CN113563464A - 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 - Google Patents
人源化高中和活性抗新型冠状病毒单克隆抗体及应用 Download PDFInfo
- Publication number
- CN113563464A CN113563464A CN202110877644.9A CN202110877644A CN113563464A CN 113563464 A CN113563464 A CN 113563464A CN 202110877644 A CN202110877644 A CN 202110877644A CN 113563464 A CN113563464 A CN 113563464A
- Authority
- CN
- China
- Prior art keywords
- seq
- antibody
- ser
- novel coronavirus
- monoclonal antibody
- 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
- 241000711573 Coronaviridae Species 0.000 title claims abstract description 34
- 238000006386 neutralization reaction Methods 0.000 title claims description 15
- 230000000694 effects Effects 0.000 title claims description 11
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 35
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims description 41
- 108091033319 polynucleotide Proteins 0.000 claims description 15
- 239000002157 polynucleotide Substances 0.000 claims description 15
- 102000040430 polynucleotide Human genes 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- 239000013598 vector Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 241000700605 Viruses Species 0.000 abstract description 14
- 210000003719 b-lymphocyte Anatomy 0.000 abstract description 8
- 230000014509 gene expression Effects 0.000 abstract description 7
- 241000831652 Salinivibrio sharmensis Species 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 3
- 208000025721 COVID-19 Diseases 0.000 abstract description 2
- 230000004544 DNA amplification Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 42
- 239000000243 solution Substances 0.000 description 20
- 241000282414 Homo sapiens Species 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 10
- 230000006287 biotinylation Effects 0.000 description 10
- 238000007413 biotinylation Methods 0.000 description 10
- 239000013604 expression vector Substances 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 239000006228 supernatant Substances 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 241001112090 Pseudovirus Species 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 239000000427 antigen Substances 0.000 description 7
- 230000000903 blocking effect Effects 0.000 description 7
- 238000003757 reverse transcription PCR Methods 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 241000880493 Leptailurus serval Species 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 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 5
- 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 5
- 238000012408 PCR amplification Methods 0.000 description 5
- 108091005634 SARS-CoV-2 receptor-binding domains Proteins 0.000 description 5
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 5
- 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 5
- 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 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 238000001962 electrophoresis Methods 0.000 description 5
- 108010010147 glycylglutamine Proteins 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 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 4
- 108010090804 Streptavidin Proteins 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012163 sequencing technique Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920000936 Agarose Polymers 0.000 description 3
- 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 3
- 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 3
- 101710139375 Corneodesmosin Proteins 0.000 description 3
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 3
- 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 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 3
- 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 3
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- 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 3
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 3
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 239000007758 minimum essential medium Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 2
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 2
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 2
- 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 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 102100031673 Corneodesmosin Human genes 0.000 description 2
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 2
- 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 2
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 2
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 2
- 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 2
- 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 2
- DBUNZBWUWCIELX-JHEQGTHGSA-N Gly-Thr-Glu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DBUNZBWUWCIELX-JHEQGTHGSA-N 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- IITVUURPOYGCTD-NAKRPEOUSA-N Ile-Pro-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IITVUURPOYGCTD-NAKRPEOUSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 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 2
- 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 2
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 2
- 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 2
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 2
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 2
- 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 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
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 239000012124 Opti-MEM Substances 0.000 description 2
- 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 2
- XWCYBVBLJRWOFR-WDSKDSINSA-N Ser-Gln-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O XWCYBVBLJRWOFR-WDSKDSINSA-N 0.000 description 2
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 2
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 2
- 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 2
- MFQMZDPAZRZAPV-NAKRPEOUSA-N Ser-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N MFQMZDPAZRZAPV-NAKRPEOUSA-N 0.000 description 2
- 108010034546 Serratia marcescens nuclease Proteins 0.000 description 2
- 101710172711 Structural protein Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 2
- 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 2
- OGPKMBOPMDTEDM-IHRRRGAJSA-N Tyr-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N OGPKMBOPMDTEDM-IHRRRGAJSA-N 0.000 description 2
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 2
- 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 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000001215 fluorescent labelling Methods 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000001806 memory b lymphocyte Anatomy 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- UKPGFKQVRITNFM-KBPBESRZSA-N 2-[[2-[[(2s)-1-[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]acetic acid Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)NCC(O)=O)C1=CC=C(O)C=C1 UKPGFKQVRITNFM-KBPBESRZSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-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
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-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
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 1
- DBKNLHKEVPZVQC-LPEHRKFASA-N Arg-Ala-Pro Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O DBKNLHKEVPZVQC-LPEHRKFASA-N 0.000 description 1
- OTCJMMRQBVDQRK-DCAQKATOSA-N Arg-Asp-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O OTCJMMRQBVDQRK-DCAQKATOSA-N 0.000 description 1
- FBLMOFHNVQBKRR-IHRRRGAJSA-N Arg-Asp-Tyr Chemical compound NC(N)=NCCC[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 FBLMOFHNVQBKRR-IHRRRGAJSA-N 0.000 description 1
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 1
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 1
- IIAXFBUTKIDDIP-ULQDDVLXSA-N Arg-Leu-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O IIAXFBUTKIDDIP-ULQDDVLXSA-N 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- LEFKSBYHUGUWLP-ACZMJKKPSA-N Asn-Ala-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LEFKSBYHUGUWLP-ACZMJKKPSA-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
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 1
- QUAWOKPCAKCHQL-SRVKXCTJSA-N Asn-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N QUAWOKPCAKCHQL-SRVKXCTJSA-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
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-N 0.000 description 1
- ANRZCQXIXGDXLR-CWRNSKLLSA-N Asn-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC(=O)N)N)C(=O)O ANRZCQXIXGDXLR-CWRNSKLLSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- DBWYWXNMZZYIRY-LPEHRKFASA-N Asp-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O DBWYWXNMZZYIRY-LPEHRKFASA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-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
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-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
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-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
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 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
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-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
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 108050003866 Bifunctional ligase/repressor BirA Proteins 0.000 description 1
- 102100033743 Biotin-[acetyl-CoA-carboxylase] ligase Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- JESJDAAGXULQOP-CIUDSAMLSA-N Gln-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N JESJDAAGXULQOP-CIUDSAMLSA-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
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 1
- XBWGJWXGUNSZAT-CIUDSAMLSA-N Gln-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N XBWGJWXGUNSZAT-CIUDSAMLSA-N 0.000 description 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 1
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- JRCUFCXYZLPSDZ-ACZMJKKPSA-N Glu-Asp-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O JRCUFCXYZLPSDZ-ACZMJKKPSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- NPMSEUWUMOSEFM-CIUDSAMLSA-N Glu-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N NPMSEUWUMOSEFM-CIUDSAMLSA-N 0.000 description 1
- JZJGEKDPWVJOLD-QEWYBTABSA-N Glu-Phe-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JZJGEKDPWVJOLD-QEWYBTABSA-N 0.000 description 1
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 1
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-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
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- XRTDOIOIBMAXCT-NKWVEPMBSA-N Gly-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)CN)C(=O)O XRTDOIOIBMAXCT-NKWVEPMBSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- RPLLQZBOVIVGMX-QWRGUYRKSA-N Gly-Asp-Phe Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RPLLQZBOVIVGMX-QWRGUYRKSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-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
- LRQXRHGQEVWGPV-NHCYSSNCSA-N Gly-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN LRQXRHGQEVWGPV-NHCYSSNCSA-N 0.000 description 1
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 1
- OJNZVYSGVYLQIN-BQBZGAKWSA-N Gly-Met-Asp Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O OJNZVYSGVYLQIN-BQBZGAKWSA-N 0.000 description 1
- WMGHDYWNHNLGBV-ONGXEEELSA-N Gly-Phe-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WMGHDYWNHNLGBV-ONGXEEELSA-N 0.000 description 1
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-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
- JQFILXICXLDTRR-FBCQKBJTSA-N Gly-Thr-Gly Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)NCC(O)=O JQFILXICXLDTRR-FBCQKBJTSA-N 0.000 description 1
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- HRGGKHFHRSFSDE-CIUDSAMLSA-N His-Asn-Ser Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N HRGGKHFHRSFSDE-CIUDSAMLSA-N 0.000 description 1
- BSVLMPMIXPQNKC-KBPBESRZSA-N His-Phe-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O BSVLMPMIXPQNKC-KBPBESRZSA-N 0.000 description 1
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- OVPYIUNCVSOVNF-ZPFDUUQYSA-N Ile-Gln-Pro Natural products CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O OVPYIUNCVSOVNF-ZPFDUUQYSA-N 0.000 description 1
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 1
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 1
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-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
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 1
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-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
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 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
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 1
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 1
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-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
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-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
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-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
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 1
- QGQGAIBGTUJRBR-NAKRPEOUSA-N Met-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCSC QGQGAIBGTUJRBR-NAKRPEOUSA-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
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 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
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-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
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- CKJACGQPCPMWIT-UFYCRDLUSA-N Phe-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CKJACGQPCPMWIT-UFYCRDLUSA-N 0.000 description 1
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-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
- QTDBZORPVYTRJU-KKXDTOCCSA-N Phe-Tyr-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O QTDBZORPVYTRJU-KKXDTOCCSA-N 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 101150010882 S gene Proteins 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
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 1
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 1
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-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
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- NNFMANHDYSVNIO-DCAQKATOSA-N Ser-Lys-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NNFMANHDYSVNIO-DCAQKATOSA-N 0.000 description 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-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
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-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
- DYEGLQRVMBWQLD-IXOXFDKPSA-N Ser-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CO)N)O DYEGLQRVMBWQLD-IXOXFDKPSA-N 0.000 description 1
- RTXKJFWHEBTABY-IHPCNDPISA-N Ser-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CO)N RTXKJFWHEBTABY-IHPCNDPISA-N 0.000 description 1
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 1
- KIEIJCFVGZCUAS-MELADBBJSA-N Ser-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N)C(=O)O KIEIJCFVGZCUAS-MELADBBJSA-N 0.000 description 1
- OSFZCEQJLWCIBG-BZSNNMDCSA-N Ser-Tyr-Tyr Chemical compound [H]N[C@@H](CO)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 OSFZCEQJLWCIBG-BZSNNMDCSA-N 0.000 description 1
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-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
- XSLXHSYIVPGEER-KZVJFYERSA-N Thr-Ala-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XSLXHSYIVPGEER-KZVJFYERSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 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
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 1
- HOVLHEKTGVIKAP-WDCWCFNPSA-N Thr-Leu-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HOVLHEKTGVIKAP-WDCWCFNPSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 1
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 1
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-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
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 1
- DLZKEQQWXODGGZ-KWQFWETISA-N Tyr-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DLZKEQQWXODGGZ-KWQFWETISA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- GAYLGYUVTDMLKC-UWJYBYFXSA-N Tyr-Asp-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GAYLGYUVTDMLKC-UWJYBYFXSA-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
- CNLKDWSAORJEMW-KWQFWETISA-N Tyr-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O CNLKDWSAORJEMW-KWQFWETISA-N 0.000 description 1
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-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
- LUMQYLVYUIRHHU-YJRXYDGGSA-N Tyr-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LUMQYLVYUIRHHU-YJRXYDGGSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 1
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 1
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 1
- GBESYURLQOYWLU-LAEOZQHASA-N Val-Glu-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N GBESYURLQOYWLU-LAEOZQHASA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-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
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-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
- AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 1
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 1
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 1
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-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
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 1
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-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
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- NKLPQNGYXWVELD-UHFFFAOYSA-M coomassie brilliant blue Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=C1 NKLPQNGYXWVELD-UHFFFAOYSA-M 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 238000012350 deep sequencing Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000003367 kinetic assay Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940126583 recombinant protein vaccine Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000012855 volatile organic compound Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
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
- 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
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- 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
- C12N2800/00—Nucleic acids vectors
- C12N2800/10—Plasmid DNA
- C12N2800/106—Plasmid DNA for vertebrates
- C12N2800/107—Plasmid DNA for vertebrates for mammalian
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2469/00—Immunoassays for the detection of microorganisms
- G01N2469/10—Detection of antigens from microorganism in sample from host
-
- 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
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Biomedical Technology (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Food Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Plant Pathology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
Abstract
本发明公开了一种人源化高中和活性抗新型冠状病毒单克隆抗体，本发明的中和抗体通过单个B细胞流式分选‑抗体基因扩增配对表达技术筛选获得，具有独特的CDR区域，能特异性与SARS‑COV‑2结合并且可以有效中和目前多株国际流行病毒(wuhan株，英国突变株B.1.1.7，南非突变株B.1.351，巴西突变株P.1，印度突变株B.1.617.1和B.1.617.2)，其IC50大部分在1μg/mL以下。本发明还涉及所述抗体制备新型冠状病毒病治疗或预防药物中的应用以及在制备新型冠状病毒检测试剂中的应用。所述抗体可以用于COVID‑19紧急预防和/或治疗，具有全人源化，高表达，稳定性好的特点，适合产业化。
Description
技术领域
本发明公开了一种多肽，更具体地，本发明公开一种抗体。
背景技术
SARS-Cov-2(也称为2019-nCov)属于正链RNA病毒的一种，属于冠状病毒家族的β属，其编码四种结构蛋白：spike(S),envelope(E),membrane(M),和nucleocapsid(N)、16种非结构蛋白，及5-8种辅助蛋白质。SARS Cov-2利用病毒表面的S蛋白与宿主细胞受体-血管紧张素转换酶II(ACE2)进入细胞。S蛋白根据蛋白结构功能又被分为两个功能单位，即S1和S2蛋白亚基。S1可分为NTD(N-terminal domain)和RBD(Receptor binding site)，RBD区域长约240个氨基酸，主要与宿主细胞受体结合，S2在病毒和细胞膜融合起作用。根据已有的报导，中和抗体主要作用于RBD区域，抗体结合于RBD，阻碍RBD与ACE2的结合，从而阻止病毒感染细胞。
目前国内外均有新冠中和抗体的分离研究报道，采用单细胞分选和抗体基因组深度测序方法，一批针对RBD的人源化单克隆抗体被分离出来，如1F11、2F6、CA1、CB6、BD-368-2等，这些抗体展现出了较强的体外中和活性(IC50<1μg/ml)，在表达ACE2的转基因小鼠动物体内也展现出了较好的治疗效果，可以显著降低小鼠肺部的病毒载量。但SARS-Cov-2处于不断变异中，一旦感染了中和表位发生变异的病毒，则已有的中和抗体将不再具有中和作用。事实上，已经有英国B.1.1.7突变株(N501Y、D614G)、巴西突变株P.1(N501Y、E484k、k417T、D614G)、南非突变株B.1.351(K417N、E484K、N501Y、D614G),印度突变株B.1.617(L452R、E484Q、D614G)相继出现，该三毒株对部分中和抗体或疫苗诱导出的抗体不敏感，且由于其较强的传播能力被世界卫生组织列为VOC(Variants of concern,受关注的变异病毒)。因此，有必要分离出更多的强效中和抗体作为备选，将这些针对不同表位的中和抗体进行各种配伍，探索鸡尾酒疗法，可以更有效地避免病毒发生免疫逃逸，目前科学界尚无已报道的类似广谱抗体以及抗体组合物。本发明的目的就是提供一组具有高中和活性抗新型冠状病毒单克隆抗体，在此基础上并提供所述高中和活性抗新型冠状病毒单克隆抗体在制备新冠病毒病治疗药物中的应用。
发明内容
基于上述发明目的，本发明首先提供了一种人源化广谱高中和活性抗新型冠状病毒单克隆抗体，所述抗体的重链可变区的CDR1、CDR2和CDR3以及轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如下所示：
(1)SEQ ID NO.1的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.3的第27-32、50-52、89-97位氨基酸；或者
(2)SEQ ID NO.5的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.7的第27-32、50-52和89-97位氨基酸；或者
(3)SEQ ID NO.9的第26-33、51-58和97-109位氨基酸以及SEQ ID NO.11的第27-32、50-52和89-97位氨基酸。
在一个优选的实施方案中，所述抗体重链的可变区以及轻链的可变区的氨基酸序列分别如下所示：
(1)SEQ ID NO.1以及SEQ ID NO.3；在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“SW-C11”，或者
(2)SEQ ID NO.5以及SEQ ID NO.7；在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“WJQ-G10”，或者
(3)SEQ ID NO.9以及SEQ ID NO.11，在本发明中，具有该重链的可变区以及轻链的可变区氨基酸序列的一个具体技术方案的抗体被命名为“WJQ-C11”。
在一个更为优选的实施方案中，所述抗体重链恒定区的氨基酸序列如SEQ IDNO.13所示，所述轻链恒定区的氨基酸序列如SEQ ID NO.15所示。
其次，本发明提供了一种编码上述人源化广谱高中和活性抗新型冠状病毒单克隆抗体的多核苷酸，编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸组合的序列分别如下所示：
(1)SEQ ID NO.2以及SEQ ID NO.4；或者
(2)SEQ ID NO.6以及SEQ ID NO.8；或者
(3)SEQ ID NO.10以及SEQ ID NO.12。
在一个优选的实施方案中，编码抗体重链恒定区的多核苷酸的序列如SEQ IDNO.14所示，所述轻链恒定区的多核苷酸的序列如SEQ ID NO.16所示。
第三，本发明还提供了一种表达上述人源化高中和活性抗新型冠状病毒单克隆抗体的载体，所述载体含有上述编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸，所述载体可以是基因工程中常规使用的真核表达载体，在本发明的一个具体实施方案中，所述载体为IgH(重链表达载体)、Igκ(κ轻链表达载体)(具体参见Tiller et al.Efficient generation of monoclonal antibodies from single humanB cells by single cell RT-PCR and expression vector cloning,J ImmunolMethods.2008January 1；329(1-2):112–124.，本发明通过引用将该现有技术文件并入到本发明的说明书中)。
第四，本发明提供了一种表达上述人源化高中和活性抗新型冠状病毒单克隆抗体的宿主细胞，所述宿主细胞含有上述的载体。
所述宿主细胞可以为基因工程中常规使用的真核宿主细胞，在本发明的一个具体实施方案中，所述宿主细胞为293F细胞。
第五，本发明提供了上述人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒病治疗和/或预防药物中的应用，所述抗体或者抗体组合物可以开发临床治疗药物，靶向药物、SARS-COV-2重组蛋白及亚单位疫苗。
在一个优选的实施方案中，所述应用可以为含有至少两种抗体的组合物应用。本发明提供的3种抗体不仅具有高中和活性，而且还具有广谱性，对目前世界范围内的多种新冠病毒变异株都具有较强的中和能力，因此应用含有本发明至少两种以上的抗体组合物能够更有效地提升对新冠病毒多个变异株广谱的中和能力，因此含有本发明的抗体组合物形式在开发临床治疗药物，靶向药物、SARS-COV-2重组蛋白及亚单位疫苗具有广阔的应用前景，具体的应用可以包括SW-C11与WJQ-G10的组合应用，SW-C11与WJQ-C11的组合应用，WJQ-G10与WJQ-C11的组合应用，以及SW-C11、WJQ-G10和WJQ-C11的3株抗体的组合应用。
最后，本发明提供了上述人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒检测试剂中的应用。
本发明提供的人源化高中和活性抗新型冠状病毒单克隆抗体通过单个B细胞流式分选-抗体基因扩增配对表达技术筛选获得，具有独特的CDR区域，能与SARS-COV-2特异性结合并且可以有效中和目前多株国际流行病毒(wuhan株，英国突变株B.1.1.7，南非突变株B.1.351，巴西突变株P.1，印度突变株B.1.617.1和B.1.617.2)，对世界范围内多个不同的新型冠状病毒代表株具有显著的广谱中和能力。因此本发明提供的抗体以及含有两种抗体的组合物可以用于制备COVID-19紧急预防和/或治疗药物，具有全人源化，高表达，稳定性好的特点，适合产业化。此外，该抗体还可用于制备SARS-COV-2病毒检测试剂，用于检测病毒抗原以及用于发现有效中和抗原表位。
附图说明
图1.生物素化RBD蛋白的效价检测结果图，其中A.磁珠法检测RBD生物素化效率；B.ELISA法检测生物素化效率；
图2.流式分选RBD特异性B细胞示意图；
图3.抗体针对RBD结合能力的ELISA结果图；
图4.采用BLI技术检测SW-C11抗体的抗体-抗原亲和力结果图；
图5.采用BLI技术检测WJQ-G10抗体的抗体-抗原亲和力结果图；
图6.采用BLI技术检测WJQ-C11抗体的抗体-抗原亲和力结果图；
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的权利要求所限定的保护范围构成任何限制。
实施例1：新冠病毒RBD探针的合成、表达和生物素化及染色
1.1依据Genbank公布的数据(NC_045512)，合成携带6×His-Avi(His-His-His-His-His-His-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-Asp-Ile-Thr-Asn-Trp-Leu-Trp-Tyr-ILe-Lys-Lys-Lys)标签的RBD全长基因序列。
1.2经EcoRI和EcoRV双酶切后重新连接入真核表达载体pDRVI1.0(发明人构建并保存)，挑选克隆后经测序无误。
1.3将两探针质粒分别转染293F细胞进行表达，5-6天后离心培养液收取细胞上清，过镍柱纯化抗原蛋白。
1.4使用BirA 500生物素蛋白连接酶试剂盒(BirA500，Avidity)对探针蛋白进行生物素化。
将1mg分子探针蛋白溶解于0.7mL PBS缓冲液中，分别加入0.1mL10×缓冲液A、0.1mL 10×缓冲液B，再加入4μL BirA 500酶，混匀，30℃孵育30分钟；将混合物转移至10K浓缩管中，加10mL PBS，离心4000g15min至剩余体积0.5mL，重复这一操作5次；收集浓缩后的蛋白并测定浓度，存放至-80℃冰箱。
1.5检测分子探针生物素化活性
采用60微升链霉素标记的琼脂糖+10微克蛋白+500微升PBS置室温振荡器中摇30min，短暂离心，用1ml的PBS洗3次，最后一次尽量将液体吸弃干净，最后剩下大概30微升的琼脂糖，同时准备30微升的2×SDS凝胶加样缓冲液(100mM pH6.8 Tris-HCl、4％SDS、0.2％溴酚兰、20％甘油、200mMβ-巯基乙醇)上样缓冲液，将琼脂糖和混合缓冲液1:1混在一起，吸取20微升置于100℃,5-10min然后进行SDS-PAGE电泳；电泳结束后加适量考马斯亮蓝染色1小时后置于振荡器中脱色后观察电泳条带的深浅，判定生物素标记的效率，至少在50％以上可考虑进行荧光标记。
采用酶联免疫吸附试验(Enzyme-linked Immunosorbent Assay，ELISA)检测两探针的生物素化活性。用PBS将新冠抗原稀释至2μg/mL，加入96孔ELISA板中，每孔100μL，置于4℃过夜，次日用PBST(含0.05％吐温20的PBS)洗3次；每孔加入370μL封闭液(含2％牛奶和5％FBS的PBS)室温封闭1小时，用PBST(含0.05％吐温20的PBS)洗3次；向每孔加入100μL封闭液，第一行每孔再加入25μL稀释好的生物素标记的探针蛋白(生物素化的探针蛋白贮存浓度为50μg/mL，使用前5倍稀释于封闭液中)，混匀后从第一行每孔吸出25μL加入到第二行中，混匀后吸出25μL加入到第三行中，依次直至最后一行吸出25μL丢掉(每行之间形成五倍稀释梯度)，37℃孵育1小时，用PBST(含0.05％吐温20的PBS)洗5次；将辣根过氧化物酶标记的链霉亲和素(Sigma KPL HRP-SA)1000倍稀释于含有0.05％吐温20的封闭液中，每孔加100μL，37℃孵育1小时，用PBST洗5次板；每孔加入100μL底物，室温孵育20分钟后每孔加入50μL硫酸终止液立即终止反应，在酶标仪上读数保存。图1为生物素化RBD蛋白的效价检测结果，其中A为磁珠法检测RBD生物素化效率，泳道1-2为链霉亲和素磁珠从10μg生物素后的RBD蛋白中捕获生物素化成功的RBD，泳道3为10μg生物素化RBD，泳道4为分子量标志；由图1A可以看出，RBD生物素化效率超过50％；B为ELISA法检测生物素化效率，探针的终末浓度(end titer)为0.0032μg/mL。由结果可以看出，RBD的生物素化成功。
1.6生物素化的探针蛋白进行荧光标记
RBD-Avi探针蛋白用PE(藻红蛋白)进行荧光标记，以备单细胞流式分选时使用。
实施例2:抗SARS-COV-2人源化单克隆抗体的筛选和鉴定
2.1配制细胞裂解液：每孔20μl细胞裂解液，包含0.5μl去RNA酶，5μl 5×FirstStrand缓冲液，1.25μL 0.1M DTT，0.0625μl Igepal，13.25μl水，盖好封板膜，4℃冰箱放置待用。
2.2样本准备：
(1)新冠感染后康复者PBMCs细胞复苏：将冻存细胞管从液氮拿出后，迅速置于37℃水浴中，待融化至有冰芯时拿出，在生物安全柜中打开，缓慢滴入R10+Benzonase培养基(1支细胞使用5mL R10+Benzonase培养基)。1500rpm离心10分钟，弃去上清，用残液悬起细胞，加入10mL R10，混匀，取50μl进行细胞计数，1500rpm离心10分钟；调整细胞浓度：弃去上清，用残液悬起细胞，使用R10培养基调整浓度，向96孔U型板中2.5×106个/孔；
(2)配制2mM的EDTA/PBS溶液，下文用E-PBS表示；
(3)将96孔细胞板置于离心机内，4℃，2000rpm离心3分钟，弃去上清(生物安全柜内操作，纸巾高压放台内)；
(4)每孔加入50μl Vivid工作液(配制Vivid(UV)工作液：1:1000用PBS稀释，混匀)，混匀，避光冰上孵育20分钟；
(5)每孔加入150μl E-PBS，4℃，2000rpm离心3分钟；
(6)弃去上清，加入50μl胞外抗体混合液(2μl Anti-CD3-Alexflour700，1.5μlAnti-CD8-Pacific Blue，1.5μl Anti-CD14-Pacific Blue，1μl Anti-CD19-PECy7，2.5μlAnti-CD20-ECD，2μl Anti-CD27-APCCy7，1μl Anti-IgG-FITC，1μl Anti-IgM-PECy5，5μlAnti-RBD-PE，不足用E-PBS补齐)，混匀，避光冰上孵育60分钟；
(7)每孔加入150μL E-PBS，4℃，2000rpm离心3分钟，弃去上清；
(8)每孔加入200μL E-PBS，4℃，2000rpm离心3分钟，弃去上清；
(9)每孔加入200μL E-PBS，混匀，同一样本细胞悬液过滤到同一支流式管内，4℃避光保存供分选。
(10)单染管对照：设置1个未染色管对照(加入1滴补偿微球，200μl E-PBS)和10个单独染色管(每管加入补偿微球1滴，分别加入2μl Anti-CD3-Alexflour 700，1.5μl Anti-CD8-Pacific Blue，1.5μl Anti-CD14-Pacific Blue，1μl Anti-CD19-PECy7，2.5μl Anti-CD20-ECD，2μl Anti-CD27-APCCy7，1μl Anti-IgG-FITC，1μl Anti-IgM-PECy5，5μl Anti-RBD-PE，50μl UV工作液)，混匀，避光冰上孵育20分钟后每孔加入150μl E-PBS，4℃，2000rpm离心3分钟，弃上清，200μl E-PBS重悬。
2.3单个B细胞流式分选：选择CD3-CD8-CD14-CD19+CD20+CD27+IgG+IgM-RBD+的细胞进行分选，合计分选到56个细胞。首选圈定出单淋巴细胞群，再圈定出CD3-CD8-CD14-的活细胞以排除T细胞和巨噬细胞，再圈出CD19+CD20+的B细胞，再圈定出CD27+的记忆B细胞，再圈出IgG+IgM-的B细胞，最后圈出与探针RBD结合的记忆性B细胞。将这些B细胞每孔1个分选入含有以下裂解液体系的96孔板中(表1)。分选结束后，立刻用封口膜封好96孔板，在干冰上凝固，再转移入-80℃冰箱，过夜，第二天进行PCR操作。结果：流式分选的结果如图2所示。
表1.B细胞裂解液体系
2.4利用RT-PCR技术扩增全人源抗体可变区基因
配置如表2所示RT-PCR反应体系，每孔加入6μl，进行RT-PCR反应
表2.RT-PCR反应体系
RT-PCR反应程序设定：42℃反应10min，25℃反应10min，50℃反应50min，94℃反应5min，4度保存。
(1)进行两轮PCR反应，反应体系如下
第一轮PCR反应体系(表3)补充引物序列(表4)
表3.第一轮PCR反应体系
表4.第一轮PCR扩增用引物序列如下
第一轮PCR扩增用引物的扩增目的片段如表5所示。
表5.第一轮PCR扩增用引物的扩增目的片段
第一轮PCR反应程序如表6所示。
表6.第一轮PCR程序
第一轮PCR反应结束后进行第二轮PCR反应，第二轮PCR反应体系如表7所示。
表7.第二轮PCR反应体系
第二轮PCR引物序列如表8所示。
表8.第二轮PCR引物序列
第二轮PCR扩增用引物的扩增目的片段如表9所示。
表9.第二轮PCR扩增用引物的扩增目的片段
第二轮PCR反应程序如表10所示。
表10.第二轮PCR程序
(2)电泳、测序、家系分析
电泳检测二轮PCR产物，将重链和轻链产物直接测序；使用抗体家系基因数据库(http://www.imgt.org/IMGT_vquest/vquest)对测序结果进行分析，设计并合成带有酶切位点的抗体可变区序列(重链：5‘-Age I，3’-Sal I；Kappa链：5‘-Age I，3‘-BsiW I；Lambda链：5‘-Age I，3’-Xho I)，共计获得97对重链和轻链配对克隆。
2.5单克隆抗体表达载体构建和质粒转化
将合成的基因用相应的酶进行酶切后再次凝胶电泳回收，使用T4DNA连接酶将可变区基因与相应载体IgH(重链表达载体)、Igκ(κ轻链表达载体)、Igλ(λ轻链表达载体)(具体参见Tiller et al.Efficient generation of monoclonal antibodies from singlehuman B cells by single cell RT-PCR and expression vector cloning,J ImmunolMethods.2008January 1；329(1-2):112–124.，本发明通过引用将该现有技术文件并入到本发明的说明书中)在16℃连接仪上连接过夜16℃水浴过夜，转化。将10μL连接产物加入50μL DH5α感受态细胞中，振动摇匀，冰浴30分钟，42℃水浴热激45秒。离心管放入冰浴2分钟后，加入1mL无抗性的LB培养基，37℃，200rpm振荡培养1小时，4000rpm离心4分钟，将残留菌液涂布在抗性的LB平板上。37℃倒置培养14-16小时。挑取单克隆菌落接种到抗性的LB液体培养基中，37℃，200rpm振荡培养14-16小时后进行质粒提取(Omega公司的Plasmid MidiKit)。
2.6抗体表达和纯化
将293F细胞浓度调整为1.2×106个/ml，培养2小时。配置A液：25ml的opti-MEM加入500μg抗体重链DNA和500μg抗体轻链DNA，B液：25ml的opti-MEM中加入5ml的PEI转染试剂，静置5分钟。将A和B液混合，静置20分钟，逐滴加入1L的293F细胞中，边滴边摇匀，置于8％CO2，37℃下，摇动培养5天。
利用Protein A亲和柱(GE health公司产品)纯化得到抗体。利用NanoDrop2000超微量分光光度计(Thermo公司产品)测定抗体浓度，4℃放置待检测。本步骤从97个抗体轻/重链配对中表达出61个抗体(抗体量>10μg,抗体浓度>10μg/mL)。
实施例3抗体对SARS-COV-2假病毒的中和活性测定
3.1假病毒的包装：人工合成SARS-CoV-2(GenBank:MN908947)的S蛋白基因全长插入pcDNA3.1表达质粒，构建pcDNA-SARS-CoV2-S。带有突变的假病毒突变位点如表11所示，在S基因上引入。
表11.假病毒突变位点
将3×106(300万)个293T/17细胞接种于T75细胞培养瓶，5％CO2 37℃培养20-24小时。使用Fugene 6Transfection Reagent(Promega,Cat#E2691)进行转染：将30ug质粒pcDNA-SARS-CoV2-S转染T75培养瓶中的293T细胞，同时加入1.05×106TCID50的G*ΔG-VSV病毒感染293T，8小时后更换培养基。转染24小时后，收集培养上清并过滤获得SARS-CoV2 S蛋白的假病毒，-80℃冷冻保存。
3.2中和实验：
在一块96孔板中每孔加入100μL梯度稀释的抗体稀释液随后，用DMEM完全培养基将假病毒稀释至1.3×104TCID50/mL，于第3-11列每孔加50μL，使假病毒的加入量为650TCID50/孔。将上述96孔板置于细胞培养箱中(37℃、5％CO2)孵育1小时。当孵育时间至半小时，取出准备好的Vero细胞，吸弃培养基，加入PBS缓冲液清洗细胞，弃去PBS，加入胰酶-EDTA消化离心后，加入完全培养基重悬细胞，细胞计数。将细胞悬液稀释至2×105个/mL。孵育至1小时，向96孔板中每孔加100μL细胞，使每孔细胞为2×104个。将96孔板前后左右轻轻晃动，使细胞在孔中分散均匀，将96孔板放入细胞培养箱中，37℃、5％CO2培养28小时。从细胞培养箱中取出96孔板，用多道移液器从每个上样孔中吸弃150μL上清，然后加入100μL荧光素酶检测试剂，室温避光反应2分钟。反应结束后，于平板振荡器震荡混匀，放入多功能读板机中读取发光值。
计算中和抑制率：根据中和抑制率结果，计算抗体的IC50。
从61个测试抗体中，我们筛选出3株针对新冠南非突变株、新冠巴西变异株、新冠英国变异株、新冠印度变异株、新冠武汉株假病毒均具备较强中和活性的广谱中和抗体，所述3株抗体的编号分别为SW-C11、WJQ-G10和WJQ-C11。3株抗体针对不同变异株假病毒的中和能力结果见表12。
表12.抗体针对不同变异株假病毒的中和能力(IC50，μg/mL)
通过对编码上述抗体株的克隆进行测序，所述3株抗体的氨基酸及核苷酸序列如下：
抗体SW-C11的重链可变区核苷酸序列如SEQ ID NO.2所示，重链可变区的氨基酸序列如SEQ ID NO.1所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.1的第26-33、51-57和96-106位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.4所示，轻链可变区的氨基酸序列如SEQ ID NO.3所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.3的第27-32、50-52、89-97位氨基酸所示。
抗体WJQ-G10的重链可变区核苷酸序列如SEQ ID NO.6所示，重链可变区的氨基酸序列如SEQ ID NO.5所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.5的第26-33、51-57和96-106位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.8所示，轻链可变区的氨基酸序列如SEQ ID NO.7所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.7的第27-32、50-52、89-97位氨基酸所示。
抗体WJQ-C11的重链可变区核苷酸序列如SEQ ID NO.10所示，重链可变区的氨基酸序列如SEQ ID NO.9所示，其中，重链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQID NO.9的第26-33、51-58和97-109位氨基酸所示；轻链可变区核苷酸序列如SEQ ID NO.12所示，轻链可变区的氨基酸序列如SEQ ID NO.11所示，其中，轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如SEQ ID NO.11的第27-32、50-52、89-97位氨基酸所示。
上述3株抗体享有相同的重链恒定区和轻链恒定区。所述重链恒定区的核苷酸序列如SEQ ID NO.14所示，所述重链恒定区的氨基酸序列如SEQ ID NO.13所示，所述轻链为Kappa型，其恒定区的核苷酸序列如SEQ ID NO.16所示，所述重链恒定区的氨基酸序列如SEQ ID NO.15所示.
实施例4：抗体对活病毒的中和实验
提前1天将Vero-E6细胞按照25000/孔的细胞数接种于48孔板，用含10％FBS和双抗的MEM培养基培养。
抗体配置：用含5％FBS和双抗的MEM培养基稀释抗体。按照48孔板最终体积500μL/孔、每个浓度3个复孔计算，每个浓度的抗体配置750μL(250μL/孔)，按照实际作用浓度的2倍配置抗体。从最高浓度开始，按照一定倍数(如3倍)进行倍比稀释。同时，设置相应的阳性和阴性对照。将配置好的抗体加入48孔板，带入P3实验室。
将新冠病毒储存液按照MOI＝100比例用含5％FBS的MEM培养基稀释，按照1：1的体积比将病毒液(250μL/孔)加入配置好的抗体，37℃孵育3小时。将对数生长期的Vero-E6细胞板上清吸净，加入孵育好的抗体病毒混合液(500μL/孔)，37℃培养7天。后续检测：观察细胞病变，推算中和百分比为50％的中和抗体的浓度，计为IC50。结果见表13。三种单抗均能有效中和武汉株活病毒和印度变异株活病毒，SW-C11和WJQ-G10对武汉、巴西、南非、印度变异株均有良好的中和作用；SW-C11中和武汉和印度毒株能力最强，IC50可分别达到0.0173μg/mL和0.0056μg/mL。
表13.抗体针对活病毒的中和能力(IC50,μg/mL)
实施例5抗体结合能力测定
通过ELISA方法测定所述3种抗体的抗原结合能力。将RBD蛋白(NC_045512)用PBS稀释至2μg/ml，每孔100μl包被96孔ELISA板(Corning Costar公司)，4℃过夜。用PBS-T溶液(0.05％吐温-20)洗板5次；每孔加入250μl封闭液(PBS，2％BSA+5％脱脂奶粉)室温封闭1小时。PBS-T洗板3次。将抗体以10μg/ml为起始浓度，用封闭液进行5倍系列稀释，分别取100μl样本加入到ELISA板中，37℃孵育1小时。PBS-T洗板5次。每孔加入100μl用封闭液1：5000稀释后的辣根酶标记的山羊抗人IgG(H+L)(北京中杉金桥生物技术有限公司)，37℃孵育1小时。PBS-T洗板5次。加入TMB显色溶液(北京金豪制药股份有限公司)100μl，室温避光显色20分钟。每孔加入50μl终止液(北京金豪制药股份有限公司)终止反应，酶标仪读取450nm波长的吸光度值(OD)结果如图3所示，图3中VRC01为抗HIV中和抗体，作为阴性对照。并计算End-titer值如下表14所示。
表14.中和抗体的End-titer值
实施例6抗原-抗体亲和力动力学测定
利用Octet Red 96系统(Fortebio,USA)和链霉亲和素传感器，采用BLI技术对SW-C11、WJQ-G10、WJQ-C11与RBD蛋白(NC_045512)的亲和力进行检测，用PBST(含有0.02％吐温20和0.1％牛血清白蛋白的PBS)将SARS-Cov-2的生物素化RBD稀释至5μg/mL的浓度，然后固定到链霉亲和素生物传感器(Sartorius AG，Germany)上60秒。在用PBST进行60秒洗涤步骤后，将生物传感器探针浸入含有连续稀释抗体(500nM、250nM、125nM、62.5nM、31.25nM、15.625nM和7.8125nM)的孔中并结合120秒，然后进行300秒解离步骤。KD值采用数据分析软件9.0中的1:1结合模型计算。得出WJQ-G10的亲和力常数为(1.37×10-9±3.53×10-11)M，WJQ-C11的亲和力常数为(5.29×10-9±6.16×10-11)M,SW-C11与RBD的亲和力常数KD<10-12M(10-12M为BLI技术测定的亲和力下限)，结果如图4-图6所示。显示这3个抗体针对RBD具有极强的亲和力。
序列表
<110> 中国疾病预防控制中心性病艾滋病预防控制中心
<120> 人源化高中和活性抗新型冠状病毒单克隆抗体及应用
<160> 16
<170> SIPOSequenceListing 1.0
<210> 1
<211> 119
<212> PRT
<213> Homo sapiens
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Ile Val Ser Arg Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Thr Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Pro Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asp Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Tyr Gly Asp Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser
115
<210> 2
<211> 357
<212> DNA
<213> Homo sapiens
<400> 2
gaggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctgagtt catcgtcagt agaaactaca tgagctgggt ccgccaggct 120
ccagggacgg ggctggagtg ggtctcagtt atttatcctg gaggcagcac attctacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240
caaatggaca gcctgagagt cgaggacacg gccgtgtatt actgtgcgag agactacggt 300
gacttctatt ttgactactg gggccaggga accctggtca ccgtctcctc agcgtcg 357
<210> 3
<211> 109
<212> PRT
<213> Homo sapiens
<400> 3
Glu Ile Val Met Thr Gln Ser Pro Val Ser Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Val Ala Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Thr Leu Gln Ser
65 70 75 80
Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asp Arg Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr
100 105
<210> 4
<211> 327
<212> DNA
<213> Homo sapiens
<400> 4
gaaatagtga tgacgcagtc tccagtctcc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gggtgttgcc agcaacttag cctggtacca gcagaaagct 120
ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg aatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcac cctgcagtct 240
gaagattctg cagtttatta ctgccagcag tataatgata ggcccaggac ttttggccag 300
gggaccaagc tggagatcaa acgtacg 327
<210> 5
<211> 119
<212> PRT
<213> Homo sapiens
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ala Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Asp Leu Ser Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser
115
<210> 6
<211> 357
<212> DNA
<213> Homo sapiens
<400> 6
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggagtc cctgagactc 60
tcctgtgcag cctctggatt aaccgtcagt agcaactaca tgagttgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatgccg gtggtagcac attctacgca 180
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaatac gctgtatctt 240
caaatgaaca gcctgagagc tgaggatatg gctatttatt actgtgcgag agatctcagc 300
tactacggta tggacgtctg gggccaaggg accacggtca ccgtctcctc agcgtcg 357
<210> 7
<211> 109
<212> PRT
<213> Homo sapiens
<400> 7
Asp Ile Gln Leu Thr Gln Phe Pro Phe Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Leu Leu Asn Ser Tyr Pro Val
85 90 95
His Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr
100 105
<210> 8
<211> 327
<212> DNA
<213> Homo sapiens
<400> 8
gacatccagt tgacccagtt tccattctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcattagc acttatttag cctggtatca gcaaaaacca 120
gggagagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatcg 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240
gaagattttg caacttatta ctgtcaactg cttaatagtt accctgtaca ctttggccag 300
gggaccaagc tggagatcaa acgtacg 327
<210> 9
<211> 122
<212> PRT
<213> Homo sapiens
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Thr Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile His Asn Ser Gly Asn Pro Val Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Ala Leu Arg Tyr Ser Thr Ser Trp Tyr Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser
115 120
<210> 10
<211> 366
<212> DNA
<213> Homo sapiens
<400> 10
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt cgccttcagt acttatgaga tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attcataata gtggtaatcc cgtatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccgagaa ctcactatat 240
ctgcaaatga acagcctgag agccgaggac acggctattt attactgtgc gagagcctta 300
cgttacagca ccagctggta tgactactgg ggccagggaa ccctggtcac cgtctcctca 360
gcgtcg 366
<210> 11
<211> 109
<212> PRT
<213> Homo sapiens
<400> 11
Glu Ile Val Leu Thr Gln Ser Pro Val Ser Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Phe Ile
35 40 45
Tyr Asp Ala Ser Lys Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105
<210> 12
<211> 327
<212> DNA
<213> Homo sapiens
<400> 12
gaaattgtgt tgacacagtc cccagtctcc ctgtctttgt ccccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120
ggccaggctc ccaggctctt catttatgat gcatccaaga gggccactgg catcccagcc 180
aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctcgaac gttcggccaa 300
gggaccaagg tggaaatcaa acgtacg 327
<210> 13
<211> 328
<212> PRT
<213> Homo sapiens
<400> 13
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
1 5 10 15
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
20 25 30
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
35 40 45
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
50 55 60
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
65 70 75 80
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
85 90 95
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
100 105 110
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
115 120 125
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
130 135 140
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
145 150 155 160
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
165 170 175
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
180 185 190
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
195 200 205
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
210 215 220
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
225 230 235 240
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
245 250 255
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
260 265 270
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
275 280 285
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
290 295 300
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
305 310 315 320
Ser Leu Ser Leu Ser Pro Gly Lys
325
<210> 14
<211> 984
<212> DNA
<213> Homo sapiens
<400> 14
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 60
gcggccctgg gctgcctggt caaggactac ttccccgaac ccgtgacggt gtcgtggaac 120
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 180
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 240
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 300
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 360
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 420
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 480
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 540
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 600
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 660
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 720
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 780
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 840
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 900
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 960
agcctctccc tgtctccggg taaa 984
<210> 15
<211> 105
<212> PRT
<213> Homo sapiens
<400> 15
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
1 5 10 15
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
20 25 30
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
35 40 45
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
50 55 60
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
65 70 75 80
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
85 90 95
Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 16
<211> 315
<212> DNA
<213> Homo sapiens
<400> 16
gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact 60
gcctctgttg tgtgcctgct gaataacttc taccccagag aagccaaagt gcagtggaag 120
gtggacaacg ccctgcagag cggaaacagc caggaaagcg tgacagagca ggattccaag 180
gattccacat acagcctgag cagcacactg acactgtcca aggccgacta cgagaagcac 240
aaggtgtacg cctgcgaagt gacacaccag ggactgtcct cccctgtgac aaagagcttc 300
aacagaggag aatgc 315
Claims (11)
1.一种人源化高中和活性抗新型冠状病毒单克隆抗体及应用，其特征在于，所述抗体的重链可变区的CDR1、CDR2和CDR3以及轻链可变区的CDR1、CDR2和CDR3的氨基酸序列分别如下所示：
(1)SEQ ID NO.1的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.3的第27-32、50-52、89-97位氨基酸；或者
(2)SEQ ID NO.5的第26-33、51-57和96-106位氨基酸以及SEQ ID NO.7的第27-32、50-52和89-97位氨基酸；或者
(3)SEQ ID NO.9的第26-33、51-58和97-109位氨基酸以及SEQ ID NO.11的第27-32、50-52和89-97位氨基酸。
2.根据权利要求1所述的单克隆抗体，其特征在于，所述抗体重链的可变区以及轻链的可变区的氨基酸序列分别如下所示：
(1)SEQ ID NO.1以及SEQ ID NO.3；或者
(2)SEQ ID NO.5以及SEQ ID NO.7；或者
(3)SEQ ID NO.9以及SEQ ID NO.11。
3.根据权利要求2所述的单克隆抗体，其特征在于，所述抗体重链恒定区的氨基酸序列如SEQ ID NO.13所示，所述轻链恒定区的氨基酸序列如SEQ ID NO.15所示。
4.一种编码权利要求2或3所述人源化广谱高中和活性抗新型冠状病毒单克隆抗体的多核苷酸，其特征在于，编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸组合的序列分别如下所示：
(1)SEQ ID NO.2以及SEQ ID NO.4；或者
(2)SEQ ID NO.6以及SEQ ID NO.8；或者
(3)SEQ ID NO.10以及SEQ ID NO.12。
5.根据权利要求4所述的编码单克隆抗体的多核苷酸，其特征在于，编码抗体重链恒定区的多核苷酸的序列如SEQ ID NO.14所示，所述轻链恒定区的多核苷酸的序列如SEQ IDNO.16所示。
6.一种表达权利要求2或3所述人源化高中和活性抗新型冠状病毒单克隆抗体的载体，其特征在于，所述载体含有权利要求4所述编码所述抗体重链的可变区的多核苷酸以及编码所述抗体轻链的可变区的多核苷酸。
7.一种表达权利要求2或3所述人源化高中和活性抗新型冠状病毒单克隆抗体的宿主细胞，其特征在于，所述宿主细胞含有权利要求6所述的载体。
8.根据权利要求7所述的宿主细胞，其特征在于，所述宿主细胞为293F细胞。
9.权利要求1-3任一所述的人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒病治疗和/或预防药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述应用为含有至少两种抗体的组合物应用。
11.权利要求1-3任一所述的人源化高中和活性抗新型冠状病毒单克隆抗体在制备新型冠状病毒检测试剂中的应用。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110877644.9A CN113563464B (zh) | 2021-08-01 | 2021-08-01 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
| PCT/CN2022/106147 WO2023011147A1 (zh) | 2021-08-01 | 2022-07-17 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110877644.9A CN113563464B (zh) | 2021-08-01 | 2021-08-01 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113563464A true CN113563464A (zh) | 2021-10-29 |
| CN113563464B CN113563464B (zh) | 2023-02-03 |
Family
ID=78169757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110877644.9A Active CN113563464B (zh) | 2021-08-01 | 2021-08-01 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113563464B (zh) |
| WO (1) | WO2023011147A1 (zh) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114044821A (zh) * | 2022-01-10 | 2022-02-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒全人源广谱中和抗体zwc12及应用 |
| CN114106166A (zh) * | 2022-01-29 | 2022-03-01 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体d2及其应用 |
| CN114316040A (zh) * | 2022-03-02 | 2022-04-12 | 南昌大学 | 一种抗新型冠状病毒的全人源单克隆抗体及其用途 |
| CN114426577A (zh) * | 2022-02-07 | 2022-05-03 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化广谱抗新型冠状病毒单克隆抗体及应用 |
| CN114790240A (zh) * | 2022-06-10 | 2022-07-26 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
| CN114805557A (zh) * | 2021-12-31 | 2022-07-29 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN114989292A (zh) * | 2021-11-25 | 2022-09-02 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| WO2023011147A1 (zh) * | 2021-08-01 | 2023-02-09 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
| WO2023102692A1 (zh) * | 2021-12-06 | 2023-06-15 | 广州医科大学附属市八医院 | 协同中和新型冠状病毒的人源抗体和抗体组合及其应用 |
| CN116891531A (zh) * | 2023-06-30 | 2023-10-17 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒变异株的全人源双特异性抗体 |
| CN116891531B (zh) * | 2023-06-30 | 2024-11-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新型冠状病毒变异株的全人源双特异性抗体 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018227023A1 (en) * | 2017-06-07 | 2018-12-13 | Silverback Therapeutics, Inc. | Antibody construct conjugates |
| CN109476726A (zh) * | 2016-06-30 | 2019-03-15 | 汉诺威医学院 | 在治疗HvG病中使用的融合蛋白 |
| CN112794899A (zh) * | 2021-03-16 | 2021-05-14 | 易康生物(苏州)有限公司 | 一种抗新型冠状病毒的全人源单克隆中和抗体及其应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10822379B1 (en) * | 2020-03-12 | 2020-11-03 | University of Pittsburgh—of the Commonwealth System of Higher Education | Molecules that bind to SARS-CoV-2 |
| CN111909261B (zh) * | 2020-08-19 | 2022-10-04 | 重庆医科大学 | 新冠病毒rbd特异性单克隆抗体和应用 |
| CN114933650A (zh) * | 2020-08-19 | 2022-08-23 | 重庆医科大学 | 新冠病毒rbd特异性单克隆抗体和应用 |
| CN112159469B (zh) * | 2020-09-30 | 2022-08-02 | 上海市公共卫生临床中心 | 冠状病毒的抗体或其抗原结合片段 |
| CN112430265B (zh) * | 2020-11-23 | 2022-04-12 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体nCoV-61及其应用 |
| CN112341541B (zh) * | 2020-11-23 | 2022-05-06 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体nCoV-163及其应用 |
| CN113563464B (zh) * | 2021-08-01 | 2023-02-03 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
-
2021
- 2021-08-01 CN CN202110877644.9A patent/CN113563464B/zh active Active
-
2022
- 2022-07-17 WO PCT/CN2022/106147 patent/WO2023011147A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109476726A (zh) * | 2016-06-30 | 2019-03-15 | 汉诺威医学院 | 在治疗HvG病中使用的融合蛋白 |
| WO2018227023A1 (en) * | 2017-06-07 | 2018-12-13 | Silverback Therapeutics, Inc. | Antibody construct conjugates |
| CN112794899A (zh) * | 2021-03-16 | 2021-05-14 | 易康生物(苏州)有限公司 | 一种抗新型冠状病毒的全人源单克隆中和抗体及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| 李鹤等: "冠状病毒及其治疗药物研究进展", 《中国药学杂志》 * |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023011147A1 (zh) * | 2021-08-01 | 2023-02-09 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 |
| CN114989292A (zh) * | 2021-11-25 | 2022-09-02 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| CN114989292B (zh) * | 2021-11-25 | 2023-01-06 | 浙江安维珞诊断技术有限公司 | 一种抗SARS-CoV-2全人源化单克隆抗体及应用 |
| WO2023102692A1 (zh) * | 2021-12-06 | 2023-06-15 | 广州医科大学附属市八医院 | 协同中和新型冠状病毒的人源抗体和抗体组合及其应用 |
| CN114805557B (zh) * | 2021-12-31 | 2023-07-21 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114805557A (zh) * | 2021-12-31 | 2022-07-29 | 中国科学院微生物研究所 | 人源化抗SARS-CoV-2单克隆抗体及其应用 |
| CN114044821A (zh) * | 2022-01-10 | 2022-02-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒全人源广谱中和抗体zwc12及应用 |
| CN114106166A (zh) * | 2022-01-29 | 2022-03-01 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体d2及其应用 |
| CN114106166B (zh) * | 2022-01-29 | 2022-05-06 | 中国疾病预防控制中心病毒病预防控制所 | 人源抗新冠病毒中和性抗体d2及其应用 |
| CN114426577A (zh) * | 2022-02-07 | 2022-05-03 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化广谱抗新型冠状病毒单克隆抗体及应用 |
| CN114426577B (zh) * | 2022-02-07 | 2023-10-13 | 中国疾病预防控制中心性病艾滋病预防控制中心 | 人源化广谱抗新型冠状病毒单克隆抗体及应用 |
| CN114316040A (zh) * | 2022-03-02 | 2022-04-12 | 南昌大学 | 一种抗新型冠状病毒的全人源单克隆抗体及其用途 |
| CN114316040B (zh) * | 2022-03-02 | 2024-03-29 | 南昌大学 | 一种抗新型冠状病毒的全人源单克隆抗体及其用途 |
| CN114805562A (zh) * | 2022-05-07 | 2022-07-29 | 广东菲鹏制药股份有限公司 | 抗新型冠状病毒人源化纳米抗体及其应用 |
| CN114790240B (zh) * | 2022-06-10 | 2023-06-06 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
| CN114790240A (zh) * | 2022-06-10 | 2022-07-26 | 郑州大学 | SARS-CoV-2中和性单克隆抗体及应用 |
| CN116891531A (zh) * | 2023-06-30 | 2023-10-17 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新冠病毒变异株的全人源双特异性抗体 |
| CN116891531B (zh) * | 2023-06-30 | 2024-11-15 | 中国人民解放军军事科学院军事医学研究院 | 一种抗新型冠状病毒变异株的全人源双特异性抗体 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113563464B (zh) | 2023-02-03 |
| WO2023011147A1 (zh) | 2023-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113563464B (zh) | 人源化高中和活性抗新型冠状病毒单克隆抗体及应用 | |
| CN113512113B (zh) | 人源化广谱高中和活性抗新型冠状病毒单克隆抗体及应用 | |
| KR102716514B1 (ko) | 신규 항-c-KIT 항체 | |
| CN101133158B (zh) | 人抗狂犬病抗体及其用途 | |
| CN109053895B (zh) | 抗pd-1-抗vegfa的双功能抗体、其药物组合物及其用途 | |
| CN110144010B9 (zh) | 阻断型pd-l1驼源单域抗体及其用途 | |
| CN101291954B (zh) | 具有改变的细胞信号传导活性的修饰的抗原结合分子 | |
| KR102260680B1 (ko) | 신규 항 인간 tslp 수용체 항체 | |
| CN114149509B (zh) | 抗冠状病毒双特异性中和抗体与应用 | |
| CN107002045A (zh) | 细胞 | |
| CN103145849A (zh) | 嵌合抗原受体及其用途 | |
| CN111819198A (zh) | 具有非FcγR依赖性激动活性的肿瘤坏死因子(TNF)受体超家族(TNFRSF)受体-激活抗体融合蛋白(具有非FcγR依赖性激动活性的TNFRSF受体-激活抗体融合蛋白；TRAAFFIAA) | |
| KR20140019385A (ko) | 이중특이성 및 단일특이성, 비대칭성 항체 및 이의 제조방법 | |
| CN109796535A (zh) | 靶向叶酸受体α的嵌合抗原受体及其在制备预防或治疗恶性肿瘤药物中的用途 | |
| CN105384819B (zh) | 一种抗人Delta-like 4人源化抗体及其制备与应用 | |
| CN108424461B (zh) | Cd47-car-t细胞 | |
| KR20220038397A (ko) | Mage-a4 특이성을 갖는 키메라 항원 수용체 및 이들의 용도 | |
| CN114480501B (zh) | 一种人源抗体表达质粒及其构建方法 | |
| CN107936118B (zh) | 一种抗体-海兔毒素偶联物及其制备方法和应用 | |
| CN106866824B (zh) | 一种抗ddx5的全人源单克隆抗体及其制备方法和应用 | |
| CN108794622A (zh) | 一种人3型腺病毒的中和性人源化单克隆抗体及其制备方法和应用 | |
| CN114409774B (zh) | 广谱人源化抗新型冠状病毒单克隆抗体及应用 | |
| AU2021273789A1 (en) | Human IL-15 mutant and use thereof | |
| CN114426577B (zh) | 人源化广谱抗新型冠状病毒单克隆抗体及应用 | |
| CN108752472B (zh) | 一种抗h7n9抗体及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240125 Address after: No.155 Changbai Road, Changping District, Beijing 102206 Patentee after: NATIONAL CENTER FOR AIDS/STD CONTROL AND PREVENTION, CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION Country or region after: China Patentee after: THE FIRST AFFILIATED HOSPITAL,ZHEJIANG University SCHOOL OF MEDICINE Address before: No.155 Changbai Road, Changping District, Beijing 102206 Patentee before: NATIONAL CENTER FOR AIDS/STD CONTROL AND PREVENTION, CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION Country or region before: China |
|
| TR01 | Transfer of patent right |