CN109929033A - 一种特异性结合四种血清型登革病毒的人源抗体 - Google Patents
一种特异性结合四种血清型登革病毒的人源抗体 Download PDFInfo
- Publication number
- CN109929033A CN109929033A CN201910196495.2A CN201910196495A CN109929033A CN 109929033 A CN109929033 A CN 109929033A CN 201910196495 A CN201910196495 A CN 201910196495A CN 109929033 A CN109929033 A CN 109929033A
- Authority
- CN
- China
- Prior art keywords
- antibody
- seq
- dengue virus
- nucleic acid
- recombinant
- 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.)
- Granted
Links
- 241000725619 Dengue virus Species 0.000 title claims abstract description 53
- 206010012310 Dengue fever Diseases 0.000 claims abstract description 16
- 208000025729 dengue disease Diseases 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 10
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 8
- 108020004707 nucleic acids Proteins 0.000 claims description 28
- 102000039446 nucleic acids Human genes 0.000 claims description 28
- 150000007523 nucleic acids Chemical class 0.000 claims description 28
- 239000002773 nucleotide Substances 0.000 claims description 23
- 125000003729 nucleotide group Chemical group 0.000 claims description 23
- 101710204837 Envelope small membrane protein Proteins 0.000 claims description 17
- 101710145006 Lysis protein Proteins 0.000 claims description 17
- 241000894006 Bacteria Species 0.000 claims description 16
- 239000013598 vector Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 3
- 102000036639 antigens Human genes 0.000 claims description 3
- 108091007433 antigens Proteins 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 claims description 3
- 125000003835 nucleoside group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000010985 leather Substances 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 abstract description 13
- 231100000636 lethal dose Toxicity 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 26
- 150000001413 amino acids Chemical group 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 13
- 238000006386 neutralization reaction Methods 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 230000003472 neutralizing effect Effects 0.000 description 11
- 208000009714 Severe Dengue Diseases 0.000 description 7
- 241000880493 Leptailurus serval Species 0.000 description 6
- 201000002950 dengue hemorrhagic fever Diseases 0.000 description 6
- 238000003259 recombinant expression Methods 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 230000009385 viral infection Effects 0.000 description 6
- 208000001490 Dengue Diseases 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 4
- 201000009892 dengue shock syndrome Diseases 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000013613 expression plasmid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 230000002633 protecting effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- QAPSNMNOIOSXSQ-YNEHKIRRSA-N 1-[(2r,4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C1 QAPSNMNOIOSXSQ-YNEHKIRRSA-N 0.000 description 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- 229920000936 Agarose Polymers 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-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
- 101000619564 Homo sapiens Putative testis-specific prion protein Proteins 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 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 2
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 2
- 102100022208 Putative testis-specific prion protein Human genes 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 2
- 108020005038 Terminator Codon Proteins 0.000 description 2
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- 241000256118 Aedes aegypti Species 0.000 description 1
- 241000256173 Aedes albopictus Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 1
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 1
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- OVQJAKFLFTZDNC-GUBZILKMSA-N Arg-Pro-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O OVQJAKFLFTZDNC-GUBZILKMSA-N 0.000 description 1
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- 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 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 1
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- 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 1
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 1
- 101150074432 EDE1 gene Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101001065501 Escherichia phage MS2 Lysis protein Proteins 0.000 description 1
- 208000015220 Febrile disease Diseases 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- REJJNXODKSHOKA-ACZMJKKPSA-N Gln-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N REJJNXODKSHOKA-ACZMJKKPSA-N 0.000 description 1
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 1
- CKNUKHBRCSMKMO-XHNCKOQMSA-N Gln-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O CKNUKHBRCSMKMO-XHNCKOQMSA-N 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- 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 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- 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 1
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 1
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 1
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 1
- 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 1
- 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 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 1
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- TWTPDFFBLQEBOE-IUCAKERBSA-N Gly-Leu-Gln Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O TWTPDFFBLQEBOE-IUCAKERBSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- 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 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- JYPCXBJRLBHWME-IUCAKERBSA-N Gly-Pro-Arg Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JYPCXBJRLBHWME-IUCAKERBSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 1
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 1
- 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 1
- 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 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 1
- 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 1
- UAQSZXGJGLHMNV-XEGUGMAKSA-N Ile-Gly-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N UAQSZXGJGLHMNV-XEGUGMAKSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 1
- 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 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 1
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 1
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 1
- 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 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 1
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 1
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 1
- 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 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- YIRIDPUGZKHMHT-ACRUOGEOSA-N Leu-Tyr-Tyr 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](CC1=CC=C(O)C=C1)C(O)=O YIRIDPUGZKHMHT-ACRUOGEOSA-N 0.000 description 1
- 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 1
- 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 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 1
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 1
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 1
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 1
- 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 1
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 1
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 1
- 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 1
- 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 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 1
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 1
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 1
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 1
- ZENDEDYRYVHBEG-SRVKXCTJSA-N Phe-Asp-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 ZENDEDYRYVHBEG-SRVKXCTJSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- 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 1
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 1
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 1
- 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 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 1
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- 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 1
- 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 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 1
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 1
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 1
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 1
- 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 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- 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 1
- HEYZPTCCEIWHRO-IHRRRGAJSA-N Ser-Met-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HEYZPTCCEIWHRO-IHRRRGAJSA-N 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
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 1
- HAUVENOGHPECML-BPUTZDHNSA-N Ser-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CO)=CNC2=C1 HAUVENOGHPECML-BPUTZDHNSA-N 0.000 description 1
- 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 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- 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 1
- 241000218636 Thuja Species 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- 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 1
- DWAMXBFJNZIHMC-KBPBESRZSA-N Tyr-Leu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O DWAMXBFJNZIHMC-KBPBESRZSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- XUIOBCQESNDTDE-FQPOAREZSA-N Tyr-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O XUIOBCQESNDTDE-FQPOAREZSA-N 0.000 description 1
- 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 1
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 1
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 1
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 1
- 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 1
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- 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 1
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 1
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 1
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005238 degreasing Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- JYPCXBJRLBHWME-UHFFFAOYSA-N glycyl-L-prolyl-L-arginine Natural products NCC(=O)N1CCCC1C(=O)NC(CCCN=C(N)N)C(O)=O JYPCXBJRLBHWME-UHFFFAOYSA-N 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010025801 glycyl-prolyl-arginine Proteins 0.000 description 1
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 239000012516 mab select resin Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 238000013326 plasmid cotransfection Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 239000013636 protein dimer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- General Engineering & Computer Science (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明公开了一种特异性结合四种血清型登革病毒的人源抗体。本发明所提供的人源抗体,其重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26‑33位、第51‑58位、第97‑121位所示,轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27‑32位、第50‑52位、第89‑97位所示。本发明所提供的抗体可有效预防四种血清型DENV的感染,治疗致死剂量DENV‑1和DENV‑2的感染。本发明对于开发预防及治疗登革病毒感染的药物具有重要意义。
Description
技术领域
本发明涉及生物技术领域,特别涉及一种特异性结合四种血清型登革病毒的人源抗体。
背景技术
登革病毒(Dengue virus,DENV)属于黄病毒科黄病毒属,是有包膜的单正链RNA病毒,根据其包膜的抗原性不同,分为四种血清型(DENV I-IV)。登革病毒主要以埃及伊蚊和白纹伊蚊为传播媒介,广泛流行于热带和亚热带地区。人类首次感染登革病毒会引起登革热(Classic Dengue Fever,DF),是一种自限性发热性疾病,同时登革病毒可以激发良好的细胞免疫和体液免疫,对感染的该亚型可提供终身的免疫力。但是当再次感染其他亚型的登革病毒时,首次感染产生的抗体会携带病毒攻击靶细胞,造成病毒大量的增殖,从而引发严重的登革出血热(Dengue Hemorrhagic Fever,DHF)和登革休克综合征(Dengue ShockSyndrome,DSS)甚至死亡,即抗体依赖增强(Antibody dependent enhancement,ADE)。世界上约有半数的人口生活在登革热疫区,每年有超过5000万的感染病例,其中有50万人发展为严重的DHF和DSS。但是,由于ADE现象的存在,临床上缺乏预防和治疗DENV感染的有效疫苗和药物,主要以对症支持治疗为主。
免疫球蛋白是治疗病毒感染类疾病的重要手段,不仅能中和病毒,还能通过补体依赖的细胞毒作用(complement dependent cytotoxicity,CDC)和抗体依赖细胞介导的细胞毒作用(antibody dependent cell-mediated cytotoxicity,ADCC)激活体内免疫系统清除病毒。大量体内、外实验证明:中和抗体能有效阻止DENV的感染,不仅能发挥病毒感染前的预防作用,而且在病毒感染后的一段时期内,依然能发挥治疗病毒感染的作用。基于临床上针对DENV感染无有效防治手段的现状,以及近年来单克隆抗体技术在人源化、规模化培养制备等方面均取得的巨大进步,登革病毒的治疗性抗体研究也得到了长足的发展。
DENV的E蛋白是感染性病毒粒子表面暴露最充分的蛋白,也是中和抗体的主要靶点。目前全球报道的DENV中和抗体表位也多与E蛋白有关:(1)识别DENV EDⅡ:FL loop对应的交叉中和性抗体(E53)大都中和效率低且易产生ADE效应;针对BC loop的交叉中和抗体(1C19)不仅能高效中和DENV且还能与低效抗FL抗体竞争结合。(2)识别DENV EDⅢ:AB loop对应交叉中和抗体一般具弱中和性,EF loop附近形成的单抗(2B11A35/2D73A7)具高效交叉中和能力,A strand表位(单抗,DB32-6)具有高效中和活性;(3)识别E蛋白二聚体依赖性表位(E-dimer-dependent epitope,EDE):单抗(EDE1/EDE2)是一类新型高效广谱的人源中和抗体。此外,在抗体来源方面,大多数中和抗体为鼠源,少量人源化及人源抗体。人源化抗体与鼠源抗体相比具有以下特点:(1)免疫原性低于鼠源抗体;(2)亲和力弱于鼠源抗体,特异性优于鼠源抗体;(3)人源化抗体Fc段能够诱发机体的效应功能;(4)在体内半衰期长;(5)价格仍较昂贵。但人源化抗体仍含有10%~30%的鼠源蛋白,在临床应用时仍存在免疫排斥反应的潜在威胁,因而全人源中和抗体是DENV治疗性抗体的重要研发目标之一。
基于临床需求,探索和研发登革病毒中和抗体具有重要的生物学和医学意义。
发明内容
本发明的目的是提供一种特异性结合四种血清型登革病毒的人源抗体。
第一方面,本发明要求保护一种抗体。
本发明所要求保护的抗体为全人源单抗6B1,其重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26-33位、第51-58位、第97-121位所示;所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27-32位、第50-52位、第89-97位所示。
其中,HCDR1、HCDR2和HCDR3为重链可变区中的三个互补决定区,LCDR1、LCDR2和LHCDR3为轻链可变区中的三个互补决定区。互补决定区的序列根据Kabat定义。
进一步地,所述重链可变区的氨基酸序列可为SEQ ID No.1自N端起第1-121位,或者与SEQ ID No.1自N端起第1-121位具有至少90%的一致性(不一致处可在骨架区(FR))。所述轻链可变区的氨基酸序列可为SEQ ID No.2自N端起第1-109位,或者与SEQ ID No.2自N端起第1-109位具有至少90%的一致性(不一致处可在骨架区(FR))。
在本发明中,所述抗体为IgG。进一步地,所述IgG为IgG1。所述抗体的轻链类型为kappa(κ)型。
更进一步地,所述抗体的重链的氨基酸序列可为SEQ ID No.1,或者与SEQ IDNo.1具有至少90%的一致性(不一致处可在骨架区(FR))。所述抗体的轻链的氨基酸序列可为SEQ ID No.2或者与SEQ ID No.2具有至少90%的一致性(不一致处可在骨架区(FR))。
第二方面,本发明要求保护一种核酸分子。
本发明所要求保护的核酸分子为编码前文第一方面所述的抗体或所述抗体中的抗原结合部分的核酸分子。
进一步地,在所述核酸分子中,编码所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的核苷酸序列可依次如SEQ ID No.3自5’端起第76-99位、第151-174位、第289-363位所示,编码所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的核苷酸序列可依次如SEQ IDNo.4自5’端起第79-96位、第148-156位、第265-291位所示。
更进一步地,在所述核酸分子中,编码所述抗体的所述重链可变区的核苷酸序列可为SEQ ID No.3自5’端起第1-363位或者与SEQ ID No.3自5’端起第1-363位具有至少90%的一致性(不一致处在骨架区(FR)),编码所述抗体的所述轻链可变区的核苷酸序列可为SEQ ID No.4自5’端起第1-327位或者与SEQ ID No.4自5’端起第1-327位具有至少90%的一致性(不一致处在骨架区(FR))。
更加具体地,在所述核酸分子中,编码所述抗体的重链的核苷酸序列可为SEQ IDNo.3或者与SEQ ID No.3具有至少90%的一致性(不一致处可在骨架区(FR)),编码所述抗体的轻链的核苷酸序列可为SEQ ID No.4或者与SEQ ID No.4具有至少90%的一致性(不一致处可在骨架区(FR))。
第三方面,本发明要求保护含有前文第二方面所述核酸分子的表达盒、重组载体、重组细胞或重组菌。
在本发明的一个实施例中,将SEQ ID No.3自5’端起第1-363位所示DNA片段(抗体重链可变区的编码基因)克隆到pTSEG1n-S载体的酶切位点Sal I和Pml I之间后得到表达所述抗体的重链的重组表达载体;将SEQ ID No.4自5’端起第1-327位所示DNA片段(抗体轻链可变区的编码基因)克隆到pTSEK-S载体的酶切位点Sal I和Pml I之间后得到表达所述抗体的轻链的重组表达载体。所述重组细胞为将上述分别表达所述抗体重链和轻链的两个重组表达载体共转染FreeStyleTM 293F细胞后得到的重组细胞。
第四方面,本发明要求保护一种药物组合物。
本发明所要求保护的药物组合物包含前文第一方面中所述的抗体和药学可接受的赋形剂、稀释剂或载体。
第五方面,本发明要求保护如下任一所示应用:
(A1)前文所述核酸分子或表达盒、重组载体、重组细胞或重组菌在制备前文所述抗体或所述药物组合物中的应用;
(A2)前文所述抗体在制备前文所述药物组合物中的应用;
(A3)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于预防和/或治疗由登革病毒感染所致疾病的产品中的应用;
其中,所述由登革病毒感染所致疾病可为登革热(Classic Dengue Fever,DF)、登革出血热(Dengue Hemorrhagic Fever,DHF)或者登革休克综合征(Dengue ShockSyndrome,DSS)。
(A4)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于抑制登革病毒感染(中和登革病毒)的产品中的应用;
(A5)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的产品中的应用;
(A6)前文所述或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的产品中的应用;
(A7)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的E蛋白的产品中的应用;
(A8)前文所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的E蛋白的产品中的应用。
进一步地,所述登革病毒可为I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒。
本发明制备了一种能够特异性结合四种血清型登革病毒的人源抗体——全人源单抗6B1。实验证明,该抗体能够识别四种血清型登革病毒的E蛋白,对DENV-1和DENV-2的亲和力较高,但对DENV-3和DENV-4的亲和力较弱,对DENV-1和DENV-2的中和活性较强,但对DENV-3和DENV-4的中和活性较弱,可有效预防四种血清型DENV的感染,治疗致死剂量DENV-1和DENV-2的感染。本发明对于开发预防及治疗登革病毒感染的药物具有重要意义。
附图说明
图1为单抗6B1的抗体血清型特异性检测。注:非还原电泳;1:DENV-1;2:DENV-2;3:DENV-3;4:DENV-4。
图2为ELISA分析6B1与灭活登革病毒的结合。
图3为ELISA分析6B1与登革病毒重组E蛋白的结合。
图4为分析6B1与DENV-1重组E蛋白的亲和力。
图5为单抗6B1对四种血清型登革病毒的体外中和活性。
图6为乳鼠体内分析6B1对四种血清型登革病毒感染的预防作用。A:DENV-1;B:DENV-2;C:DENV-3;D:DENV-4。
图7为乳鼠体内分析6B1对DENV-1和DENV-2感染的治疗作用。A:DENV-1;B:DENV-2。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
四种血清型登革病毒,即I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒:分离株,由军事医学研究院微生物流行病研究所提供。
重链表达载体为pTSEG1n-S:由北京百特美博生物有限公司提供。
轻链表达载体为pTSEK-S:由北京百特美博生物有限公司提供。
FreeStyleTM 293F细胞:Invitrogen公司,货号R79007。
C6/36细胞:ATCC。
BHK-21细胞:ATCC。
实施例1、全人源单抗6B1的制备
采集3例临床上确诊为登革热恢复期患者的外周血(患者知情同意),每人10mL,共30mL。分离单核淋巴细胞,利用流式细胞术两步分选单个B细胞,先分选出CD19highCD20low to negativeCD3negative,在从中分选出CD27highCD38high的B细胞,分至96孔板,每个孔一个细胞。利用反转录PCR和巢式PCR从单B细胞扩增抗体轻重链可变区基因,轻重链正确配对者进行PCR产物测序,获得了包括6B1在内的多对轻重链可变区基因序列。其中,抗体6B1的重链可变区基因如SEQ ID No.3自5’端起第1-363位所示;抗体6B1的轻链可变区基因如SEQ ID No.4自5’端起第1-327位所示。
全合成6B1的轻重链可变区基因,重链表达载体pTSEG1n-S和轻链表达载体pTSEK-S利用Sal I和Pml I双酶切,将6B1的轻重链可变区基因分别与酶切后的轻重链表达载体连接,构建能够表达抗体6B1的重链和轻链的两个真核表达质粒。其中,用于表达抗体6B1的重链的重组表达质粒中携带完整的SEQ ID No.3(SEQ ID No.3为抗体6B1的重链编码基因),用于表达抗体6B1的轻链的重组表达质粒中携带完整的SEQ ID No.4(SEQ ID No.4为抗体6B1的轻链编码基因)。
抗体6B1,其重链氨基酸序列如SEQ ID No.1所示,轻链氨基酸序列如SEQ ID No.2所示。
SEQ ID No.1,自N端第1-121位氨基酸残基组成重链可变区VH(其中,第26-33位氨基酸残基组成HCDR1,第51-58位氨基酸残基组成HCDR2,第97-121位氨基酸残基组成HCDR3),第122-222位氨基酸残基组成重链恒定区CH1,第223-237位氨基酸残基组成重链铰链区Hinge,第238-347位氨基酸残基组成重链恒定区CH2,第348-454位氨基酸残基组成重链恒定区CH3。
SEQ ID No.2中,自N端第1-109位氨基酸残基组成轻链可变区VL(其中,第27-32位氨基酸残基组成LCDR1,第50-52位氨基酸残基组成LCDR2,第89-97位氨基酸残基组成LCDR3),第110-214位氨基酸残基组成轻链恒定区CL。
SEQ ID No.3所示的DNA分子编码SEQ ID No.1所示的多肽(重链)。SEQ ID No.3中,自5’端第1-363位核苷酸编码VH(其中,第76-99位核苷酸编码HCDR1,第151-174位核苷酸编码HCDR2,第289-363位核苷酸编码HCDR3),第364-666位核苷酸编码CH1,第667-711位核苷酸编码Hinge,第712-1041位核苷酸编码CH2,第1042-1362位核苷酸编码CH3,第1363-1365位核苷酸为终止密码子。
SEQ ID No.4所示的DNA分子编码SEQ ID No.2所示的多肽(轻链)。SEQ ID No.4中,自5’端第1-327位核苷酸编码VL(其中,第79-96位核苷酸编码LCDR1,第148-156位核苷酸编码LCDR2,第265-291位核苷酸编码LCDR3),第328-642位核苷酸编码CL,第643-645位核苷酸为终止密码子。
其中,互补决定区的序列根据Kabat定义。
抗体6B1为全人源单抗,为IgG1,轻链类型为kappa(κ)型。
利用FectoPRO转染试剂(Polyplus-transfection公司产品,货号116-010),按说明书将上述构建好的抗体6B1的轻重链重组表达质粒共转染FreeStyleTM 293F细胞,在无血清悬浮培养条件下培养3天,离心收获培养上清。上清中的抗体用HitrapTM MabSelectXtra/SuRe(GE公司产品,货号28-4082-55)等ProteinA/G亲和层析柱按说明书进行纯化。然后利用HitrapTM Desalting(GE公司产品,货号29-0486-84)将抗体保存缓冲液置换为10mM柠檬酸盐缓冲液(pH6.0)或者其他合适的缓冲液。必要时,可以对抗体样品进行过滤除菌,然后分装分别置于4℃和-20℃保存。
实施例2、单抗6B1的血清型特异性
利用C6/36细胞分别接种培养四种血清型的登革病毒,收集培养上清收获病毒原液。取适量病毒原液,加入4×Loading buffer,水浴煮沸制备蛋白样品。取10μL蛋白样品行SDS-PAGE,然后将蛋白样品电转至PVDF膜(Amersham公司产品,货号10600023),用5%脱脂牛奶封闭。加入待检抗体6B1(1μg/mL)室温孵育2h或4℃冰箱孵育过夜。用TBS-T洗膜三次,每次10min,加入1:5000稀释的HRP-Goat anti human IgG(中杉金桥公司产品,货号ZB2304),室温孵育1h。用TBS-T洗膜三次,每次10min。膜上加显影液,用凝胶成像仪曝光显影。
图1显示6B1与四种血清型登革病毒都结合,但是与DENV-1和DENV-2结合较强,与DENV-3和DENV-4结合较弱,结合条带在70kD左右,与E蛋白的分子量一致,表明它识别的是四种血清型登革病毒的E蛋白。
实施例3、ELISA检测单抗6B1与抗原的结合
96孔酶联板分别包被四种血清型的登革病毒重组E蛋白(RayBiotech公司产品,货号分别为228-11688,228-11689,228-11690,228-11691),2μg/mL,100μL/孔,4℃包被过夜;或包被四种血清型的灭活登革病毒培养上清,100μL/孔,4℃包被过夜。弃包被液后PBST洗涤5min/次×3次,加入2%BSA-PBST,200μL/孔,置于37℃封闭2h。加入3倍倍比稀释的6B1抗体(浓度:30μg/mL-0.17ng/mL),50μL/孔,37℃孵育2h。弃一抗,PBST洗涤5min/次×3次,加入1:5000稀释的二抗HRP-Goat anti human IgG(中杉金桥公司产品,货号ZB2304),37℃孵育1h。弃二抗,PBST洗涤5min/次×3次,每孔加入100μL显色液,置于避光处,待显色完全每孔加入100μL终止液。酶标仪读取293nm/630nm波长吸光值。
图2、图3显示单抗6B1既可以结合灭活登革病毒,也可以结合重组E蛋白,说明6B1识别的可能是E蛋白上的线性表位。单抗6B1对DENV-1和DENV-2的亲和力较高,但对DENV-3和DENV-4的亲和力较弱,这也与图1显示的结果一致。
实施例4、单抗6B1的亲和力测定
将纯化后的待检测抗体6B1用HBS-EP缓冲液(CM5芯片试剂盒中)稀释至1μg/mL,并偶联至预先包被有Protein G的CM5芯片(GE公司产品,货号BR100014)上,偶联条件为:温度25℃,流速5μL/min,偶联量为200RU。DENV重组E蛋白(RayBiotech公司产品,货号分别为228-11688,228-11689,228-11690,228-11691)作为流动相,用HBS-EP缓冲液做两倍浓度梯度稀释,其浓度范围为20nM-625pM,测试条件:温度25℃,流速30μL/min;结合时间为3min,解离时间为15min。完成一个反应后,对芯片进行再生,再生条件:3M MgCl2,30μL/min×30s,再生后继续偶联相同量的待测抗体,进行下一个反应。实验结束后,扣除空白对照的值,用BIAevaluation软件进行结果分析。检测结果显示单抗6B1对DENV-1重组E蛋白的亲和力KD=0.44nM(图4)。
实施例5、单抗6B1的体外中和活性
利用空斑减少中和实验(Plaque Reduction Neutralization Test,PRNT)检测抗体的体外中和活性。实验前24h取生长状态良好的BHK-21细胞,胰酶消化后调整细胞密度至2.5×105个/mL,接种6孔细胞培养板,每孔2mL。实验当天在96孔板中,3倍梯度稀释抗体6B1,由100μg/mL至5.65×10-4μg/mL,并设置无抗体阴性对照,100μL/孔。每孔加入等体积含约100PFU的登革病毒悬液,混匀后置于37℃5%CO2的培养箱中作用1h。弃去BHK-21细胞的培养基,每孔加入800μL DMEM细胞维持液。将孵育结束的登革病毒与抗体混合物加入到6孔板中,37℃5%CO2培养箱中继续孵育1h。弃上清,PBS缓冲液洗2遍,加入上层半固体培养基(1g低熔点琼脂糖(Amresco公司产品,货号0815)加入50mL水中,加热熔化后温度降至42℃左右,与50mL 2×DMEM培养基(含2mL胎牛血清)混合,使胎牛血清和低熔点琼脂糖的终浓度分别为2%和1%),继续培养4-5天。待细胞出现病变后,每孔加入1mL 4%多聚甲醛溶液,放置于4℃1h以固定细胞。去除上层琼脂糖,每孔加入1mL 1%结晶紫染液,室温染色30min。用去离子水冲洗后计数空斑,计算抗体对所有四种血清型登革病毒的抑制率。计算方法:抑制率=(阴性对照空斑数-实验组空斑数)/阴性对照空斑数×100%。
结果如图5所示,抗体的中和活性具有剂量依赖关系,在一定浓度范围内,随着抗体浓度的提高,对病毒感染的抑制作用显著增强。通过对抗体的中和活性效价进行非线性统计分析,计算得到PRNT50值。单抗6B1对四种血清型登革病毒的中和活性分别为:PRNT50=2.33μg/mL、2.89μg/mL、19.65μg/mL、12.64μg/mL。单抗6B1对DENV-1和DENV-2的中和活性较强,但对DENV-3和DENV-4的中和活性较弱,与亲和力结果一致。
实施例6、单抗6B1的体内抗病毒活性
一、病毒感染乳鼠的半数致死剂量(LD50)测定
将测定病毒滴度后的登革病毒原液10倍梯度稀释。出生24h内昆明种乳鼠颅内接种病毒原液,每个浓度接种1窝(约10只),每只1μL。继续观察21天,每天记录乳鼠的发病和死亡情况,根据每个浓度组小鼠存活数计算小鼠的存活率,并利用Graphpad软件,计算小鼠半数致死剂量(LD50)
二、乳鼠保护试验
1、预防效果评价
出生24h内昆明种乳鼠颅内注射5μL浓度为200μg/mL、20μg/mL、2μg/mL的抗体,24h后经颅途径接种10LD50的登革病毒5μL。观察21天,每天记录乳鼠发病和死亡情况,根据小鼠存活数计算小鼠的存活率,并用Graphpad软件作图分析,结果见图6。6B1针对DENV-1的感染,0.1μg/只的剂量可以保护70%的乳鼠,而1μg/只的剂量可以保护100%的乳鼠;6B1对DENV-2感染的保护效果更佳,0.01μg/只的剂量就可以保护90%的乳鼠,而1μg/只的剂量可以保护100%的乳鼠;6B1对DENV-3感染的保护效果稍弱一些,1μg/只的剂量只可以保护70%的乳鼠;6B1对DENV-4感染的保护效果最弱,5μg/只的剂量才可以保护70%的乳鼠。
2、治疗效果评级
出生24h内昆明种乳鼠颅内接种10LD50的登革病毒5μL,6h后经颅途径注射5μL浓度为200μg/mL的抗体,观察21天,每天记录乳鼠发病和死亡情况,根据小鼠存活数计算小鼠的存活率,并用Graphpad软件作图分析,结果见图7。6B1针对DENV-1和DENV-2的攻击,1μg/只的剂量可以保护50%的乳鼠。
综上所述,6B1可有效预防四种血清型DENV的感染,治疗致死剂量DENV-1和DENV-2的感染。
<110> 中国人民解放军军事科学院军事医学研究院
<120> 一种特异性结合四种血清型登革病毒的人源抗体
<130> GNCLN190313
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 454
<212> PRT
<213> Artificial sequence
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Ser
1 5 10 15
Ser Leu Ser Met Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ser Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ser Gly Ile Ser Trp Asn Ser Ala Thr Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Asp
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Asp Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Pro Arg Gly Leu Gln Leu Leu Ser Ser Trp Val Glu
100 105 110
Tyr Leu Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys
450
<210> 2
<211> 214
<212> PRT
<213> Artificial sequence
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Arg Arg Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Gln Asn Pro Gln
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 3
<211> 1365
<212> DNA
<213> Artificial sequence
<400> 3
gaagtgcagc tggtggaatc tggcggcgga ctggtgcagc ctggcagtag cctgagtatg 60
agctgtgccg ccagcggctt caccttcgac gactactcca tgttctgggt gcgccaggcc 120
cctggcaaag gcctggaatg gatcagcggc atcagctgga acagcgccac catcggctac 180
gccgatagcg tgaagggccg gttcaccatc agccgggaca acgccaagaa gtccctggac 240
ctgcagatga acagcctgcg gcctgatgac accgccctgt actattgtgc caagggcgga 300
cctcgtggcc tgcagctgct gagtagctgg gtggagtatt tgggccaggg caccctcgtg 360
accgtgtcct cagctagcac caagggccca tcggtcttcc ccctggcacc ctcctccaag 420
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 480
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 540
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 600
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 660
agagttgagc ccaaatcttg tgacaaaact cacacatgcc caccgtgccc agcacctgaa 720
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 780
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 840
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 900
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 960
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1020
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1080
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1140
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1200
acgcctcccg tgctggactc cgacggctcc ttcttcctct atagcaagct caccgtggac 1260
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcatga ggctctgcac 1320
aaccactaca cgcagaagag cctctccctg tccccgggta aatga 1365
<210> 4
<211> 645
<212> DNA
<213> Artificial sequence
<400> 4
gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggtga tcgcgtgacc 60
attacctgcc gcgcgagcca ggatgtccgt agatacctga attggtatca gcagaaaccg 120
ggtaaagcgc cgaaactgtt aatttatact gccagcaccc gggagtctgg cgtgccgtcg 180
cgttttagcg gctcgggttc gggcaccgat tttaccctga ccatctcgag cttgcagccg 240
gaggacttcg ccacctacta ttgccagcaa gcggaccaga acccacagac cttcggtcag 300
ggcaccaaag tggagatcaa acgtacggtg gcggcgccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggtaccgct agcgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttga 645
Claims (10)
1.抗体,其特征在于:所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26-33位、第51-58位、第97-121位所示;所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第27-32位、第50-52位、第89-97位所示。
2.根据权利要求1所述的抗体,其特征在于:所述重链可变区的氨基酸序列为SEQ IDNo.1自N端起第1-121位,或者与SEQ ID No.1自N端起第1-121位具有至少90%的一致性;
所述轻链可变区的氨基酸序列为SEQ ID No.2自N端起第1-109位,或者与SEQ ID No.2自N端起第1-109位具有至少90%的一致性。
3.根据权利要求1或2所述的抗体,其特征在于:所述抗体为IgG;
进一步地,所述IgG为IgG1。
4.根据权利要求1-3中任一所述的抗体,其特征在于:所述抗体的轻链类型为kappa型。
5.根据权利要求1-4中任一所述的抗体,其特征在于:所述抗体的重链的氨基酸序列为SEQ ID No.1,或者与SEQ ID No.1具有至少90%的一致性;
所述抗体的轻链的氨基酸序列为SEQ ID No.2或者与SEQ ID No.2具有至少90%的一致性。
6.核酸分子,其特征在于:所述核酸分子编码权利要求1-5中任一所述的抗体或所述抗体中的抗原结合部分。
7.根据权利要求6所述的核酸分子,其特征在于:在所述核酸分子中,编码所述抗体的重链可变区中HCDR1、HCDR2和HCDR3的核苷酸序列依次如SEQ ID No.3自5’端起第76-99位、第151-174位、第289-363所示,编码所述抗体的轻链可变区中LCDR1、LCDR2和LHCDR3的核苷酸序列依次如SEQ ID No.4自5’端起第79-96位、第148-156位、第265-291位所示;
进一步地,在所述核酸分子中,编码所述抗体的所述重链可变区的核苷酸序列为SEQID No.3自5’端起第1-363位或者与SEQ ID No.3自5’端起第1-363位具有至少90%的一致性,编码所述抗体的所述轻链可变区的核苷酸序列为SEQ ID No.4自5’端起第1-327位或者与SEQ ID No.4自5’端起第1-327位具有至少90%的一致性;
更进一步地,在所述核酸分子中,编码所述抗体的重链的核苷酸序列为SEQ ID No.3或者与SEQ ID No.3具有至少90%的一致性,编码所述抗体的轻链的核苷酸序列为SEQ IDNo.4或者与SEQ ID No.4具有至少90%的一致性。
8.含有权利要求6或7所述核酸分子的表达盒、重组载体、重组细胞或重组菌。
9.药物组合物,其特征在于:所述药物组合物包含权利要求1-5中任一所述的抗体和药学可接受的赋形剂、稀释剂或载体。
10.应用,为如下任一所示:
(A1)权利要求6-8中任一所述的核酸分子或表达盒、重组载体、重组细胞或重组菌在制备权利要求1-5中任一所述抗体或权利要求9所述药物组合物中的应用;
(A2)权利要求1-5中任一所述抗体在制备权利要求9所述药物组合物中的应用;
(A3)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于预防和/或治疗由登革病毒感染所致疾病的产品中的应用;
(A4)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于抑制登革病毒感染的产品中的应用;
(A5)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的产品中的应用;
(A6)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的产品中的应用;
(A7)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于检测登革病毒的E蛋白的产品中的应用;
(A8)权利要求1-9中任一所述抗体或核酸分子或表达盒、重组载体、重组细胞或重组菌或药物组合物在制备用于结合登革病毒的E蛋白的产品中的应用;
进一步地,所述登革病毒为I型登革病毒、II型登革病毒、III型登革病毒和/或IV型登革病毒。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910196495.2A CN109929033B (zh) | 2019-03-15 | 2019-03-15 | 一种特异性结合四种血清型登革病毒的人源抗体 |
PCT/CN2019/100150 WO2020186687A1 (zh) | 2019-03-15 | 2019-08-12 | 一种特异性结合四种血清型登革病毒的人源抗体 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910196495.2A CN109929033B (zh) | 2019-03-15 | 2019-03-15 | 一种特异性结合四种血清型登革病毒的人源抗体 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109929033A true CN109929033A (zh) | 2019-06-25 |
CN109929033B CN109929033B (zh) | 2020-06-02 |
Family
ID=66987101
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910196495.2A Active CN109929033B (zh) | 2019-03-15 | 2019-03-15 | 一种特异性结合四种血清型登革病毒的人源抗体 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN109929033B (zh) |
WO (1) | WO2020186687A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111032077A (zh) * | 2017-05-22 | 2020-04-17 | 叶才明 | 抗-登革热病毒抗体、包含该抗体的药学组合物及其用途 |
CN111995674A (zh) * | 2020-09-03 | 2020-11-27 | 中国人民解放军军事科学院军事医学研究院 | 抗COVID-19病毒中和抗体mhC3及其人源化抗体与应用 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024036265A2 (en) * | 2022-08-12 | 2024-02-15 | Takeda Vaccines, Inc. | Novel anti-denv3 antibodies |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013035345A2 (en) * | 2011-09-09 | 2013-03-14 | Osaka University | Dengue-virus serotype neutralizing antibodies |
WO2016148653A1 (en) * | 2015-03-17 | 2016-09-22 | Agency For Science, Technology And Research | A serotype cross-reactive, dengue neutralizing antibody and uses thereof |
CN106211773A (zh) * | 2014-02-11 | 2016-12-07 | 威特拉公司 | 用于登革病毒的抗体分子及其应用 |
-
2019
- 2019-03-15 CN CN201910196495.2A patent/CN109929033B/zh active Active
- 2019-08-12 WO PCT/CN2019/100150 patent/WO2020186687A1/zh active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013035345A2 (en) * | 2011-09-09 | 2013-03-14 | Osaka University | Dengue-virus serotype neutralizing antibodies |
CN106211773A (zh) * | 2014-02-11 | 2016-12-07 | 威特拉公司 | 用于登革病毒的抗体分子及其应用 |
WO2016148653A1 (en) * | 2015-03-17 | 2016-09-22 | Agency For Science, Technology And Research | A serotype cross-reactive, dengue neutralizing antibody and uses thereof |
Non-Patent Citations (3)
Title |
---|
FIBRIANSAH,G.等: "A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins", 《NATURE COMMUNICATIONS》 * |
SMITH,S.A.等: "The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein", 《MBIO》 * |
尹庆庆等: "登革病毒治疗性抗体的基础研究进展", 《分子诊断与治疗杂志》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111032077A (zh) * | 2017-05-22 | 2020-04-17 | 叶才明 | 抗-登革热病毒抗体、包含该抗体的药学组合物及其用途 |
CN111995674A (zh) * | 2020-09-03 | 2020-11-27 | 中国人民解放军军事科学院军事医学研究院 | 抗COVID-19病毒中和抗体mhC3及其人源化抗体与应用 |
CN111995674B (zh) * | 2020-09-03 | 2022-02-11 | 中国人民解放军军事科学院军事医学研究院 | 抗COVID-19病毒中和抗体mhC3及其人源化抗体与应用 |
Also Published As
Publication number | Publication date |
---|---|
WO2020186687A1 (zh) | 2020-09-24 |
CN109929033B (zh) | 2020-06-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103980361B (zh) | 抗体 | |
AU2003243139B2 (en) | Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors | |
CN111647077A (zh) | 新型冠状病毒(sars-cov-2)刺突蛋白结合分子及其应用 | |
DK2420572T3 (en) | MONOCLONAL ANTIBODY THAT CAN BIND TO SPECIFIC discontinuous EPITOPE, OCCURRING IN AD 1 REGION OF HUMAN cytomegalovirus GB-glycoprotein AND ANTIBODY-binding fragment thereof. | |
RU2717651C2 (ru) | Антитела к церамиду | |
EA013614B1 (ru) | Изолированное антитело к фактору роста нервов (ngf) и способы его применения | |
KR20100034015A (ko) | 알레르기 질환 치료를 위한 방법 및 조성물 | |
CN114292326B (zh) | 新型冠状病毒(sars-cov-2)刺突蛋白结合分子及其应用 | |
CN108484767A (zh) | 人抗pd-1、pd-l1和pd-l2的抗体及其应用 | |
CN102083858A (zh) | 抗il-17a/il-17f交叉反应性抗体及其使用方法 | |
CN109929033B (zh) | 一种特异性结合四种血清型登革病毒的人源抗体 | |
CN101374944A (zh) | 用于获得永生化抗体分泌细胞的方法 | |
CN109385400A (zh) | 共表达pd-l1阻断剂的嵌合抗原受体修饰的免疫效应细胞 | |
WO2021052307A1 (zh) | 一种抗b7-h3抗体及其应用 | |
EP2582389B1 (en) | High affinity human antibodies to human cytomegalovirus (cmv) gb protein | |
CN109678963A (zh) | 一种靶向cd24且激活nk细胞的双特异性抗体的制备及其应用 | |
CN112794904B (zh) | 一种抗4-1bb的人源化抗体的用途 | |
CN111471655B (zh) | 抗人il12/23稳转细胞株及其构建方法和应用 | |
CN112794905B (zh) | 一种能够与人4-1bb结合的分子 | |
CN103087155A (zh) | 一种狂犬病毒疫苗增效蛋白及编码该蛋白的基因和应用 | |
US20040013672A1 (en) | Recombinant antibodies, and compositions and methods for making and using the same | |
WO2023046097A1 (zh) | 抗tigit人源化抗体或其抗原结合片段及其应用 | |
US20180244787A1 (en) | Anti-human cxcr3 antibodies for treatment of vitiligo | |
WO2021093753A1 (zh) | 一种能够与人4-1bb结合的分子及其应用 | |
CN109706164A (zh) | 微环dna表达连接人和猴cd20与效应细胞抗原的桥接分子及其应用 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |