1 (en) * | 1983-10-22 | 1985-05-22 | Akzo N.V. | Preparation of immunogens consisting of antigens and/or antigenic determinants bound to glycoside-containing carriers |
| JPS61292398A (en) * | 1985-06-19 | 1986-12-23 | 富士通株式会社 | Manufacture of multilayer circuit board |
| DE3546150A1 (en) * | 1985-06-24 | 1987-01-22 | Hoechst Ag | MEMBRANE ANCHOR ACTIVE CONJUGATE, ITS PRODUCTION AND USE |
-
1988
- 1988-04-22 DE DE3813821A patent/DE3813821A1/en not_active Withdrawn
-
1989
- 1989-04-12 AR AR89313718A patent/AR243081A1/en active
- 1989-04-13 ES ES89106628T patent/ES2068215T3/en not_active Expired - Lifetime
- 1989-04-13 EP EP89106628A patent/EP0338437B1/en not_active Expired - Lifetime
- 1989-04-13 DE DE58908990T patent/DE58908990D1/en not_active Expired - Fee Related
- 1989-04-13 AT AT89106628T patent/ATE118507T1/en not_active IP Right Cessation
- 1989-04-20 DK DK198901928A patent/DK175629B1/en not_active IP Right Cessation
- 1989-04-20 PT PT90333A patent/PT90333B/en not_active IP Right Cessation
- 1989-04-20 NZ NZ228824A patent/NZ228824A/en unknown
- 1989-04-21 AU AU33265/89A patent/AU619826B2/en not_active Ceased
- 1989-04-21 ZA ZA892954A patent/ZA892954B/en unknown
- 1989-04-21 RU SU894613910A patent/RU1836102C/en active
- 1989-04-21 IE IE129689A patent/IE67124B1/en not_active IP Right Cessation
- 1989-04-21 CA CA000597445A patent/CA1333563C/en not_active Expired - Fee Related
- 1989-04-21 JP JP1100345A patent/JP2837866B2/en not_active Expired - Fee Related
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1995
- 1995-03-10 GR GR950400516T patent/GR3015358T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK192889A (en) | 1989-10-23 |
| AU619826B2 (en) | 1992-02-06 |
| DE3813821A1 (en) | 1989-11-02 |
| PT90333A (en) | 1989-11-10 |
| AU3326589A (en) | 1989-10-26 |
| IE891296L (en) | 1989-10-22 |
| EP0338437A2 (en) | 1989-10-25 |
| DK175629B1 (en) | 2004-12-27 |
| JP2837866B2 (en) | 1998-12-16 |
| ATE118507T1 (en) | 1995-03-15 |
| EP0338437A3 (en) | 1991-05-08 |
| ZA892954B (en) | 1989-12-27 |
| EP0338437B1 (en) | 1995-02-15 |
| AR243081A1 (en) | 1993-07-30 |
| DK192889D0 (en) | 1989-04-20 |
| PT90333B (en) | 1994-08-31 |
| CA1333563C (en) | 1994-12-20 |
| RU1836102C (en) | 1993-08-23 |
| ES2068215T3 (en) | 1995-04-16 |
| GR3015358T3 (en) | 1995-06-30 |
| DE58908990D1 (en) | 1995-03-23 |
| JPH026410A (en) | 1990-01-10 |
| NZ228824A (en) | 1992-05-26 |
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