CN117412769A - 具有复制能力的4型腺病毒sars-cov-2疫苗及其用途 - Google Patents
具有复制能力的4型腺病毒sars-cov-2疫苗及其用途 Download PDFInfo
- Publication number
- CN117412769A CN117412769A CN202280010458.8A CN202280010458A CN117412769A CN 117412769 A CN117412769 A CN 117412769A CN 202280010458 A CN202280010458 A CN 202280010458A CN 117412769 A CN117412769 A CN 117412769A
- Authority
- CN
- China
- Prior art keywords
- seq
- recombinant
- cov
- sars
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 241001135572 Human adenovirus E4 Species 0.000 title claims abstract description 12
- 229940022962 COVID-19 vaccine Drugs 0.000 title description 13
- 101000629318 Severe acute respiratory syndrome coronavirus 2 Spike glycoprotein Proteins 0.000 claims abstract description 80
- 238000012217 deletion Methods 0.000 claims abstract description 39
- 230000037430 deletion Effects 0.000 claims abstract description 39
- 230000010076 replication Effects 0.000 claims abstract description 38
- 108091026890 Coding region Proteins 0.000 claims abstract description 18
- 238000003780 insertion Methods 0.000 claims abstract description 8
- 230000037431 insertion Effects 0.000 claims abstract description 8
- 108010027410 Adenovirus E3 Proteins Proteins 0.000 claims abstract description 7
- 239000013598 vector Substances 0.000 claims description 85
- 230000002163 immunogen Effects 0.000 claims description 73
- 241001678559 COVID-19 virus Species 0.000 claims description 72
- 239000000203 mixture Substances 0.000 claims description 68
- 150000007523 nucleic acids Chemical group 0.000 claims description 57
- 108090000623 proteins and genes Proteins 0.000 claims description 52
- 230000028993 immune response Effects 0.000 claims description 43
- 102000004169 proteins and genes Human genes 0.000 claims description 42
- 102100031673 Corneodesmosin Human genes 0.000 claims description 41
- 101710139375 Corneodesmosin Proteins 0.000 claims description 41
- 238000006467 substitution reaction Methods 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 39
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 38
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 33
- 230000003053 immunization Effects 0.000 claims description 33
- 208000015181 infectious disease Diseases 0.000 claims description 27
- 230000004927 fusion Effects 0.000 claims description 19
- 108020004705 Codon Proteins 0.000 claims description 17
- 108700026244 Open Reading Frames Proteins 0.000 claims description 17
- 239000002773 nucleotide Substances 0.000 claims description 16
- 125000003729 nucleotide group Chemical group 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 10
- 238000012986 modification Methods 0.000 claims description 9
- 230000004048 modification Effects 0.000 claims description 9
- 239000000443 aerosol Substances 0.000 claims description 5
- 101710198474 Spike protein Proteins 0.000 abstract description 39
- 229940096437 Protein S Drugs 0.000 abstract description 33
- 208000025721 COVID-19 Diseases 0.000 abstract description 21
- 208000037847 SARS-CoV-2-infection Diseases 0.000 abstract description 19
- 230000036039 immunity Effects 0.000 abstract description 17
- 210000002345 respiratory system Anatomy 0.000 abstract description 11
- 230000002265 prevention Effects 0.000 abstract description 5
- 230000014599 transmission of virus Effects 0.000 abstract description 2
- 229960005486 vaccine Drugs 0.000 description 66
- 235000018102 proteins Nutrition 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 35
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 29
- 235000001014 amino acid Nutrition 0.000 description 29
- 241000700605 Viruses Species 0.000 description 28
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 28
- 238000002649 immunization Methods 0.000 description 27
- 150000001413 amino acids Chemical class 0.000 description 26
- 108010050848 glycylleucine Proteins 0.000 description 26
- 108010037850 glycylvaline Proteins 0.000 description 26
- 108020004707 nucleic acids Proteins 0.000 description 26
- 102000039446 nucleic acids Human genes 0.000 description 26
- 229940024606 amino acid Drugs 0.000 description 25
- 241000701161 unidentified adenovirus Species 0.000 description 25
- 239000002671 adjuvant Substances 0.000 description 24
- 108010061238 threonyl-glycine Proteins 0.000 description 23
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 21
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 21
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 20
- 241000880493 Leptailurus serval Species 0.000 description 20
- 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 20
- 108010057821 leucylproline Proteins 0.000 description 20
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 19
- GHKXHCMRAUYLBS-CIUDSAMLSA-N Lys-Ser-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O GHKXHCMRAUYLBS-CIUDSAMLSA-N 0.000 description 19
- 108010079364 N-glycylalanine Proteins 0.000 description 19
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 19
- 108010017391 lysylvaline Proteins 0.000 description 19
- 108010051242 phenylalanylserine Proteins 0.000 description 19
- 235000013930 proline Nutrition 0.000 description 19
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 19
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 description 18
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 18
- IBLAOXSULLECQZ-IUKAMOBKSA-N Asn-Ile-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(N)=O IBLAOXSULLECQZ-IUKAMOBKSA-N 0.000 description 18
- ZYVTXBXHIKGZMD-QSFUFRPTSA-N Ile-Val-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ZYVTXBXHIKGZMD-QSFUFRPTSA-N 0.000 description 18
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 18
- HHOOEUSPFGPZFP-QWRGUYRKSA-N Phe-Asn-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O HHOOEUSPFGPZFP-QWRGUYRKSA-N 0.000 description 18
- RMKGXGPQIPLTFC-KKUMJFAQSA-N Phe-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RMKGXGPQIPLTFC-KKUMJFAQSA-N 0.000 description 18
- 108010044940 alanylglutamine Proteins 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 108010073969 valyllysine Proteins 0.000 description 18
- 230000003612 virological effect Effects 0.000 description 18
- IVPNEDNYYYFAGI-GARJFASQSA-N Asp-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N IVPNEDNYYYFAGI-GARJFASQSA-N 0.000 description 17
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 238000006386 neutralization reaction Methods 0.000 description 17
- 230000004044 response Effects 0.000 description 17
- 210000002966 serum Anatomy 0.000 description 17
- 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 16
- 239000000427 antigen Substances 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 16
- 102000036639 antigens Human genes 0.000 description 16
- 241000711573 Coronaviridae Species 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 15
- MMEDVBWCMGRKKC-GARJFASQSA-N Leu-Asp-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N MMEDVBWCMGRKKC-GARJFASQSA-N 0.000 description 15
- 108010038633 aspartylglutamate Proteins 0.000 description 15
- 238000007918 intramuscular administration Methods 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 15
- 238000002255 vaccination Methods 0.000 description 15
- KXFCBAHYSLJCCY-ZLUOBGJFSA-N Asn-Asn-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O KXFCBAHYSLJCCY-ZLUOBGJFSA-N 0.000 description 14
- 230000005847 immunogenicity Effects 0.000 description 14
- 230000003362 replicative effect Effects 0.000 description 14
- 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 13
- 102000004196 processed proteins & peptides Human genes 0.000 description 13
- 241001112090 Pseudovirus Species 0.000 description 12
- PMTWIUBUQRGCSB-FXQIFTODSA-N Ser-Val-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O PMTWIUBUQRGCSB-FXQIFTODSA-N 0.000 description 12
- 108010073628 glutamyl-valyl-phenylalanine Proteins 0.000 description 12
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 12
- 108010027338 isoleucylcysteine Proteins 0.000 description 12
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 12
- UMYZBHKAVTXWIW-GMOBBJLQSA-N Ile-Asp-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N UMYZBHKAVTXWIW-GMOBBJLQSA-N 0.000 description 11
- XXXXOVFBXRERQL-ULQDDVLXSA-N Leu-Pro-Phe Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XXXXOVFBXRERQL-ULQDDVLXSA-N 0.000 description 11
- OSBADCBXAMSPQD-YESZJQIVSA-N Phe-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N OSBADCBXAMSPQD-YESZJQIVSA-N 0.000 description 11
- CXBFHZLODKPIJY-AAEUAGOBSA-N Ser-Gly-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CO)N CXBFHZLODKPIJY-AAEUAGOBSA-N 0.000 description 11
- OJRNZRROAIAHDL-LKXGYXEUSA-N Thr-Asn-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OJRNZRROAIAHDL-LKXGYXEUSA-N 0.000 description 11
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 11
- KXUKIBHIVRYOIP-ZKWXMUAHSA-N Val-Asp-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N KXUKIBHIVRYOIP-ZKWXMUAHSA-N 0.000 description 11
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 11
- 108010087823 glycyltyrosine Proteins 0.000 description 11
- 238000011081 inoculation Methods 0.000 description 11
- 108010009962 valyltyrosine Proteins 0.000 description 11
- UGLPMYSCWHTZQU-AUTRQRHGSA-N Ala-Ala-Tyr Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](C)C(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 UGLPMYSCWHTZQU-AUTRQRHGSA-N 0.000 description 10
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 10
- SGYSTDWPNPKJPP-GUBZILKMSA-N Arg-Ala-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SGYSTDWPNPKJPP-GUBZILKMSA-N 0.000 description 10
- QNJIRRVTOXNGMH-GUBZILKMSA-N Asn-Gln-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O QNJIRRVTOXNGMH-GUBZILKMSA-N 0.000 description 10
- QPTAGIPWARILES-AVGNSLFASA-N Asn-Gln-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QPTAGIPWARILES-AVGNSLFASA-N 0.000 description 10
- NCFJQJRLQJEECD-NHCYSSNCSA-N Asn-Leu-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O NCFJQJRLQJEECD-NHCYSSNCSA-N 0.000 description 10
- XOQYDFCQPWAMSA-KKHAAJSZSA-N Asn-Val-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XOQYDFCQPWAMSA-KKHAAJSZSA-N 0.000 description 10
- WQAOZCVOOYUWKG-LSJOCFKGSA-N Asn-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CC(=O)N)N WQAOZCVOOYUWKG-LSJOCFKGSA-N 0.000 description 10
- KLYPOCBLKMPBIQ-GHCJXIJMSA-N Asp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N KLYPOCBLKMPBIQ-GHCJXIJMSA-N 0.000 description 10
- 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 10
- XEYMBRRKIFYQMF-GUBZILKMSA-N Gln-Asp-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O XEYMBRRKIFYQMF-GUBZILKMSA-N 0.000 description 10
- ZBKUIQNCRIYVGH-SDDRHHMPSA-N Gln-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZBKUIQNCRIYVGH-SDDRHHMPSA-N 0.000 description 10
- NHMRJKKAVMENKJ-WDCWCFNPSA-N Gln-Thr-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NHMRJKKAVMENKJ-WDCWCFNPSA-N 0.000 description 10
- SGVGIVDZLSHSEN-RYUDHWBXSA-N Gln-Tyr-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O SGVGIVDZLSHSEN-RYUDHWBXSA-N 0.000 description 10
- FVGOGEGGQLNZGH-DZKIICNBSA-N Glu-Val-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FVGOGEGGQLNZGH-DZKIICNBSA-N 0.000 description 10
- XBWMTPAIUQIWKA-BYULHYEWSA-N Gly-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN XBWMTPAIUQIWKA-BYULHYEWSA-N 0.000 description 10
- ILUVWFTXAUYOBW-CUJWVEQBSA-N His-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CN=CN1)N)O ILUVWFTXAUYOBW-CUJWVEQBSA-N 0.000 description 10
- KFKWRHQBZQICHA-STQMWFEESA-N L-leucyl-L-phenylalanine Natural products CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KFKWRHQBZQICHA-STQMWFEESA-N 0.000 description 10
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 10
- DBSLVQBXKVKDKJ-BJDJZHNGSA-N Leu-Ile-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O DBSLVQBXKVKDKJ-BJDJZHNGSA-N 0.000 description 10
- RTIRBWJPYJYTLO-MELADBBJSA-N Leu-Lys-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N RTIRBWJPYJYTLO-MELADBBJSA-N 0.000 description 10
- GCXGCIYIHXSKAY-ULQDDVLXSA-N Leu-Phe-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GCXGCIYIHXSKAY-ULQDDVLXSA-N 0.000 description 10
- JIHDFWWRYHSAQB-GUBZILKMSA-N Leu-Ser-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JIHDFWWRYHSAQB-GUBZILKMSA-N 0.000 description 10
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 10
- VJGQRELPQWNURN-JYJNAYRXSA-N Leu-Tyr-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O VJGQRELPQWNURN-JYJNAYRXSA-N 0.000 description 10
- GPLWGAYGROGDEN-BZSNNMDCSA-N Phe-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O GPLWGAYGROGDEN-BZSNNMDCSA-N 0.000 description 10
- XKHCJJPNXFBADI-DCAQKATOSA-N Pro-Asp-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O XKHCJJPNXFBADI-DCAQKATOSA-N 0.000 description 10
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 10
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 10
- TWLMXDWFVNEFFK-FJXKBIBVSA-N Thr-Arg-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O TWLMXDWFVNEFFK-FJXKBIBVSA-N 0.000 description 10
- JMGJDTNUMAZNLX-RWRJDSDZSA-N Thr-Glu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JMGJDTNUMAZNLX-RWRJDSDZSA-N 0.000 description 10
- 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 10
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 10
- NWEGIYMHTZXVBP-JSGCOSHPSA-N Tyr-Val-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O NWEGIYMHTZXVBP-JSGCOSHPSA-N 0.000 description 10
- VNGKMNPAENRGDC-JYJNAYRXSA-N Val-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=CC=C1 VNGKMNPAENRGDC-JYJNAYRXSA-N 0.000 description 10
- 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 10
- 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 10
- DFQZDQPLWBSFEJ-LSJOCFKGSA-N Val-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(=O)N)C(=O)O)N DFQZDQPLWBSFEJ-LSJOCFKGSA-N 0.000 description 10
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 108010054812 diprotin A Proteins 0.000 description 10
- 108010090037 glycyl-alanyl-isoleucine Proteins 0.000 description 10
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 10
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 10
- 108010047926 leucyl-lysyl-tyrosine Proteins 0.000 description 10
- 108010044056 leucyl-phenylalanine Proteins 0.000 description 10
- 108010009298 lysylglutamic acid Proteins 0.000 description 10
- 108010089198 phenylalanyl-prolyl-arginine Proteins 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 10
- 108010020432 prolyl-prolylisoleucine Proteins 0.000 description 10
- CWFMWBHMIMNZLN-NAKRPEOUSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-amino-3-methylpentanoyl]amino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CWFMWBHMIMNZLN-NAKRPEOUSA-N 0.000 description 9
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 9
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 9
- 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 9
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 9
- AWAXZRDKUHOPBO-GUBZILKMSA-N Ala-Gln-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O AWAXZRDKUHOPBO-GUBZILKMSA-N 0.000 description 9
- ZDYNWWQXFRUOEO-XDTLVQLUSA-N Ala-Gln-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDYNWWQXFRUOEO-XDTLVQLUSA-N 0.000 description 9
- FAJIYNONGXEXAI-CQDKDKBSSA-N Ala-His-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 FAJIYNONGXEXAI-CQDKDKBSSA-N 0.000 description 9
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 9
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 9
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-N 0.000 description 9
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 9
- 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 9
- IETUUAHKCHOQHP-KZVJFYERSA-N Ala-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)O)C(O)=O IETUUAHKCHOQHP-KZVJFYERSA-N 0.000 description 9
- MTDDMSUUXNQMKK-BPNCWPANSA-N Ala-Tyr-Arg Chemical compound C[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 MTDDMSUUXNQMKK-BPNCWPANSA-N 0.000 description 9
- JSHVMZANPXCDTL-GMOBBJLQSA-N Arg-Asp-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JSHVMZANPXCDTL-GMOBBJLQSA-N 0.000 description 9
- CZUHPNLXLWMYMG-UBHSHLNASA-N Arg-Phe-Ala Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 CZUHPNLXLWMYMG-UBHSHLNASA-N 0.000 description 9
- VEAIMHJZTIDCIH-KKUMJFAQSA-N Arg-Phe-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O VEAIMHJZTIDCIH-KKUMJFAQSA-N 0.000 description 9
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 9
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 9
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 9
- XSGBIBGAMKTHMY-WHFBIAKZSA-N Asn-Asp-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O XSGBIBGAMKTHMY-WHFBIAKZSA-N 0.000 description 9
- UGXVKHRDGLYFKR-CIUDSAMLSA-N Asn-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(N)=O UGXVKHRDGLYFKR-CIUDSAMLSA-N 0.000 description 9
- CZIXHXIJJZLYRJ-SRVKXCTJSA-N Asn-Cys-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CZIXHXIJJZLYRJ-SRVKXCTJSA-N 0.000 description 9
- ZMUQQMGITUJQTI-CIUDSAMLSA-N Asn-Leu-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ZMUQQMGITUJQTI-CIUDSAMLSA-N 0.000 description 9
- UHGUKCOQUNPSKK-CIUDSAMLSA-N Asn-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N UHGUKCOQUNPSKK-CIUDSAMLSA-N 0.000 description 9
- OROMFUQQTSWUTI-IHRRRGAJSA-N Asn-Phe-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N OROMFUQQTSWUTI-IHRRRGAJSA-N 0.000 description 9
- 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 9
- VHQSGALUSWIYOD-QXEWZRGKSA-N Asn-Pro-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O VHQSGALUSWIYOD-QXEWZRGKSA-N 0.000 description 9
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 9
- HBUJSDCLZCXXCW-YDHLFZDLSA-N Asn-Val-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HBUJSDCLZCXXCW-YDHLFZDLSA-N 0.000 description 9
- FTNVLGCFIJEMQT-CIUDSAMLSA-N Asp-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N FTNVLGCFIJEMQT-CIUDSAMLSA-N 0.000 description 9
- PZXPWHFYZXTFBI-YUMQZZPRSA-N Asp-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PZXPWHFYZXTFBI-YUMQZZPRSA-N 0.000 description 9
- SPKCGKRUYKMDHP-GUDRVLHUSA-N Asp-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N SPKCGKRUYKMDHP-GUDRVLHUSA-N 0.000 description 9
- SPWXXPFDTMYTRI-IUKAMOBKSA-N Asp-Ile-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SPWXXPFDTMYTRI-IUKAMOBKSA-N 0.000 description 9
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 9
- UJGRZQYSNYTCAX-SRVKXCTJSA-N Asp-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UJGRZQYSNYTCAX-SRVKXCTJSA-N 0.000 description 9
- XWSIYTYNLKCLJB-CIUDSAMLSA-N Asp-Lys-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O XWSIYTYNLKCLJB-CIUDSAMLSA-N 0.000 description 9
- RXBGWGRSWXOBGK-KKUMJFAQSA-N Asp-Lys-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RXBGWGRSWXOBGK-KKUMJFAQSA-N 0.000 description 9
- NJLLRXWFPQQPHV-SRVKXCTJSA-N Asp-Tyr-Asn 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](CC(N)=O)C(O)=O NJLLRXWFPQQPHV-SRVKXCTJSA-N 0.000 description 9
- WXKWQSDHEXKKNC-ZKWXMUAHSA-N Cys-Asp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N WXKWQSDHEXKKNC-ZKWXMUAHSA-N 0.000 description 9
- ATPDEYTYWVMINF-ZLUOBGJFSA-N Cys-Cys-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O ATPDEYTYWVMINF-ZLUOBGJFSA-N 0.000 description 9
- GUKYYUFHWYRMEU-WHFBIAKZSA-N Cys-Gly-Asp Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O GUKYYUFHWYRMEU-WHFBIAKZSA-N 0.000 description 9
- SKSJPIBFNFPTJB-NKWVEPMBSA-N Cys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CS)N)C(=O)O SKSJPIBFNFPTJB-NKWVEPMBSA-N 0.000 description 9
- UCSXXFRXHGUXCQ-SRVKXCTJSA-N Cys-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N UCSXXFRXHGUXCQ-SRVKXCTJSA-N 0.000 description 9
- QQOWCDCBFFBRQH-IXOXFDKPSA-N Cys-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CS)N)O QQOWCDCBFFBRQH-IXOXFDKPSA-N 0.000 description 9
- KVCJEMHFLGVINV-ZLUOBGJFSA-N Cys-Ser-Asn Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KVCJEMHFLGVINV-ZLUOBGJFSA-N 0.000 description 9
- JRZMCSIUYGSJKP-ZKWXMUAHSA-N Cys-Val-Asn Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O JRZMCSIUYGSJKP-ZKWXMUAHSA-N 0.000 description 9
- HHWQMFIGMMOVFK-WDSKDSINSA-N Gln-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O HHWQMFIGMMOVFK-WDSKDSINSA-N 0.000 description 9
- KVYVOGYEMPEXBT-GUBZILKMSA-N Gln-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O KVYVOGYEMPEXBT-GUBZILKMSA-N 0.000 description 9
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 9
- PNENQZWRFMUZOM-DCAQKATOSA-N Gln-Glu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O PNENQZWRFMUZOM-DCAQKATOSA-N 0.000 description 9
- VGTDBGYFVWOQTI-RYUDHWBXSA-N Gln-Gly-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VGTDBGYFVWOQTI-RYUDHWBXSA-N 0.000 description 9
- FTIJVMLAGRAYMJ-MNXVOIDGSA-N Gln-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(N)=O FTIJVMLAGRAYMJ-MNXVOIDGSA-N 0.000 description 9
- MLSKFHLRFVGNLL-WDCWCFNPSA-N Gln-Leu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MLSKFHLRFVGNLL-WDCWCFNPSA-N 0.000 description 9
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 9
- QBEWLBKBGXVVPD-RYUDHWBXSA-N Gln-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)N)N QBEWLBKBGXVVPD-RYUDHWBXSA-N 0.000 description 9
- DCWNCMRZIZSZBL-KKUMJFAQSA-N Gln-Pro-Tyr Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)N)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O DCWNCMRZIZSZBL-KKUMJFAQSA-N 0.000 description 9
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-ACZMJKKPSA-N 0.000 description 9
- ARYKRXHBIPLULY-XKBZYTNZSA-N Gln-Thr-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ARYKRXHBIPLULY-XKBZYTNZSA-N 0.000 description 9
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 9
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 9
- QXDXIXFSFHUYAX-MNXVOIDGSA-N Glu-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O QXDXIXFSFHUYAX-MNXVOIDGSA-N 0.000 description 9
- KRRFFAHEAOCBCQ-SIUGBPQLSA-N Glu-Ile-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KRRFFAHEAOCBCQ-SIUGBPQLSA-N 0.000 description 9
- PJBVXVBTTFZPHJ-GUBZILKMSA-N Glu-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N PJBVXVBTTFZPHJ-GUBZILKMSA-N 0.000 description 9
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 9
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 9
- LKOAAMXDJGEYMS-ZPFDUUQYSA-N Glu-Met-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LKOAAMXDJGEYMS-ZPFDUUQYSA-N 0.000 description 9
- FQFWFZWOHOEVMZ-IHRRRGAJSA-N Glu-Phe-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O FQFWFZWOHOEVMZ-IHRRRGAJSA-N 0.000 description 9
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 9
- 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 9
- SYAYROHMAIHWFB-KBIXCLLPSA-N Glu-Ser-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SYAYROHMAIHWFB-KBIXCLLPSA-N 0.000 description 9
- IDEODOAVGCMUQV-GUBZILKMSA-N Glu-Ser-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IDEODOAVGCMUQV-GUBZILKMSA-N 0.000 description 9
- 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 9
- QSTLUOIOYLYLLF-WDSKDSINSA-N Gly-Asp-Glu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QSTLUOIOYLYLLF-WDSKDSINSA-N 0.000 description 9
- NMROINAYXCACKF-WHFBIAKZSA-N Gly-Cys-Cys Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O NMROINAYXCACKF-WHFBIAKZSA-N 0.000 description 9
- NPSWCZIRBAYNSB-JHEQGTHGSA-N Gly-Gln-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPSWCZIRBAYNSB-JHEQGTHGSA-N 0.000 description 9
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 9
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 9
- DGKBSGNCMCLDSL-BYULHYEWSA-N Gly-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN DGKBSGNCMCLDSL-BYULHYEWSA-N 0.000 description 9
- LUJVWKKYHSLULQ-ZKWXMUAHSA-N Gly-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN LUJVWKKYHSLULQ-ZKWXMUAHSA-N 0.000 description 9
- XVYKMNXXJXQKME-XEGUGMAKSA-N Gly-Ile-Tyr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XVYKMNXXJXQKME-XEGUGMAKSA-N 0.000 description 9
- PTIIBFKSLCYQBO-NHCYSSNCSA-N Gly-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)CN PTIIBFKSLCYQBO-NHCYSSNCSA-N 0.000 description 9
- CVFOYJJOZYYEPE-KBPBESRZSA-N Gly-Lys-Tyr Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CVFOYJJOZYYEPE-KBPBESRZSA-N 0.000 description 9
- 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 9
- WTUSRDZLLWGYAT-KCTSRDHCSA-N Gly-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN WTUSRDZLLWGYAT-KCTSRDHCSA-N 0.000 description 9
- BNMRSWQOHIQTFL-JSGCOSHPSA-N Gly-Val-Phe Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 BNMRSWQOHIQTFL-JSGCOSHPSA-N 0.000 description 9
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-N 0.000 description 9
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 9
- HTZKFIYQMHJWSQ-INTQDDNPSA-N His-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N HTZKFIYQMHJWSQ-INTQDDNPSA-N 0.000 description 9
- MJUUWJJEUOBDGW-IHRRRGAJSA-N His-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 MJUUWJJEUOBDGW-IHRRRGAJSA-N 0.000 description 9
- UWSMZKRTOZEGDD-CUJWVEQBSA-N His-Thr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O UWSMZKRTOZEGDD-CUJWVEQBSA-N 0.000 description 9
- RGSOCXHDOPQREB-ZPFDUUQYSA-N Ile-Asp-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N RGSOCXHDOPQREB-ZPFDUUQYSA-N 0.000 description 9
- LLHYWBGDMBGNHA-VGDYDELISA-N Ile-Cys-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N LLHYWBGDMBGNHA-VGDYDELISA-N 0.000 description 9
- NZOCIWKZUVUNDW-ZKWXMUAHSA-N Ile-Gly-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O NZOCIWKZUVUNDW-ZKWXMUAHSA-N 0.000 description 9
- MQFGXJNSUJTXDT-QSFUFRPTSA-N Ile-Gly-Ile Chemical compound N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)O MQFGXJNSUJTXDT-QSFUFRPTSA-N 0.000 description 9
- VOBYAKCXGQQFLR-LSJOCFKGSA-N Ile-Gly-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O VOBYAKCXGQQFLR-LSJOCFKGSA-N 0.000 description 9
- APDIECQNNDGFPD-PYJNHQTQSA-N Ile-His-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N APDIECQNNDGFPD-PYJNHQTQSA-N 0.000 description 9
- WIZPFZKOFZXDQG-HTFCKZLJSA-N Ile-Ile-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O WIZPFZKOFZXDQG-HTFCKZLJSA-N 0.000 description 9
- KYLIZSDYWQQTFM-PEDHHIEDSA-N Ile-Ile-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N KYLIZSDYWQQTFM-PEDHHIEDSA-N 0.000 description 9
- AXNGDPAKKCEKGY-QPHKQPEJSA-N Ile-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N AXNGDPAKKCEKGY-QPHKQPEJSA-N 0.000 description 9
- CEPIAEUVRKGPGP-DSYPUSFNSA-N Ile-Lys-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 CEPIAEUVRKGPGP-DSYPUSFNSA-N 0.000 description 9
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 9
- 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 9
- YCKPUHHMCFSUMD-IUKAMOBKSA-N Ile-Thr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YCKPUHHMCFSUMD-IUKAMOBKSA-N 0.000 description 9
- RTSQPLLOYSGMKM-DSYPUSFNSA-N Ile-Trp-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(C)C)C(=O)O)N RTSQPLLOYSGMKM-DSYPUSFNSA-N 0.000 description 9
- ZUWSVOYKBCHLRR-MGHWNKPDSA-N Ile-Tyr-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCCN)C(=O)O)N ZUWSVOYKBCHLRR-MGHWNKPDSA-N 0.000 description 9
- KKXDHFKZWKLYGB-GUBZILKMSA-N Leu-Asn-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KKXDHFKZWKLYGB-GUBZILKMSA-N 0.000 description 9
- ZYLJULGXQDNXDK-GUBZILKMSA-N Leu-Gln-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ZYLJULGXQDNXDK-GUBZILKMSA-N 0.000 description 9
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 9
- SGIIOQQGLUUMDQ-IHRRRGAJSA-N Leu-His-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N SGIIOQQGLUUMDQ-IHRRRGAJSA-N 0.000 description 9
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 9
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 9
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 9
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 9
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 9
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 9
- VHNOAIFVYUQOOY-XUXIUFHCSA-N Lys-Arg-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VHNOAIFVYUQOOY-XUXIUFHCSA-N 0.000 description 9
- WALVCOOOKULCQM-ULQDDVLXSA-N Lys-Arg-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WALVCOOOKULCQM-ULQDDVLXSA-N 0.000 description 9
- ZQCVMVCVPFYXHZ-SRVKXCTJSA-N Lys-Asn-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN ZQCVMVCVPFYXHZ-SRVKXCTJSA-N 0.000 description 9
- DZQYZKPINJLLEN-KKUMJFAQSA-N Lys-Cys-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)O DZQYZKPINJLLEN-KKUMJFAQSA-N 0.000 description 9
- RZHLIPMZXOEJTL-AVGNSLFASA-N Lys-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)N RZHLIPMZXOEJTL-AVGNSLFASA-N 0.000 description 9
- NNKLKUUGESXCBS-KBPBESRZSA-N Lys-Gly-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NNKLKUUGESXCBS-KBPBESRZSA-N 0.000 description 9
- ATNKHRAIZCMCCN-BZSNNMDCSA-N Lys-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N ATNKHRAIZCMCCN-BZSNNMDCSA-N 0.000 description 9
- UWHCKWNPWKTMBM-WDCWCFNPSA-N Lys-Thr-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O UWHCKWNPWKTMBM-WDCWCFNPSA-N 0.000 description 9
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 9
- QFSYGUMEANRNJE-DCAQKATOSA-N Lys-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N QFSYGUMEANRNJE-DCAQKATOSA-N 0.000 description 9
- KLFPZIUIXZNEKY-DCAQKATOSA-N Met-Gln-Met Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O KLFPZIUIXZNEKY-DCAQKATOSA-N 0.000 description 9
- GWADARYJIJDYRC-XGEHTFHBSA-N Met-Thr-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GWADARYJIJDYRC-XGEHTFHBSA-N 0.000 description 9
- LIIXIZKVWNYQHB-STECZYCISA-N Met-Tyr-Ile Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LIIXIZKVWNYQHB-STECZYCISA-N 0.000 description 9
- KAHUBGWSIQNZQQ-KKUMJFAQSA-N Phe-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KAHUBGWSIQNZQQ-KKUMJFAQSA-N 0.000 description 9
- AWAYOWOUGVZXOB-BZSNNMDCSA-N Phe-Asn-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 AWAYOWOUGVZXOB-BZSNNMDCSA-N 0.000 description 9
- OMHMIXFFRPMYHB-SRVKXCTJSA-N Phe-Cys-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N OMHMIXFFRPMYHB-SRVKXCTJSA-N 0.000 description 9
- ALHULIGNEXGFRM-QWRGUYRKSA-N Phe-Cys-Gly Chemical compound OC(=O)CNC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=CC=C1 ALHULIGNEXGFRM-QWRGUYRKSA-N 0.000 description 9
- PSBJZLMFFTULDX-IXOXFDKPSA-N Phe-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N)O PSBJZLMFFTULDX-IXOXFDKPSA-N 0.000 description 9
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 9
- QPVFUAUFEBPIPT-CDMKHQONSA-N Phe-Gly-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O QPVFUAUFEBPIPT-CDMKHQONSA-N 0.000 description 9
- PMKIMKUGCSVFSV-CQDKDKBSSA-N Phe-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N PMKIMKUGCSVFSV-CQDKDKBSSA-N 0.000 description 9
- 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 9
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 9
- YFXXRYFWJFQAFW-JHYOHUSXSA-N Phe-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N)O YFXXRYFWJFQAFW-JHYOHUSXSA-N 0.000 description 9
- AJLVKXCNXIJHDV-CIUDSAMLSA-N Pro-Ala-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O AJLVKXCNXIJHDV-CIUDSAMLSA-N 0.000 description 9
- LCRSGSIRKLXZMZ-BPNCWPANSA-N Pro-Ala-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LCRSGSIRKLXZMZ-BPNCWPANSA-N 0.000 description 9
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 9
- ILMLVTGTUJPQFP-FXQIFTODSA-N Pro-Asp-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ILMLVTGTUJPQFP-FXQIFTODSA-N 0.000 description 9
- YFNOUBWUIIJQHF-LPEHRKFASA-N Pro-Asp-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O YFNOUBWUIIJQHF-LPEHRKFASA-N 0.000 description 9
- XUSDDSLCRPUKLP-QXEWZRGKSA-N Pro-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 XUSDDSLCRPUKLP-QXEWZRGKSA-N 0.000 description 9
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 9
- VWXGFAIZUQBBBG-UWVGGRQHSA-N Pro-His-Gly Chemical compound C([C@@H](C(=O)NCC(=O)[O-])NC(=O)[C@H]1[NH2+]CCC1)C1=CN=CN1 VWXGFAIZUQBBBG-UWVGGRQHSA-N 0.000 description 9
- DWPXHLIBFQLKLK-CYDGBPFRSA-N Pro-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 DWPXHLIBFQLKLK-CYDGBPFRSA-N 0.000 description 9
- CNUIHOAISPKQPY-HSHDSVGOSA-N Pro-Thr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O CNUIHOAISPKQPY-HSHDSVGOSA-N 0.000 description 9
- DIDLUFMLRUJLFB-FKBYEOEOSA-N Pro-Trp-Tyr Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC4=CC=C(C=C4)O)C(=O)O DIDLUFMLRUJLFB-FKBYEOEOSA-N 0.000 description 9
- UCXDHBORXLVBNC-ZLUOBGJFSA-N Ser-Asn-Cys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(O)=O UCXDHBORXLVBNC-ZLUOBGJFSA-N 0.000 description 9
- BCKYYTVFBXHPOG-ACZMJKKPSA-N Ser-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N BCKYYTVFBXHPOG-ACZMJKKPSA-N 0.000 description 9
- SNNSYBWPPVAXQW-ZLUOBGJFSA-N Ser-Cys-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N)O SNNSYBWPPVAXQW-ZLUOBGJFSA-N 0.000 description 9
- 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 9
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 9
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 9
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 9
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 9
- 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 9
- PTWIYDNFWPXQSD-GARJFASQSA-N Ser-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)N)C(=O)O PTWIYDNFWPXQSD-GARJFASQSA-N 0.000 description 9
- RXSWQCATLWVDLI-XGEHTFHBSA-N Ser-Met-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RXSWQCATLWVDLI-XGEHTFHBSA-N 0.000 description 9
- XVWDJUROVRQKAE-KKUMJFAQSA-N Ser-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CC=CC=C1 XVWDJUROVRQKAE-KKUMJFAQSA-N 0.000 description 9
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 9
- FBLNYDYPCLFTSP-IXOXFDKPSA-N Ser-Phe-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FBLNYDYPCLFTSP-IXOXFDKPSA-N 0.000 description 9
- KKKVOZNCLALMPV-XKBZYTNZSA-N Ser-Thr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O KKKVOZNCLALMPV-XKBZYTNZSA-N 0.000 description 9
- FRPNVPKQVFHSQY-BPUTZDHNSA-N Ser-Trp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N FRPNVPKQVFHSQY-BPUTZDHNSA-N 0.000 description 9
- 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 9
- ODRUTDLAONAVDV-IHRRRGAJSA-N Ser-Val-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ODRUTDLAONAVDV-IHRRRGAJSA-N 0.000 description 9
- 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 9
- PQLXHSACXPGWPD-GSSVUCPTSA-N Thr-Asn-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PQLXHSACXPGWPD-GSSVUCPTSA-N 0.000 description 9
- LMMDEZPNUTZJAY-GCJQMDKQSA-N Thr-Asp-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O LMMDEZPNUTZJAY-GCJQMDKQSA-N 0.000 description 9
- MFEBUIFJVPNZLO-OLHMAJIHSA-N Thr-Asp-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O MFEBUIFJVPNZLO-OLHMAJIHSA-N 0.000 description 9
- QILPDQCTQZDHFM-HJGDQZAQSA-N Thr-Gln-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QILPDQCTQZDHFM-HJGDQZAQSA-N 0.000 description 9
- VUVCRYXYUUPGSB-GLLZPBPUSA-N Thr-Gln-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O VUVCRYXYUUPGSB-GLLZPBPUSA-N 0.000 description 9
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 9
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 9
- RRRRCRYTLZVCEN-HJGDQZAQSA-N Thr-Leu-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O RRRRCRYTLZVCEN-HJGDQZAQSA-N 0.000 description 9
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 9
- HPQHHRLWSAMMKG-KATARQTJSA-N Thr-Lys-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N)O HPQHHRLWSAMMKG-KATARQTJSA-N 0.000 description 9
- 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 9
- NWECYMJLJGCBOD-UNQGMJICSA-N Thr-Phe-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O NWECYMJLJGCBOD-UNQGMJICSA-N 0.000 description 9
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 9
- KVEWWQRTAVMOFT-KJEVXHAQSA-N Thr-Tyr-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O KVEWWQRTAVMOFT-KJEVXHAQSA-N 0.000 description 9
- 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 9
- UQHPXCFAHVTWFU-BVSLBCMMSA-N Trp-Phe-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O UQHPXCFAHVTWFU-BVSLBCMMSA-N 0.000 description 9
- PEVVXUGSAKEPEN-AVGNSLFASA-N Tyr-Asn-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PEVVXUGSAKEPEN-AVGNSLFASA-N 0.000 description 9
- NRFTYDWKWGJLAR-MELADBBJSA-N Tyr-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O NRFTYDWKWGJLAR-MELADBBJSA-N 0.000 description 9
- IWRMTNJCCMEBEX-AVGNSLFASA-N Tyr-Glu-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O IWRMTNJCCMEBEX-AVGNSLFASA-N 0.000 description 9
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 9
- WVGKPKDWYQXWLU-BZSNNMDCSA-N Tyr-His-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CCCCN)C(=O)O)N)O WVGKPKDWYQXWLU-BZSNNMDCSA-N 0.000 description 9
- FMXFHNSFABRVFZ-BZSNNMDCSA-N Tyr-Lys-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FMXFHNSFABRVFZ-BZSNNMDCSA-N 0.000 description 9
- TYFLVOUZHQUBGM-IHRRRGAJSA-N Tyr-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 TYFLVOUZHQUBGM-IHRRRGAJSA-N 0.000 description 9
- XFEMMSGONWQACR-KJEVXHAQSA-N Tyr-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O XFEMMSGONWQACR-KJEVXHAQSA-N 0.000 description 9
- FZSPNKUFROZBSG-ZKWXMUAHSA-N Val-Ala-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O FZSPNKUFROZBSG-ZKWXMUAHSA-N 0.000 description 9
- RUCNAYOMFXRIKJ-DCAQKATOSA-N Val-Ala-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN RUCNAYOMFXRIKJ-DCAQKATOSA-N 0.000 description 9
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 9
- LIQJSDDOULTANC-QSFUFRPTSA-N Val-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N LIQJSDDOULTANC-QSFUFRPTSA-N 0.000 description 9
- VLDMQVZZWDOKQF-AUTRQRHGSA-N Val-Glu-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VLDMQVZZWDOKQF-AUTRQRHGSA-N 0.000 description 9
- ZXAGTABZUOMUDO-GVXVVHGQSA-N Val-Glu-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N ZXAGTABZUOMUDO-GVXVVHGQSA-N 0.000 description 9
- UKEVLVBHRKWECS-LSJOCFKGSA-N Val-Ile-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](C(C)C)N UKEVLVBHRKWECS-LSJOCFKGSA-N 0.000 description 9
- 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 9
- LJSZPMSUYKKKCP-UBHSHLNASA-N Val-Phe-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 LJSZPMSUYKKKCP-UBHSHLNASA-N 0.000 description 9
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 9
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 9
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 9
- XNLUVJPMPAZHCY-JYJNAYRXSA-N Val-Val-Phe Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 XNLUVJPMPAZHCY-JYJNAYRXSA-N 0.000 description 9
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 9
- 108010047495 alanylglycine Proteins 0.000 description 9
- 108010047857 aspartylglycine Proteins 0.000 description 9
- 230000008901 benefit Effects 0.000 description 9
- 230000005540 biological transmission Effects 0.000 description 9
- 230000002121 endocytic effect Effects 0.000 description 9
- 108010078274 isoleucylvaline Proteins 0.000 description 9
- 230000000670 limiting effect Effects 0.000 description 9
- 108010064235 lysylglycine Proteins 0.000 description 9
- 108010038320 lysylphenylalanine Proteins 0.000 description 9
- 230000003472 neutralizing effect Effects 0.000 description 9
- 108010012581 phenylalanylglutamate Proteins 0.000 description 9
- 230000037452 priming Effects 0.000 description 9
- 108010029020 prolylglycine Proteins 0.000 description 9
- NJPMYXWVWQWCSR-ACZMJKKPSA-N Ala-Glu-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NJPMYXWVWQWCSR-ACZMJKKPSA-N 0.000 description 8
- LJFNNUBZSZCZFN-WHFBIAKZSA-N Ala-Gly-Cys Chemical compound N[C@@H](C)C(=O)NCC(=O)N[C@@H](CS)C(=O)O LJFNNUBZSZCZFN-WHFBIAKZSA-N 0.000 description 8
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 8
- YNSCBOUZTAGIGO-ZLUOBGJFSA-N Asn-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)C(=O)N YNSCBOUZTAGIGO-ZLUOBGJFSA-N 0.000 description 8
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 8
- ANPFQTJEPONRPL-UGYAYLCHSA-N Asn-Ile-Asp Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O ANPFQTJEPONRPL-UGYAYLCHSA-N 0.000 description 8
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 8
- XUVTWGPERWIERB-IHRRRGAJSA-N Asp-Pro-Phe Chemical compound N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O XUVTWGPERWIERB-IHRRRGAJSA-N 0.000 description 8
- 241000699800 Cricetinae Species 0.000 description 8
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 8
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 8
- VZRAXPGTUNDIDK-GUBZILKMSA-N Gln-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N VZRAXPGTUNDIDK-GUBZILKMSA-N 0.000 description 8
- MQJDLNRXBOELJW-KKUMJFAQSA-N Gln-Pro-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O MQJDLNRXBOELJW-KKUMJFAQSA-N 0.000 description 8
- GHAXJVNBAKGWEJ-AVGNSLFASA-N Gln-Ser-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O GHAXJVNBAKGWEJ-AVGNSLFASA-N 0.000 description 8
- DYVMTEWCGAVKSE-HJGDQZAQSA-N Gln-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O DYVMTEWCGAVKSE-HJGDQZAQSA-N 0.000 description 8
- JPHYJQHPILOKHC-ACZMJKKPSA-N Glu-Asp-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O JPHYJQHPILOKHC-ACZMJKKPSA-N 0.000 description 8
- KRGZZKWSBGPLKL-IUCAKERBSA-N Glu-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N KRGZZKWSBGPLKL-IUCAKERBSA-N 0.000 description 8
- LCNXZQROPKFGQK-WHFBIAKZSA-N Gly-Asp-Ser Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O LCNXZQROPKFGQK-WHFBIAKZSA-N 0.000 description 8
- 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 8
- RHRLHXQWHCNJKR-PMVVWTBXSA-N Gly-Thr-His Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 RHRLHXQWHCNJKR-PMVVWTBXSA-N 0.000 description 8
- OCRQUYDOYKCOQG-IRXDYDNUSA-N Gly-Tyr-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 OCRQUYDOYKCOQG-IRXDYDNUSA-N 0.000 description 8
- 241000282412 Homo Species 0.000 description 8
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 8
- VCSBGUACOYUIGD-CIUDSAMLSA-N Leu-Asn-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O VCSBGUACOYUIGD-CIUDSAMLSA-N 0.000 description 8
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 8
- QJXHMYMRGDOHRU-NHCYSSNCSA-N Leu-Ile-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O QJXHMYMRGDOHRU-NHCYSSNCSA-N 0.000 description 8
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 8
- UCRJTSIIAYHOHE-ULQDDVLXSA-N Leu-Tyr-Arg Chemical compound CC(C)C[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 UCRJTSIIAYHOHE-ULQDDVLXSA-N 0.000 description 8
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 8
- QIJVAFLRMVBHMU-KKUMJFAQSA-N Lys-Asp-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QIJVAFLRMVBHMU-KKUMJFAQSA-N 0.000 description 8
- XREQQOATSMMAJP-MGHWNKPDSA-N Lys-Ile-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XREQQOATSMMAJP-MGHWNKPDSA-N 0.000 description 8
- TWPCWKVOZDUYAA-KKUMJFAQSA-N Lys-Phe-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O TWPCWKVOZDUYAA-KKUMJFAQSA-N 0.000 description 8
- OSOLWRWQADPDIQ-DCAQKATOSA-N Met-Asp-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O OSOLWRWQADPDIQ-DCAQKATOSA-N 0.000 description 8
- LJUUGSWZPQOJKD-JYJNAYRXSA-N Phe-Arg-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)Cc1ccccc1)C(O)=O LJUUGSWZPQOJKD-JYJNAYRXSA-N 0.000 description 8
- BBFRBZYKHIKFBX-GMOBBJLQSA-N Pro-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@@H]1CCCN1 BBFRBZYKHIKFBX-GMOBBJLQSA-N 0.000 description 8
- SUENWIFTSTWUKD-AVGNSLFASA-N Pro-Leu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SUENWIFTSTWUKD-AVGNSLFASA-N 0.000 description 8
- AJBQTGZIZQXBLT-STQMWFEESA-N Pro-Phe-Gly Chemical compound C([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 AJBQTGZIZQXBLT-STQMWFEESA-N 0.000 description 8
- WVXQQUWOKUZIEG-VEVYYDQMSA-N Pro-Thr-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O WVXQQUWOKUZIEG-VEVYYDQMSA-N 0.000 description 8
- RNFKSBPHLTZHLU-WHFBIAKZSA-N Ser-Cys-Gly Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N)O RNFKSBPHLTZHLU-WHFBIAKZSA-N 0.000 description 8
- UFKPDBLKLOBMRH-XHNCKOQMSA-N Ser-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N)C(=O)O UFKPDBLKLOBMRH-XHNCKOQMSA-N 0.000 description 8
- SRKMDKACHDVPMD-SRVKXCTJSA-N Ser-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)N SRKMDKACHDVPMD-SRVKXCTJSA-N 0.000 description 8
- 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 8
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 8
- 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 8
- ZSDXEKUKQAKZFE-XAVMHZPKSA-N Ser-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N)O ZSDXEKUKQAKZFE-XAVMHZPKSA-N 0.000 description 8
- WFUAUEQXPVNAEF-ZJDVBMNYSA-N Thr-Arg-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CCCN=C(N)N WFUAUEQXPVNAEF-ZJDVBMNYSA-N 0.000 description 8
- NZRUWPIYECBYRK-HTUGSXCWSA-N Thr-Phe-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O NZRUWPIYECBYRK-HTUGSXCWSA-N 0.000 description 8
- RVGVIWNHABGIFH-IHRRRGAJSA-N Tyr-Val-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O RVGVIWNHABGIFH-IHRRRGAJSA-N 0.000 description 8
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 8
- BVWPHWLFGRCECJ-JSGCOSHPSA-N Val-Gly-Tyr Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N BVWPHWLFGRCECJ-JSGCOSHPSA-N 0.000 description 8
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 8
- WBAJDGWKRIHOAC-GVXVVHGQSA-N Val-Lys-Gln Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O WBAJDGWKRIHOAC-GVXVVHGQSA-N 0.000 description 8
- MHHAWNPHDLCPLF-ULQDDVLXSA-N Val-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=CC=C1 MHHAWNPHDLCPLF-ULQDDVLXSA-N 0.000 description 8
- 108010041407 alanylaspartic acid Proteins 0.000 description 8
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 8
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 108010056582 methionylglutamic acid Proteins 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- BVSGPHDECMJBDE-HGNGGELXSA-N Ala-Glu-His Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N BVSGPHDECMJBDE-HGNGGELXSA-N 0.000 description 7
- QRIYOHQJRDHFKF-UWJYBYFXSA-N Ala-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 QRIYOHQJRDHFKF-UWJYBYFXSA-N 0.000 description 7
- MFAMTAVAFBPXDC-LPEHRKFASA-N Arg-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O MFAMTAVAFBPXDC-LPEHRKFASA-N 0.000 description 7
- MOGMYRUNTKYZFB-UNQGMJICSA-N Arg-Thr-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MOGMYRUNTKYZFB-UNQGMJICSA-N 0.000 description 7
- QTAIIXQCOPUNBQ-QXEWZRGKSA-N Arg-Val-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QTAIIXQCOPUNBQ-QXEWZRGKSA-N 0.000 description 7
- OOWSBIOUKIUWLO-RCOVLWMOSA-N Asn-Gly-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O OOWSBIOUKIUWLO-RCOVLWMOSA-N 0.000 description 7
- FHETWELNCBMRMG-HJGDQZAQSA-N Asn-Leu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FHETWELNCBMRMG-HJGDQZAQSA-N 0.000 description 7
- YXVAESUIQFDBHN-SRVKXCTJSA-N Asn-Phe-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O YXVAESUIQFDBHN-SRVKXCTJSA-N 0.000 description 7
- HPNDKUOLNRVRAY-BIIVOSGPSA-N Asn-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N)C(=O)O HPNDKUOLNRVRAY-BIIVOSGPSA-N 0.000 description 7
- DZQKLNLLWFQONU-LKXGYXEUSA-N Asp-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N)O DZQKLNLLWFQONU-LKXGYXEUSA-N 0.000 description 7
- LMPBBFWHCRURJD-LAEOZQHASA-N Gln-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N LMPBBFWHCRURJD-LAEOZQHASA-N 0.000 description 7
- UWMDGPFFTKDUIY-HJGDQZAQSA-N Gln-Pro-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O UWMDGPFFTKDUIY-HJGDQZAQSA-N 0.000 description 7
- DIXKFOPPGWKZLY-CIUDSAMLSA-N Glu-Arg-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O DIXKFOPPGWKZLY-CIUDSAMLSA-N 0.000 description 7
- GMVCSRBOSIUTFC-FXQIFTODSA-N Glu-Ser-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMVCSRBOSIUTFC-FXQIFTODSA-N 0.000 description 7
- OLPPXYMMIARYAL-QMMMGPOBSA-N Gly-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)CN OLPPXYMMIARYAL-QMMMGPOBSA-N 0.000 description 7
- UMBDRSMLCUYIRI-DVJZZOLTSA-N Gly-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN)O UMBDRSMLCUYIRI-DVJZZOLTSA-N 0.000 description 7
- FNXSYBOHALPRHV-ONGXEEELSA-N Gly-Val-Lys Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN FNXSYBOHALPRHV-ONGXEEELSA-N 0.000 description 7
- KZTLOHBDLMIFSH-XVYDVKMFSA-N His-Ala-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O KZTLOHBDLMIFSH-XVYDVKMFSA-N 0.000 description 7
- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- QICVAHODWHIWIS-HTFCKZLJSA-N Ile-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N QICVAHODWHIWIS-HTFCKZLJSA-N 0.000 description 7
- HASRFYOMVPJRPU-SRVKXCTJSA-N Leu-Arg-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O HASRFYOMVPJRPU-SRVKXCTJSA-N 0.000 description 7
- GZAUZBUKDXYPEH-CIUDSAMLSA-N Leu-Cys-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N GZAUZBUKDXYPEH-CIUDSAMLSA-N 0.000 description 7
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 7
- HMDDEJADNKQTBR-BZSNNMDCSA-N Leu-His-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMDDEJADNKQTBR-BZSNNMDCSA-N 0.000 description 7
- ORWTWZXGDBYVCP-BJDJZHNGSA-N Leu-Ile-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(C)C ORWTWZXGDBYVCP-BJDJZHNGSA-N 0.000 description 7
- IWMJFLJQHIDZQW-KKUMJFAQSA-N Leu-Ser-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IWMJFLJQHIDZQW-KKUMJFAQSA-N 0.000 description 7
- ICYRCNICGBJLGM-HJGDQZAQSA-N Leu-Thr-Asp 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)CC(O)=O ICYRCNICGBJLGM-HJGDQZAQSA-N 0.000 description 7
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 7
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 7
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 7
- IDUCUXTUHHIQIP-SOUVJXGZSA-N Phe-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O IDUCUXTUHHIQIP-SOUVJXGZSA-N 0.000 description 7
- KRYSMKKRRRWOCZ-QEWYBTABSA-N Phe-Ile-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KRYSMKKRRRWOCZ-QEWYBTABSA-N 0.000 description 7
- WEMYTDDMDBLPMI-DKIMLUQUSA-N Phe-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N WEMYTDDMDBLPMI-DKIMLUQUSA-N 0.000 description 7
- 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 7
- ZUZINZIJHJFJRN-UBHSHLNASA-N Pro-Phe-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 ZUZINZIJHJFJRN-UBHSHLNASA-N 0.000 description 7
- MLKVIVZCFYRTIR-KKUMJFAQSA-N Pro-Phe-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O MLKVIVZCFYRTIR-KKUMJFAQSA-N 0.000 description 7
- 241000315672 SARS coronavirus Species 0.000 description 7
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 7
- VEVYMLNYMULSMS-AVGNSLFASA-N Ser-Tyr-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O VEVYMLNYMULSMS-AVGNSLFASA-N 0.000 description 7
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 7
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 7
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 7
- IBBBOLAPFHRDHW-BPUTZDHNSA-N Trp-Asn-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N IBBBOLAPFHRDHW-BPUTZDHNSA-N 0.000 description 7
- 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 7
- NSTPFWRAIDTNGH-BZSNNMDCSA-N Tyr-Asn-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NSTPFWRAIDTNGH-BZSNNMDCSA-N 0.000 description 7
- CPGJELLYDQEDRK-NAKRPEOUSA-N Val-Ile-Ala Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C)C(O)=O CPGJELLYDQEDRK-NAKRPEOUSA-N 0.000 description 7
- KDKLLPMFFGYQJD-CYDGBPFRSA-N Val-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N KDKLLPMFFGYQJD-CYDGBPFRSA-N 0.000 description 7
- 108010087924 alanylproline Proteins 0.000 description 7
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 7
- 108010062796 arginyllysine Proteins 0.000 description 7
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 208000023504 respiratory system disease Diseases 0.000 description 7
- 108010026333 seryl-proline Proteins 0.000 description 7
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 6
- FKGNJUCQKXQNRA-NRPADANISA-N Glu-Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(O)=O FKGNJUCQKXQNRA-NRPADANISA-N 0.000 description 6
- FIYMBBHGYNQFOP-IUCAKERBSA-N Leu-Gly-Gln Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N FIYMBBHGYNQFOP-IUCAKERBSA-N 0.000 description 6
- JYVCOTWSRGFABJ-DCAQKATOSA-N Lys-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCCN)N JYVCOTWSRGFABJ-DCAQKATOSA-N 0.000 description 6
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 6
- LHALYDBUDCWMDY-CIUDSAMLSA-N Pro-Glu-Ala Chemical compound C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O LHALYDBUDCWMDY-CIUDSAMLSA-N 0.000 description 6
- TZKPNGDGUVREEB-FOHZUACHSA-N Thr-Asn-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O TZKPNGDGUVREEB-FOHZUACHSA-N 0.000 description 6
- 108010005233 alanylglutamic acid Proteins 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000002458 infectious effect Effects 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 102000040430 polynucleotide Human genes 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 239000002157 polynucleotide Substances 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- 108010078580 tyrosylleucine Proteins 0.000 description 6
- BKFXFUPYETWGGA-XVSYOHENSA-N Asn-Phe-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BKFXFUPYETWGGA-XVSYOHENSA-N 0.000 description 5
- 108090000288 Glycoproteins Proteins 0.000 description 5
- 102000003886 Glycoproteins Human genes 0.000 description 5
- -1 IFN- γ Proteins 0.000 description 5
- SLQJJFAVWSZLBL-BJDJZHNGSA-N Lys-Ile-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN SLQJJFAVWSZLBL-BJDJZHNGSA-N 0.000 description 5
- 241000699673 Mesocricetus auratus Species 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 210000005220 cytoplasmic tail Anatomy 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 241000991587 Enterovirus C Species 0.000 description 4
- ZWQVYZXPYSYPJD-RYUDHWBXSA-N Glu-Gly-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZWQVYZXPYSYPJD-RYUDHWBXSA-N 0.000 description 4
- IBYOLNARKHMLBG-WHOFXGATSA-N Gly-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IBYOLNARKHMLBG-WHOFXGATSA-N 0.000 description 4
- MYGQXVYRZMKRDB-SRVKXCTJSA-N Leu-Asp-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN MYGQXVYRZMKRDB-SRVKXCTJSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 4
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 4
- 108010093581 aspartyl-proline Proteins 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 108010089804 glycyl-threonine Proteins 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 241000712461 unidentified influenza virus Species 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- XMIAMUXIMWREBJ-HERUPUMHSA-N Ala-Trp-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)N)C(=O)O)N XMIAMUXIMWREBJ-HERUPUMHSA-N 0.000 description 3
- NLRJGXZWTKXRHP-DCAQKATOSA-N Asn-Leu-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NLRJGXZWTKXRHP-DCAQKATOSA-N 0.000 description 3
- XTMZYFMTYJNABC-ZLUOBGJFSA-N Asn-Ser-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N XTMZYFMTYJNABC-ZLUOBGJFSA-N 0.000 description 3
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 3
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- CIJLNXXMDUOFPH-HJWJTTGWSA-N Ile-Pro-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CIJLNXXMDUOFPH-HJWJTTGWSA-N 0.000 description 3
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 3
- PBLLTSKBTAHDNA-KBPBESRZSA-N Lys-Gly-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PBLLTSKBTAHDNA-KBPBESRZSA-N 0.000 description 3
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
- HOYQLNNGMHXZDW-KKUMJFAQSA-N Phe-Glu-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O HOYQLNNGMHXZDW-KKUMJFAQSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 3
- 101710176177 Protein A56 Proteins 0.000 description 3
- OOKCGAYXSNJBGQ-ZLUOBGJFSA-N Ser-Asn-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OOKCGAYXSNJBGQ-ZLUOBGJFSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-N 0.000 description 3
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000005875 antibody response Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 239000000185 hemagglutinin Substances 0.000 description 3
- 239000012678 infectious agent Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 108010053037 kyotorphin Proteins 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 108010070643 prolylglutamic acid Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000013638 trimer Substances 0.000 description 3
- 230000007485 viral shedding Effects 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- QHASENCZLDHBGX-ONGXEEELSA-N Ala-Gly-Phe Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QHASENCZLDHBGX-ONGXEEELSA-N 0.000 description 2
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 2
- SYIFFFHSXBNPMC-UWJYBYFXSA-N Ala-Ser-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N SYIFFFHSXBNPMC-UWJYBYFXSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 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 2
- HYQYLOSCICEYTR-YUMQZZPRSA-N Asn-Gly-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O HYQYLOSCICEYTR-YUMQZZPRSA-N 0.000 description 2
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 2
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 2
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 2
- PGUYEUCYVNZGGV-QWRGUYRKSA-N Asp-Gly-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PGUYEUCYVNZGGV-QWRGUYRKSA-N 0.000 description 2
- RQHLMGCXCZUOGT-ZPFDUUQYSA-N Asp-Leu-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RQHLMGCXCZUOGT-ZPFDUUQYSA-N 0.000 description 2
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108010061994 Coronavirus Spike Glycoprotein Proteins 0.000 description 2
- OIMUAKUQOUEPCZ-WHFBIAKZSA-N Cys-Asn-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIMUAKUQOUEPCZ-WHFBIAKZSA-N 0.000 description 2
- JTEGHEWKBCTIAL-IXOXFDKPSA-N Cys-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](CS)N)O JTEGHEWKBCTIAL-IXOXFDKPSA-N 0.000 description 2
- NGOIQDYZMIKCOK-NAKRPEOUSA-N Cys-Val-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NGOIQDYZMIKCOK-NAKRPEOUSA-N 0.000 description 2
- KZZYVYWSXMFYEC-DCAQKATOSA-N Cys-Val-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KZZYVYWSXMFYEC-DCAQKATOSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- KPNWAJMEMRCLAL-GUBZILKMSA-N Gln-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KPNWAJMEMRCLAL-GUBZILKMSA-N 0.000 description 2
- 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 2
- MKRDNSWGJWTBKZ-GVXVVHGQSA-N Gln-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MKRDNSWGJWTBKZ-GVXVVHGQSA-N 0.000 description 2
- KXTAGESXNQEZKB-DZKIICNBSA-N Glu-Phe-Val Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 KXTAGESXNQEZKB-DZKIICNBSA-N 0.000 description 2
- HBMRTXJZQDVRFT-DZKIICNBSA-N Glu-Tyr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O HBMRTXJZQDVRFT-DZKIICNBSA-N 0.000 description 2
- MFVQGXGQRIXBPK-WDSKDSINSA-N Gly-Ala-Glu Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFVQGXGQRIXBPK-WDSKDSINSA-N 0.000 description 2
- OVSKVOOUFAKODB-UWVGGRQHSA-N Gly-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OVSKVOOUFAKODB-UWVGGRQHSA-N 0.000 description 2
- BGVYNAQWHSTTSP-BYULHYEWSA-N Gly-Asn-Ile Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BGVYNAQWHSTTSP-BYULHYEWSA-N 0.000 description 2
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 2
- MTBIKIMYHUWBRX-QWRGUYRKSA-N Gly-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN MTBIKIMYHUWBRX-QWRGUYRKSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- UPJODPVSKKWGDQ-KLHWPWHYSA-N His-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O UPJODPVSKKWGDQ-KLHWPWHYSA-N 0.000 description 2
- 241000598171 Human adenovirus sp. Species 0.000 description 2
- 241000711467 Human coronavirus 229E Species 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- JLWLMGADIQFKRD-QSFUFRPTSA-N Ile-His-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CN=CN1 JLWLMGADIQFKRD-QSFUFRPTSA-N 0.000 description 2
- KTNGVMMGIQWIDV-OSUNSFLBSA-N Ile-Pro-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O KTNGVMMGIQWIDV-OSUNSFLBSA-N 0.000 description 2
- HXIDVIFHRYRXLZ-NAKRPEOUSA-N Ile-Ser-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)O)N HXIDVIFHRYRXLZ-NAKRPEOUSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- QCSFMCFHVGTLFF-NHCYSSNCSA-N Leu-Asp-Val Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O QCSFMCFHVGTLFF-NHCYSSNCSA-N 0.000 description 2
- LIINDKYIGYTDLG-PPCPHDFISA-N Leu-Ile-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LIINDKYIGYTDLG-PPCPHDFISA-N 0.000 description 2
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 2
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 2
- VSRXPEHZMHSFKU-IUCAKERBSA-N Lys-Gln-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VSRXPEHZMHSFKU-IUCAKERBSA-N 0.000 description 2
- YDDDRTIPNTWGIG-SRVKXCTJSA-N Lys-Lys-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O YDDDRTIPNTWGIG-SRVKXCTJSA-N 0.000 description 2
- RMLLCGYYVZKKRT-CIUDSAMLSA-N Met-Ser-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O RMLLCGYYVZKKRT-CIUDSAMLSA-N 0.000 description 2
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 2
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 2
- 206010028748 Nasal obstruction Diseases 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 229940026233 Pfizer-BioNTech COVID-19 vaccine Drugs 0.000 description 2
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 2
- KPEIBEPEUAZWNS-ULQDDVLXSA-N Phe-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 KPEIBEPEUAZWNS-ULQDDVLXSA-N 0.000 description 2
- ZUQACJLOHYRVPJ-DKIMLUQUSA-N Phe-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 ZUQACJLOHYRVPJ-DKIMLUQUSA-N 0.000 description 2
- BQMFWUKNOCJDNV-HJWJTTGWSA-N Phe-Val-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BQMFWUKNOCJDNV-HJWJTTGWSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- XYHMFGGWNOFUOU-QXEWZRGKSA-N Pro-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 XYHMFGGWNOFUOU-QXEWZRGKSA-N 0.000 description 2
- SXJOPONICMGFCR-DCAQKATOSA-N Pro-Ser-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O SXJOPONICMGFCR-DCAQKATOSA-N 0.000 description 2
- AJJDPGVVNPUZCR-RHYQMDGZSA-N Pro-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1)O AJJDPGVVNPUZCR-RHYQMDGZSA-N 0.000 description 2
- XDKKMRPRRCOELJ-GUBZILKMSA-N Pro-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 XDKKMRPRRCOELJ-GUBZILKMSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 2
- GYXVUTAOICLGKJ-ACZMJKKPSA-N Ser-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N GYXVUTAOICLGKJ-ACZMJKKPSA-N 0.000 description 2
- SFTZTYBXIXLRGQ-JBDRJPRFSA-N Ser-Ile-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SFTZTYBXIXLRGQ-JBDRJPRFSA-N 0.000 description 2
- KZPRPBLHYMZIMH-MXAVVETBSA-N Ser-Phe-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KZPRPBLHYMZIMH-MXAVVETBSA-N 0.000 description 2
- PLQWGQUNUPMNOD-KKUMJFAQSA-N Ser-Tyr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PLQWGQUNUPMNOD-KKUMJFAQSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- UTSWGQNAQRIHAI-UNQGMJICSA-N Thr-Arg-Phe Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 UTSWGQNAQRIHAI-UNQGMJICSA-N 0.000 description 2
- PZVGOVRNGKEFCB-KKHAAJSZSA-N Thr-Asn-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N)O PZVGOVRNGKEFCB-KKHAAJSZSA-N 0.000 description 2
- GCXFWAZRHBRYEM-NUMRIWBASA-N Thr-Gln-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O GCXFWAZRHBRYEM-NUMRIWBASA-N 0.000 description 2
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 2
- BNGDYRRHRGOPHX-IFFSRLJSSA-N Thr-Glu-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O BNGDYRRHRGOPHX-IFFSRLJSSA-N 0.000 description 2
- DCRHJDRLCFMEBI-RHYQMDGZSA-N Thr-Lys-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O DCRHJDRLCFMEBI-RHYQMDGZSA-N 0.000 description 2
- YRJOLUDFVAUXLI-GSSVUCPTSA-N Thr-Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(O)=O YRJOLUDFVAUXLI-GSSVUCPTSA-N 0.000 description 2
- 102000002689 Toll-like receptor Human genes 0.000 description 2
- 108020000411 Toll-like receptor Proteins 0.000 description 2
- 101800001055 Truncated S protein Proteins 0.000 description 2
- RYSNTWVRSLCAJZ-RYUDHWBXSA-N Tyr-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RYSNTWVRSLCAJZ-RYUDHWBXSA-N 0.000 description 2
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 2
- NMANTMWGQZASQN-QXEWZRGKSA-N Val-Arg-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N NMANTMWGQZASQN-QXEWZRGKSA-N 0.000 description 2
- BYOHPUZJVXWHAE-BYULHYEWSA-N Val-Asn-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N BYOHPUZJVXWHAE-BYULHYEWSA-N 0.000 description 2
- DCOOGDCRFXXQNW-ZKWXMUAHSA-N Val-Asn-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N DCOOGDCRFXXQNW-ZKWXMUAHSA-N 0.000 description 2
- TZVUSFMQWPWHON-NHCYSSNCSA-N Val-Asp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N TZVUSFMQWPWHON-NHCYSSNCSA-N 0.000 description 2
- AGKDVLSDNSTLFA-UMNHJUIQSA-N Val-Gln-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N AGKDVLSDNSTLFA-UMNHJUIQSA-N 0.000 description 2
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 2
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 2
- ZHQWPWQNVRCXAX-XQQFMLRXSA-N Val-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N ZHQWPWQNVRCXAX-XQQFMLRXSA-N 0.000 description 2
- UGFMVXRXULGLNO-XPUUQOCRSA-N Val-Ser-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O UGFMVXRXULGLNO-XPUUQOCRSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 2
- 229940037003 alum Drugs 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 108010004073 cysteinylcysteine Proteins 0.000 description 2
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 108010069495 cysteinyltyrosine Proteins 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 108010083708 leucyl-aspartyl-valine Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000004779 membrane envelope Anatomy 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 238000011587 new zealand white rabbit Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 210000002741 palatine tonsil Anatomy 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 108010015796 prolylisoleucine Proteins 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 229940023143 protein vaccine Drugs 0.000 description 2
- 229910052611 pyroxene Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 239000013605 shuttle vector Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940035044 sorbitan monolaurate Drugs 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 229960004854 viral vaccine Drugs 0.000 description 2
- NTUPOKHATNSWCY-PMPSAXMXSA-N (2s)-2-[[(2s)-1-[(2r)-2-amino-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-PMPSAXMXSA-N 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- NWFLONJLUJYCNS-UHFFFAOYSA-N 2-[[2-[[2-[(2-amino-3-phenylpropanoyl)amino]acetyl]amino]acetyl]amino]-3-phenylpropanoic acid Chemical compound C=1C=CC=CC=1CC(C(O)=O)NC(=O)CNC(=O)CNC(=O)C(N)CC1=CC=CC=C1 NWFLONJLUJYCNS-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 108010082808 4-1BB Ligand Proteins 0.000 description 1
- 102000002627 4-1BB Ligand Human genes 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LBJYAILUMSUTAM-ZLUOBGJFSA-N Ala-Asn-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O LBJYAILUMSUTAM-ZLUOBGJFSA-N 0.000 description 1
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 1
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 1
- YIGLXQRFQVWFEY-NRPADANISA-N Ala-Gln-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O YIGLXQRFQVWFEY-NRPADANISA-N 0.000 description 1
- ROLXPVQSRCPVGK-XDTLVQLUSA-N Ala-Glu-Tyr Chemical compound N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O ROLXPVQSRCPVGK-XDTLVQLUSA-N 0.000 description 1
- LMFXXZPPZDCPTA-ZKWXMUAHSA-N Ala-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N LMFXXZPPZDCPTA-ZKWXMUAHSA-N 0.000 description 1
- FOHXUHGZZKETFI-JBDRJPRFSA-N Ala-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C)N FOHXUHGZZKETFI-JBDRJPRFSA-N 0.000 description 1
- NMXKFWOEASXOGB-QSFUFRPTSA-N Ala-Ile-His Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 NMXKFWOEASXOGB-QSFUFRPTSA-N 0.000 description 1
- RZZMZYZXNJRPOJ-BJDJZHNGSA-N Ala-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C)N RZZMZYZXNJRPOJ-BJDJZHNGSA-N 0.000 description 1
- OKIKVSXTXVVFDV-MMWGEVLESA-N Ala-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C)N OKIKVSXTXVVFDV-MMWGEVLESA-N 0.000 description 1
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 1
- PVQLRJRPUTXFFX-CIUDSAMLSA-N Ala-Met-Gln Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O PVQLRJRPUTXFFX-CIUDSAMLSA-N 0.000 description 1
- XAXHGSOBFPIRFG-LSJOCFKGSA-N Ala-Pro-His Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O XAXHGSOBFPIRFG-LSJOCFKGSA-N 0.000 description 1
- GMGWOTQMUKYZIE-UBHSHLNASA-N Ala-Pro-Phe Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 GMGWOTQMUKYZIE-UBHSHLNASA-N 0.000 description 1
- SAHQGRZIQVEJPF-JXUBOQSCSA-N Ala-Thr-Lys Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN SAHQGRZIQVEJPF-JXUBOQSCSA-N 0.000 description 1
- JPOQZCHGOTWRTM-FQPOAREZSA-N Ala-Tyr-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPOQZCHGOTWRTM-FQPOAREZSA-N 0.000 description 1
- IYKVSFNGSWTTNZ-GUBZILKMSA-N Ala-Val-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IYKVSFNGSWTTNZ-GUBZILKMSA-N 0.000 description 1
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- KWKQGHSSNHPGOW-BQBZGAKWSA-N Arg-Ala-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)NCC(O)=O KWKQGHSSNHPGOW-BQBZGAKWSA-N 0.000 description 1
- KWTVWJPNHAOREN-IHRRRGAJSA-N Arg-Asn-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KWTVWJPNHAOREN-IHRRRGAJSA-N 0.000 description 1
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 1
- VRZDJJWOFXMFRO-ZFWWWQNUSA-N Arg-Gly-Trp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O VRZDJJWOFXMFRO-ZFWWWQNUSA-N 0.000 description 1
- UHFUZWSZQKMDSX-DCAQKATOSA-N Arg-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UHFUZWSZQKMDSX-DCAQKATOSA-N 0.000 description 1
- FSNVAJOPUDVQAR-AVGNSLFASA-N Arg-Lys-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FSNVAJOPUDVQAR-AVGNSLFASA-N 0.000 description 1
- YTMKMRSYXHBGER-IHRRRGAJSA-N Arg-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YTMKMRSYXHBGER-IHRRRGAJSA-N 0.000 description 1
- JPAWCMXVNZPJLO-IHRRRGAJSA-N Arg-Ser-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JPAWCMXVNZPJLO-IHRRRGAJSA-N 0.000 description 1
- QMQZYILAWUOLPV-JYJNAYRXSA-N Arg-Tyr-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)CC1=CC=C(O)C=C1 QMQZYILAWUOLPV-JYJNAYRXSA-N 0.000 description 1
- LLQIAIUAKGNOSE-NHCYSSNCSA-N Arg-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N LLQIAIUAKGNOSE-NHCYSSNCSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- XWGJDUSDTRPQRK-ZLUOBGJFSA-N Asn-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O XWGJDUSDTRPQRK-ZLUOBGJFSA-N 0.000 description 1
- VDCIPFYVCICPEC-FXQIFTODSA-N Asn-Arg-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O VDCIPFYVCICPEC-FXQIFTODSA-N 0.000 description 1
- GOVUDFOGXOONFT-VEVYYDQMSA-N Asn-Arg-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GOVUDFOGXOONFT-VEVYYDQMSA-N 0.000 description 1
- ZZXMOQIUIJJOKZ-ZLUOBGJFSA-N Asn-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O ZZXMOQIUIJJOKZ-ZLUOBGJFSA-N 0.000 description 1
- VKCOHFFSTKCXEQ-OLHMAJIHSA-N Asn-Asn-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VKCOHFFSTKCXEQ-OLHMAJIHSA-N 0.000 description 1
- ZDOQDYFZNGASEY-BIIVOSGPSA-N Asn-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O ZDOQDYFZNGASEY-BIIVOSGPSA-N 0.000 description 1
- VWJFQGXPYOPXJH-ZLUOBGJFSA-N Asn-Cys-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)C(=O)N VWJFQGXPYOPXJH-ZLUOBGJFSA-N 0.000 description 1
- AYKKKGFJXIDYLX-ACZMJKKPSA-N Asn-Gln-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O AYKKKGFJXIDYLX-ACZMJKKPSA-N 0.000 description 1
- UBKOVSLDWIHYSY-ACZMJKKPSA-N Asn-Glu-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UBKOVSLDWIHYSY-ACZMJKKPSA-N 0.000 description 1
- SUEIIIFUBHDCCS-PBCZWWQYSA-N Asn-His-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SUEIIIFUBHDCCS-PBCZWWQYSA-N 0.000 description 1
- NKLRWRRVYGQNIH-GHCJXIJMSA-N Asn-Ile-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O NKLRWRRVYGQNIH-GHCJXIJMSA-N 0.000 description 1
- YYSYDIYQTUPNQQ-SXTJYALSSA-N Asn-Ile-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YYSYDIYQTUPNQQ-SXTJYALSSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 1
- ZYPWIUFLYMQZBS-SRVKXCTJSA-N Asn-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N ZYPWIUFLYMQZBS-SRVKXCTJSA-N 0.000 description 1
- GIQCDTKOIPUDSG-GARJFASQSA-N Asn-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)N)N)C(=O)O GIQCDTKOIPUDSG-GARJFASQSA-N 0.000 description 1
- RTFWCVDISAMGEQ-SRVKXCTJSA-N Asn-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N RTFWCVDISAMGEQ-SRVKXCTJSA-N 0.000 description 1
- PPCORQFLAZWUNO-QWRGUYRKSA-N Asn-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N PPCORQFLAZWUNO-QWRGUYRKSA-N 0.000 description 1
- OOXUBGLNDRGOKT-FXQIFTODSA-N Asn-Ser-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OOXUBGLNDRGOKT-FXQIFTODSA-N 0.000 description 1
- NPZJLGMWMDNQDD-GHCJXIJMSA-N Asn-Ser-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NPZJLGMWMDNQDD-GHCJXIJMSA-N 0.000 description 1
- NCXTYSVDWLAQGZ-ZKWXMUAHSA-N Asn-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O NCXTYSVDWLAQGZ-ZKWXMUAHSA-N 0.000 description 1
- QUMKPKWYDVMGNT-NUMRIWBASA-N Asn-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QUMKPKWYDVMGNT-NUMRIWBASA-N 0.000 description 1
- PIABYSIYPGLLDQ-XVSYOHENSA-N Asn-Thr-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PIABYSIYPGLLDQ-XVSYOHENSA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- RGKKALNPOYURGE-ZKWXMUAHSA-N Asp-Ala-Val Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O RGKKALNPOYURGE-ZKWXMUAHSA-N 0.000 description 1
- HRGGPWBIMIQANI-GUBZILKMSA-N Asp-Gln-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HRGGPWBIMIQANI-GUBZILKMSA-N 0.000 description 1
- XAJRHVUUVUPFQL-ACZMJKKPSA-N Asp-Glu-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O XAJRHVUUVUPFQL-ACZMJKKPSA-N 0.000 description 1
- LTXGDRFJRZSZAV-CIUDSAMLSA-N Asp-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N LTXGDRFJRZSZAV-CIUDSAMLSA-N 0.000 description 1
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 description 1
- DWOGMPWRQQWPPF-GUBZILKMSA-N Asp-Leu-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O DWOGMPWRQQWPPF-GUBZILKMSA-N 0.000 description 1
- WZUZGDANRQPCDD-SRVKXCTJSA-N Asp-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N WZUZGDANRQPCDD-SRVKXCTJSA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- YFGUZQQCSDZRBN-DCAQKATOSA-N Asp-Pro-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O YFGUZQQCSDZRBN-DCAQKATOSA-N 0.000 description 1
- BKOIIURTQAJHAT-GUBZILKMSA-N Asp-Pro-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 BKOIIURTQAJHAT-GUBZILKMSA-N 0.000 description 1
- BRRPVTUFESPTCP-ACZMJKKPSA-N Asp-Ser-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O BRRPVTUFESPTCP-ACZMJKKPSA-N 0.000 description 1
- ZQFRDAZBTSFGGW-SRVKXCTJSA-N Asp-Ser-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZQFRDAZBTSFGGW-SRVKXCTJSA-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
- CZIVKMOEXPILDK-SRVKXCTJSA-N Asp-Tyr-Ser 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](CO)C(O)=O CZIVKMOEXPILDK-SRVKXCTJSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102100025218 B-cell differentiation antigen CD72 Human genes 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 108010084313 CD58 Antigens Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000001327 Chemokine CCL5 Human genes 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000759568 Corixa Species 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- XMTDCXXLDZKAGI-ACZMJKKPSA-N Cys-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N XMTDCXXLDZKAGI-ACZMJKKPSA-N 0.000 description 1
- NOCCABSVTRONIN-CIUDSAMLSA-N Cys-Ala-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CS)N NOCCABSVTRONIN-CIUDSAMLSA-N 0.000 description 1
- PRXCTTWKGJAPMT-ZLUOBGJFSA-N Cys-Ala-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O PRXCTTWKGJAPMT-ZLUOBGJFSA-N 0.000 description 1
- WDQXKVCQXRNOSI-GHCJXIJMSA-N Cys-Asp-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WDQXKVCQXRNOSI-GHCJXIJMSA-N 0.000 description 1
- UYYZZJXUVIZTMH-AVGNSLFASA-N Cys-Glu-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UYYZZJXUVIZTMH-AVGNSLFASA-N 0.000 description 1
- VPQZSNQICFCCSO-BJDJZHNGSA-N Cys-Leu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VPQZSNQICFCCSO-BJDJZHNGSA-N 0.000 description 1
- NLDWTJBJFVWBDQ-KKUMJFAQSA-N Cys-Lys-Phe Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 NLDWTJBJFVWBDQ-KKUMJFAQSA-N 0.000 description 1
- SNHRIJBANHPWMO-XGEHTFHBSA-N Cys-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)N)O SNHRIJBANHPWMO-XGEHTFHBSA-N 0.000 description 1
- BCWIFCLVCRAIQK-ZLUOBGJFSA-N Cys-Ser-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)O BCWIFCLVCRAIQK-ZLUOBGJFSA-N 0.000 description 1
- JLZCAZJGWNRXCI-XKBZYTNZSA-N Cys-Thr-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O JLZCAZJGWNRXCI-XKBZYTNZSA-N 0.000 description 1
- FCXJJTRGVAZDER-FXQIFTODSA-N Cys-Val-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O FCXJJTRGVAZDER-FXQIFTODSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 229940021995 DNA vaccine Drugs 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108091092566 Extrachromosomal DNA Proteins 0.000 description 1
- 208000000666 Fowlpox Diseases 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- KZEUVLLVULIPNX-GUBZILKMSA-N Gln-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N KZEUVLLVULIPNX-GUBZILKMSA-N 0.000 description 1
- LVNILKSSFHCSJZ-IHRRRGAJSA-N Gln-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LVNILKSSFHCSJZ-IHRRRGAJSA-N 0.000 description 1
- MAGNEQBFSBREJL-DCAQKATOSA-N Gln-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N MAGNEQBFSBREJL-DCAQKATOSA-N 0.000 description 1
- HDUDGCZEOZEFOA-KBIXCLLPSA-N Gln-Ile-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CCC(=O)N)N HDUDGCZEOZEFOA-KBIXCLLPSA-N 0.000 description 1
- RGAOLBZBLOJUTP-GRLWGSQLSA-N Gln-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N RGAOLBZBLOJUTP-GRLWGSQLSA-N 0.000 description 1
- JKGHMESJHRTHIC-SIUGBPQLSA-N Gln-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JKGHMESJHRTHIC-SIUGBPQLSA-N 0.000 description 1
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 1
- DSRVQBZAMPGEKU-AVGNSLFASA-N Gln-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N DSRVQBZAMPGEKU-AVGNSLFASA-N 0.000 description 1
- YRHZWVKUFWCEPW-GLLZPBPUSA-N Gln-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O YRHZWVKUFWCEPW-GLLZPBPUSA-N 0.000 description 1
- ZZLDMBMFKZFQMU-NRPADANISA-N Gln-Val-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O ZZLDMBMFKZFQMU-NRPADANISA-N 0.000 description 1
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 1
- CKRUHITYRFNUKW-WDSKDSINSA-N Glu-Asn-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O CKRUHITYRFNUKW-WDSKDSINSA-N 0.000 description 1
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 1
- KVBPDJIFRQUQFY-ACZMJKKPSA-N Glu-Cys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O KVBPDJIFRQUQFY-ACZMJKKPSA-N 0.000 description 1
- HILMIYALTUQTRC-XVKPBYJWSA-N Glu-Gly-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HILMIYALTUQTRC-XVKPBYJWSA-N 0.000 description 1
- LGYCLOCORAEQSZ-PEFMBERDSA-N Glu-Ile-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O LGYCLOCORAEQSZ-PEFMBERDSA-N 0.000 description 1
- KJBGAZSLZAQDPV-KKUMJFAQSA-N Glu-Phe-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N KJBGAZSLZAQDPV-KKUMJFAQSA-N 0.000 description 1
- SYWCGQOIIARSIX-SRVKXCTJSA-N Glu-Pro-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O SYWCGQOIIARSIX-SRVKXCTJSA-N 0.000 description 1
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 1
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 1
- MLILEEIVMRUYBX-NHCYSSNCSA-N Glu-Val-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O MLILEEIVMRUYBX-NHCYSSNCSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- CLODWIOAKCSBAN-BQBZGAKWSA-N Gly-Arg-Asp Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O CLODWIOAKCSBAN-BQBZGAKWSA-N 0.000 description 1
- LURCIJSJAKFCRO-QWRGUYRKSA-N Gly-Asn-Tyr Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LURCIJSJAKFCRO-QWRGUYRKSA-N 0.000 description 1
- SUDUYJOBLHQAMI-WHFBIAKZSA-N Gly-Asp-Cys Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(O)=O SUDUYJOBLHQAMI-WHFBIAKZSA-N 0.000 description 1
- PEZZSFLFXXFUQD-XPUUQOCRSA-N Gly-Cys-Val Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O PEZZSFLFXXFUQD-XPUUQOCRSA-N 0.000 description 1
- JSNNHGHYGYMVCK-XVKPBYJWSA-N Gly-Glu-Val Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O JSNNHGHYGYMVCK-XVKPBYJWSA-N 0.000 description 1
- HMHRTKOWRUPPNU-RCOVLWMOSA-N Gly-Ile-Gly Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O HMHRTKOWRUPPNU-RCOVLWMOSA-N 0.000 description 1
- COVXELOAORHTND-LSJOCFKGSA-N Gly-Ile-Val Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O COVXELOAORHTND-LSJOCFKGSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 1
- YYXJFBMCOUSYSF-RYUDHWBXSA-N Gly-Phe-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYXJFBMCOUSYSF-RYUDHWBXSA-N 0.000 description 1
- IALQAMYQJBZNSK-WHFBIAKZSA-N Gly-Ser-Asn Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O IALQAMYQJBZNSK-WHFBIAKZSA-N 0.000 description 1
- LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 1
- FKESCSGWBPUTPN-FOHZUACHSA-N Gly-Thr-Asn Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O FKESCSGWBPUTPN-FOHZUACHSA-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
- YDIDLLVFCYSXNY-RCOVLWMOSA-N Gly-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN YDIDLLVFCYSXNY-RCOVLWMOSA-N 0.000 description 1
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 1
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 1
- 101710114810 Glycoprotein Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 1
- LSQHWKPPOFDHHZ-YUMQZZPRSA-N His-Asp-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N LSQHWKPPOFDHHZ-YUMQZZPRSA-N 0.000 description 1
- RAVLQPXCMRCLKT-KBPBESRZSA-N His-Gly-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RAVLQPXCMRCLKT-KBPBESRZSA-N 0.000 description 1
- FHGVHXCQMJWQPK-SRVKXCTJSA-N His-Lys-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O FHGVHXCQMJWQPK-SRVKXCTJSA-N 0.000 description 1
- KECFCPNPPYCGBL-PMVMPFDFSA-N His-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CN=CN4)N KECFCPNPPYCGBL-PMVMPFDFSA-N 0.000 description 1
- GYXDQXPCPASCNR-NHCYSSNCSA-N His-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N GYXDQXPCPASCNR-NHCYSSNCSA-N 0.000 description 1
- 101000934359 Homo sapiens B-cell differentiation antigen CD72 Proteins 0.000 description 1
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 description 1
- 241001109669 Human coronavirus HKU1 Species 0.000 description 1
- 241000482741 Human coronavirus NL63 Species 0.000 description 1
- 241001428935 Human coronavirus OC43 Species 0.000 description 1
- NKVZTQVGUNLLQW-JBDRJPRFSA-N Ile-Ala-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)O)N NKVZTQVGUNLLQW-JBDRJPRFSA-N 0.000 description 1
- VSZALHITQINTGC-GHCJXIJMSA-N Ile-Ala-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VSZALHITQINTGC-GHCJXIJMSA-N 0.000 description 1
- YKRYHWJRQUSTKG-KBIXCLLPSA-N Ile-Ala-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKRYHWJRQUSTKG-KBIXCLLPSA-N 0.000 description 1
- YPQDTQJBOFOTJQ-SXTJYALSSA-N Ile-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N YPQDTQJBOFOTJQ-SXTJYALSSA-N 0.000 description 1
- PFTFEWHJSAXGED-ZKWXMUAHSA-N Ile-Cys-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N PFTFEWHJSAXGED-ZKWXMUAHSA-N 0.000 description 1
- GECLQMBTZCPAFY-PEFMBERDSA-N Ile-Gln-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N GECLQMBTZCPAFY-PEFMBERDSA-N 0.000 description 1
- LKACSKJPTFSBHR-MNXVOIDGSA-N Ile-Gln-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N LKACSKJPTFSBHR-MNXVOIDGSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- PDTMWFVVNZYWTR-NHCYSSNCSA-N Ile-Gly-Lys Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](CCCCN)C(O)=O PDTMWFVVNZYWTR-NHCYSSNCSA-N 0.000 description 1
- QZZIBQZLWBOOJH-PEDHHIEDSA-N Ile-Ile-Val Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)O QZZIBQZLWBOOJH-PEDHHIEDSA-N 0.000 description 1
- PMMMQRVUMVURGJ-XUXIUFHCSA-N Ile-Leu-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O PMMMQRVUMVURGJ-XUXIUFHCSA-N 0.000 description 1
- RMNMUUCYTMLWNA-ZPFDUUQYSA-N Ile-Lys-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N RMNMUUCYTMLWNA-ZPFDUUQYSA-N 0.000 description 1
- UAELWXJFLZBKQS-WHOFXGATSA-N Ile-Phe-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(O)=O UAELWXJFLZBKQS-WHOFXGATSA-N 0.000 description 1
- FGBRXCZYVRFNKQ-MXAVVETBSA-N Ile-Phe-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N FGBRXCZYVRFNKQ-MXAVVETBSA-N 0.000 description 1
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- SAEWJTCJQVZQNZ-IUKAMOBKSA-N Ile-Thr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SAEWJTCJQVZQNZ-IUKAMOBKSA-N 0.000 description 1
- ANTFEOSJMAUGIB-KNZXXDILSA-N Ile-Thr-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N ANTFEOSJMAUGIB-KNZXXDILSA-N 0.000 description 1
- IPFKIGNDTUOFAF-CYDGBPFRSA-N Ile-Val-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IPFKIGNDTUOFAF-CYDGBPFRSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102100034353 Integrase Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- ZRLUISBDKUWAIZ-CIUDSAMLSA-N Leu-Ala-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O ZRLUISBDKUWAIZ-CIUDSAMLSA-N 0.000 description 1
- FIJMQLGQLBLBOL-HJGDQZAQSA-N Leu-Asn-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FIJMQLGQLBLBOL-HJGDQZAQSA-N 0.000 description 1
- KTFHTMHHKXUYPW-ZPFDUUQYSA-N Leu-Asp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KTFHTMHHKXUYPW-ZPFDUUQYSA-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
- YORLGJINWYYIMX-KKUMJFAQSA-N Leu-Cys-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YORLGJINWYYIMX-KKUMJFAQSA-N 0.000 description 1
- HUEBCHPSXSQUGN-GARJFASQSA-N Leu-Cys-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N HUEBCHPSXSQUGN-GARJFASQSA-N 0.000 description 1
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- NEEOBPIXKWSBRF-IUCAKERBSA-N Leu-Glu-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O NEEOBPIXKWSBRF-IUCAKERBSA-N 0.000 description 1
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 1
- OGUUKPXUTHOIAV-SDDRHHMPSA-N Leu-Glu-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGUUKPXUTHOIAV-SDDRHHMPSA-N 0.000 description 1
- LAPSXOAUPNOINL-YUMQZZPRSA-N Leu-Gly-Asp Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O LAPSXOAUPNOINL-YUMQZZPRSA-N 0.000 description 1
- KEVYYIMVELOXCT-KBPBESRZSA-N Leu-Gly-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KEVYYIMVELOXCT-KBPBESRZSA-N 0.000 description 1
- PBGDOSARRIJMEV-DLOVCJGASA-N Leu-His-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O PBGDOSARRIJMEV-DLOVCJGASA-N 0.000 description 1
- VZBIUJURDLFFOE-IHRRRGAJSA-N Leu-His-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VZBIUJURDLFFOE-IHRRRGAJSA-N 0.000 description 1
- XQXGNBFMAXWIGI-MXAVVETBSA-N Leu-His-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 XQXGNBFMAXWIGI-MXAVVETBSA-N 0.000 description 1
- KOSWSHVQIVTVQF-ZPFDUUQYSA-N Leu-Ile-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KOSWSHVQIVTVQF-ZPFDUUQYSA-N 0.000 description 1
- JKSIBWITFMQTOA-XUXIUFHCSA-N Leu-Ile-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O JKSIBWITFMQTOA-XUXIUFHCSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- BIZNDKMFQHDOIE-KKUMJFAQSA-N Leu-Phe-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 BIZNDKMFQHDOIE-KKUMJFAQSA-N 0.000 description 1
- VDIARPPNADFEAV-WEDXCCLWSA-N Leu-Thr-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O VDIARPPNADFEAV-WEDXCCLWSA-N 0.000 description 1
- VHTIZYYHIUHMCA-JYJNAYRXSA-N Leu-Tyr-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O VHTIZYYHIUHMCA-JYJNAYRXSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- BTSXLXFPMZXVPR-DLOVCJGASA-N Lys-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCCN)N BTSXLXFPMZXVPR-DLOVCJGASA-N 0.000 description 1
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 1
- DEFGUIIUYAUEDU-ZPFDUUQYSA-N Lys-Asn-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DEFGUIIUYAUEDU-ZPFDUUQYSA-N 0.000 description 1
- FACUGMGEFUEBTI-SRVKXCTJSA-N Lys-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCN FACUGMGEFUEBTI-SRVKXCTJSA-N 0.000 description 1
- XFBBBRDEQIPGNR-KATARQTJSA-N Lys-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)O XFBBBRDEQIPGNR-KATARQTJSA-N 0.000 description 1
- OPTCSTACHGNULU-DCAQKATOSA-N Lys-Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN OPTCSTACHGNULU-DCAQKATOSA-N 0.000 description 1
- IRRZDAIFYHNIIN-JYJNAYRXSA-N Lys-Gln-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IRRZDAIFYHNIIN-JYJNAYRXSA-N 0.000 description 1
- PBIPLDMFHAICIP-DCAQKATOSA-N Lys-Glu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PBIPLDMFHAICIP-DCAQKATOSA-N 0.000 description 1
- DKTNGXVSCZULPO-YUMQZZPRSA-N Lys-Gly-Cys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CS)C(O)=O DKTNGXVSCZULPO-YUMQZZPRSA-N 0.000 description 1
- DTUZCYRNEJDKSR-NHCYSSNCSA-N Lys-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN DTUZCYRNEJDKSR-NHCYSSNCSA-N 0.000 description 1
- HAUUXTXKJNVIFY-ONGXEEELSA-N Lys-Gly-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HAUUXTXKJNVIFY-ONGXEEELSA-N 0.000 description 1
- ONPDTSFZAIWMDI-AVGNSLFASA-N Lys-Leu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ONPDTSFZAIWMDI-AVGNSLFASA-N 0.000 description 1
- QKXZCUCBFPEXNK-KKUMJFAQSA-N Lys-Leu-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 QKXZCUCBFPEXNK-KKUMJFAQSA-N 0.000 description 1
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 1
- JMNRXRPBHFGXQX-GUBZILKMSA-N Lys-Ser-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JMNRXRPBHFGXQX-GUBZILKMSA-N 0.000 description 1
- LKDXINHHSWFFJC-SRVKXCTJSA-N Lys-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N LKDXINHHSWFFJC-SRVKXCTJSA-N 0.000 description 1
- UIJVKVHLCQSPOJ-XIRDDKMYSA-N Lys-Ser-Trp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O UIJVKVHLCQSPOJ-XIRDDKMYSA-N 0.000 description 1
- ZVXSESPJMKNIQA-YXMSTPNBSA-N Lys-Thr-Pro-Pro Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 ZVXSESPJMKNIQA-YXMSTPNBSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-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](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- LMMBAXJRYSXCOQ-ACRUOGEOSA-N Lys-Tyr-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O LMMBAXJRYSXCOQ-ACRUOGEOSA-N 0.000 description 1
- VKCPHIOZDWUFSW-ONGXEEELSA-N Lys-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN VKCPHIOZDWUFSW-ONGXEEELSA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- BVXXDMUMHMXFER-BPNCWPANSA-N Met-Ala-Tyr Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVXXDMUMHMXFER-BPNCWPANSA-N 0.000 description 1
- HLQWFLJOJRFXHO-CIUDSAMLSA-N Met-Glu-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O HLQWFLJOJRFXHO-CIUDSAMLSA-N 0.000 description 1
- HLZORBMOISUNIV-DCAQKATOSA-N Met-Ser-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C HLZORBMOISUNIV-DCAQKATOSA-N 0.000 description 1
- FIZZULTXMVEIAA-IHRRRGAJSA-N Met-Ser-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FIZZULTXMVEIAA-IHRRRGAJSA-N 0.000 description 1
- 206010065764 Mucosal infection Diseases 0.000 description 1
- 208000034486 Multi-organ failure Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 1
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 1
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- UHRNIXJAGGLKHP-DLOVCJGASA-N Phe-Ala-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O UHRNIXJAGGLKHP-DLOVCJGASA-N 0.000 description 1
- QCHNRQQVLJYDSI-DLOVCJGASA-N Phe-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 QCHNRQQVLJYDSI-DLOVCJGASA-N 0.000 description 1
- HCTXJGRYAACKOB-SRVKXCTJSA-N Phe-Asn-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HCTXJGRYAACKOB-SRVKXCTJSA-N 0.000 description 1
- UUWCIPUVJJIEEP-SRVKXCTJSA-N Phe-Asn-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N UUWCIPUVJJIEEP-SRVKXCTJSA-N 0.000 description 1
- WMGVYPPIMZPWPN-SRVKXCTJSA-N Phe-Asp-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N WMGVYPPIMZPWPN-SRVKXCTJSA-N 0.000 description 1
- NKLDZIPTGKBDBB-HTUGSXCWSA-N Phe-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O NKLDZIPTGKBDBB-HTUGSXCWSA-N 0.000 description 1
- KJJROSNFBRWPHS-JYJNAYRXSA-N Phe-Glu-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O KJJROSNFBRWPHS-JYJNAYRXSA-N 0.000 description 1
- SPXWRYVHOZVYBU-ULQDDVLXSA-N Phe-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N SPXWRYVHOZVYBU-ULQDDVLXSA-N 0.000 description 1
- YKUGPVXSDOOANW-KKUMJFAQSA-N Phe-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKUGPVXSDOOANW-KKUMJFAQSA-N 0.000 description 1
- METZZBCMDXHFMK-BZSNNMDCSA-N Phe-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N METZZBCMDXHFMK-BZSNNMDCSA-N 0.000 description 1
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 1
- CJAHQEZWDZNSJO-KKUMJFAQSA-N Phe-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CJAHQEZWDZNSJO-KKUMJFAQSA-N 0.000 description 1
- AUJWXNGCAQWLEI-KBPBESRZSA-N Phe-Lys-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AUJWXNGCAQWLEI-KBPBESRZSA-N 0.000 description 1
- RVEVENLSADZUMS-IHRRRGAJSA-N Phe-Pro-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RVEVENLSADZUMS-IHRRRGAJSA-N 0.000 description 1
- AFNJAQVMTIQTCB-DLOVCJGASA-N Phe-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 AFNJAQVMTIQTCB-DLOVCJGASA-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
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 1
- IEIFEYBAYFSRBQ-IHRRRGAJSA-N Phe-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N IEIFEYBAYFSRBQ-IHRRRGAJSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- HFZNNDWPHBRNPV-KZVJFYERSA-N Pro-Ala-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HFZNNDWPHBRNPV-KZVJFYERSA-N 0.000 description 1
- LUGOKRWYNMDGTD-FXQIFTODSA-N Pro-Cys-Asn Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O LUGOKRWYNMDGTD-FXQIFTODSA-N 0.000 description 1
- ZPPVJIJMIKTERM-YUMQZZPRSA-N Pro-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@@H]1CCCN1 ZPPVJIJMIKTERM-YUMQZZPRSA-N 0.000 description 1
- DIFXZGPHVCIVSQ-CIUDSAMLSA-N Pro-Gln-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O DIFXZGPHVCIVSQ-CIUDSAMLSA-N 0.000 description 1
- XZONQWUEBAFQPO-HJGDQZAQSA-N Pro-Gln-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XZONQWUEBAFQPO-HJGDQZAQSA-N 0.000 description 1
- PULPZRAHVFBVTO-DCAQKATOSA-N Pro-Glu-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PULPZRAHVFBVTO-DCAQKATOSA-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
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- GURGCNUWVSDYTP-SRVKXCTJSA-N Pro-Leu-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GURGCNUWVSDYTP-SRVKXCTJSA-N 0.000 description 1
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 1
- DWGFLKQSGRUQTI-IHRRRGAJSA-N Pro-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 DWGFLKQSGRUQTI-IHRRRGAJSA-N 0.000 description 1
- AWQGDZBKQTYNMN-IHRRRGAJSA-N Pro-Phe-Asp Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H](CC(=O)O)C(=O)O AWQGDZBKQTYNMN-IHRRRGAJSA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 108091005774 SARS-CoV-2 proteins Proteins 0.000 description 1
- MWMKFWJYRRGXOR-ZLUOBGJFSA-N Ser-Ala-Asn Chemical compound N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)CC(N)=O)C)CO MWMKFWJYRRGXOR-ZLUOBGJFSA-N 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- PZZJMBYSYAKYPK-UWJYBYFXSA-N Ser-Ala-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PZZJMBYSYAKYPK-UWJYBYFXSA-N 0.000 description 1
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 1
- KAAPNMOKUUPKOE-SRVKXCTJSA-N Ser-Asn-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KAAPNMOKUUPKOE-SRVKXCTJSA-N 0.000 description 1
- DSSOYPJWSWFOLK-CIUDSAMLSA-N Ser-Cys-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O DSSOYPJWSWFOLK-CIUDSAMLSA-N 0.000 description 1
- YPUSXTWURJANKF-KBIXCLLPSA-N Ser-Gln-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YPUSXTWURJANKF-KBIXCLLPSA-N 0.000 description 1
- GZBKRJVCRMZAST-XKBZYTNZSA-N Ser-Glu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZBKRJVCRMZAST-XKBZYTNZSA-N 0.000 description 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 1
- HBTCFCHYALPXME-HTFCKZLJSA-N Ser-Ile-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HBTCFCHYALPXME-HTFCKZLJSA-N 0.000 description 1
- 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 1
- JAWGSPUJAXYXJA-IHRRRGAJSA-N Ser-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)N)CC1=CC=CC=C1 JAWGSPUJAXYXJA-IHRRRGAJSA-N 0.000 description 1
- HJAXVYLCKDPPDF-SRVKXCTJSA-N Ser-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N HJAXVYLCKDPPDF-SRVKXCTJSA-N 0.000 description 1
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 1
- QMCDMHWAKMUGJE-IHRRRGAJSA-N Ser-Phe-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O QMCDMHWAKMUGJE-IHRRRGAJSA-N 0.000 description 1
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 1
- FLONGDPORFIVQW-XGEHTFHBSA-N Ser-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FLONGDPORFIVQW-XGEHTFHBSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 1
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 1
- QYBRQMLZDDJBSW-AVGNSLFASA-N Ser-Tyr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYBRQMLZDDJBSW-AVGNSLFASA-N 0.000 description 1
- UKKROEYWYIHWBD-ZKWXMUAHSA-N Ser-Val-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O UKKROEYWYIHWBD-ZKWXMUAHSA-N 0.000 description 1
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 101710167605 Spike glycoprotein Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- TYVAWPFQYFPSBR-BFHQHQDPSA-N Thr-Ala-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)NCC(O)=O TYVAWPFQYFPSBR-BFHQHQDPSA-N 0.000 description 1
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- JBHMLZSKIXMVFS-XVSYOHENSA-N Thr-Asn-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JBHMLZSKIXMVFS-XVSYOHENSA-N 0.000 description 1
- RKDFEMGVMMYYNG-WDCWCFNPSA-N Thr-Gln-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O RKDFEMGVMMYYNG-WDCWCFNPSA-N 0.000 description 1
- XFTYVCHLARBHBQ-FOHZUACHSA-N Thr-Gly-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XFTYVCHLARBHBQ-FOHZUACHSA-N 0.000 description 1
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- XOWKUMFHEZLKLT-CIQUZCHMSA-N Thr-Ile-Ala 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)C(O)=O XOWKUMFHEZLKLT-CIQUZCHMSA-N 0.000 description 1
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 1
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 1
- TZJSEJOXAIWOST-RHYQMDGZSA-N Thr-Lys-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N TZJSEJOXAIWOST-RHYQMDGZSA-N 0.000 description 1
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 1
- FDQXPJCLVPFKJW-KJEVXHAQSA-N Thr-Met-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N)O FDQXPJCLVPFKJW-KJEVXHAQSA-N 0.000 description 1
- DNCUODYZAMHLCV-XGEHTFHBSA-N Thr-Pro-Cys Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N)O DNCUODYZAMHLCV-XGEHTFHBSA-N 0.000 description 1
- GVMXJJAJLIEASL-ZJDVBMNYSA-N Thr-Pro-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O GVMXJJAJLIEASL-ZJDVBMNYSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-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
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- ICNFHVUVCNWUAB-SZMVWBNQSA-N Trp-Arg-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N ICNFHVUVCNWUAB-SZMVWBNQSA-N 0.000 description 1
- JGLXHHQUSIULAK-OYDLWJJNSA-N Trp-Pro-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H]3CCCN3C(=O)[C@H](CC=3C4=CC=CC=C4NC=3)N)C(O)=O)=CNC2=C1 JGLXHHQUSIULAK-OYDLWJJNSA-N 0.000 description 1
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 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
- FBVGQXJIXFZKSQ-GMVOTWDCSA-N Tyr-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N FBVGQXJIXFZKSQ-GMVOTWDCSA-N 0.000 description 1
- DYEGCOJHFNJBKB-UFYCRDLUSA-N Tyr-Arg-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 DYEGCOJHFNJBKB-UFYCRDLUSA-N 0.000 description 1
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 1
- QHEGAOPHISYNDF-XDTLVQLUSA-N Tyr-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHEGAOPHISYNDF-XDTLVQLUSA-N 0.000 description 1
- CKHQKYHIZCRTAP-SOUVJXGZSA-N Tyr-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O CKHQKYHIZCRTAP-SOUVJXGZSA-N 0.000 description 1
- MPKPIWFFDWVJGC-IRIUXVKKSA-N Tyr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O MPKPIWFFDWVJGC-IRIUXVKKSA-N 0.000 description 1
- WAPFQMXRSDEGOE-IHRRRGAJSA-N Tyr-Glu-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O WAPFQMXRSDEGOE-IHRRRGAJSA-N 0.000 description 1
- LHTGRUZSZOIAKM-SOUVJXGZSA-N Tyr-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O LHTGRUZSZOIAKM-SOUVJXGZSA-N 0.000 description 1
- NOOMDULIORCDNF-IRXDYDNUSA-N Tyr-Gly-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NOOMDULIORCDNF-IRXDYDNUSA-N 0.000 description 1
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 1
- FBHBVXUBTYVCRU-BZSNNMDCSA-N Tyr-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CN=CN1 FBHBVXUBTYVCRU-BZSNNMDCSA-N 0.000 description 1
- WSFXJLFSJSXGMQ-MGHWNKPDSA-N Tyr-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N WSFXJLFSJSXGMQ-MGHWNKPDSA-N 0.000 description 1
- LQGDFDYGDQEMGA-PXDAIIFMSA-N Tyr-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N LQGDFDYGDQEMGA-PXDAIIFMSA-N 0.000 description 1
- PSALWJCUIAQKFW-ACRUOGEOSA-N Tyr-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N PSALWJCUIAQKFW-ACRUOGEOSA-N 0.000 description 1
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 1
- RCMWNNJFKNDKQR-UFYCRDLUSA-N Tyr-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=C(O)C=C1 RCMWNNJFKNDKQR-UFYCRDLUSA-N 0.000 description 1
- SOAUMCDLIUGXJJ-SRVKXCTJSA-N Tyr-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O SOAUMCDLIUGXJJ-SRVKXCTJSA-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
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- FPCIBLUVDNXPJO-XPUUQOCRSA-N Val-Cys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FPCIBLUVDNXPJO-XPUUQOCRSA-N 0.000 description 1
- CPTQYHDSVGVGDZ-UKJIMTQDSA-N Val-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N CPTQYHDSVGVGDZ-UKJIMTQDSA-N 0.000 description 1
- CVIXTAITYJQMPE-LAEOZQHASA-N Val-Glu-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CVIXTAITYJQMPE-LAEOZQHASA-N 0.000 description 1
- VVZDBPBZHLQPPB-XVKPBYJWSA-N Val-Glu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VVZDBPBZHLQPPB-XVKPBYJWSA-N 0.000 description 1
- GMOLURHJBLOBFW-ONGXEEELSA-N Val-Gly-His Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GMOLURHJBLOBFW-ONGXEEELSA-N 0.000 description 1
- SDUBQHUJJWQTEU-XUXIUFHCSA-N Val-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C(C)C)N SDUBQHUJJWQTEU-XUXIUFHCSA-N 0.000 description 1
- XXWBHOWRARMUOC-NHCYSSNCSA-N Val-Lys-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N)C(=O)O)N XXWBHOWRARMUOC-NHCYSSNCSA-N 0.000 description 1
- XBJKAZATRJBDCU-GUBZILKMSA-N Val-Pro-Ala Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O XBJKAZATRJBDCU-GUBZILKMSA-N 0.000 description 1
- QSPOLEBZTMESFY-SRVKXCTJSA-N Val-Pro-Val Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O QSPOLEBZTMESFY-SRVKXCTJSA-N 0.000 description 1
- DLLRRUDLMSJTMB-GUBZILKMSA-N Val-Ser-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)O)N DLLRRUDLMSJTMB-GUBZILKMSA-N 0.000 description 1
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 1
- YLBNZCJFSVJDRJ-KJEVXHAQSA-N Val-Thr-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O YLBNZCJFSVJDRJ-KJEVXHAQSA-N 0.000 description 1
- VTIAEOKFUJJBTC-YDHLFZDLSA-N Val-Tyr-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VTIAEOKFUJJBTC-YDHLFZDLSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 108070000030 Viral receptors Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010018691 arginyl-threonyl-arginine Proteins 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 238000010370 cell cloning Methods 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 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 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 108010078428 env Gene Products Proteins 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 230000005567 fecaloral disease transmission Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 238000011553 hamster model Methods 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000006054 immunological memory Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229960003971 influenza vaccine Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005960 long-lasting response Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 229940126582 mRNA vaccine Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000016379 mucosal immune response Effects 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 244000309711 non-enveloped viruses Species 0.000 description 1
- 229940023146 nucleic acid vaccine Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000001769 paralizing effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007479 persistent immune response Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108010025826 prolyl-leucyl-arginine Proteins 0.000 description 1
- 108010079317 prolyl-tyrosine Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012673 purified plant extract Substances 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003970 toll like receptor agonist Substances 0.000 description 1
- 229940044655 toll-like receptor 9 agonist Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229940126580 vector vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral 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
- A61K39/12—Viral antigens
- A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5256—Virus expressing foreign proteins
-
- 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
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/543—Mucosal route intranasal
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10041—Use of virus, viral particle or viral elements as a vector
- C12N2710/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/20011—Coronaviridae
- C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/20011—Coronaviridae
- C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- 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
- C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Plant Pathology (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明描述了具有复制能力的4型腺病毒(Ad4)，其被修饰以表达SARS‑CoV‑2刺突蛋白。该重组的Ad4的基因组被修饰为具有腺病毒E3区的至少一部分的缺失，以容纳刺突蛋白编码序列的插入。重组的Ad4向上呼吸道的施用引发粘膜免疫，这对于保护不受SARS‑CoV‑2感染和防止该病毒传播很重要。
Description
相关申请的交叉引用
本申请要求于2021年1月15日提交的美国临时申请号63/138,221的权益，该申请通过引用以其全文并入本文。
技术领域
本公开涉及表达SARS-CoV-2刺突蛋白的重组的具有复制能力的4型腺病毒(Ad4)，以及其作为免疫原性组合物用于抑制SARS-CoV-2感染和传播的用途。
背景技术
冠状病毒是一个大的病毒家族，通常会引起轻度至中度的上呼吸道疾病；然而，这个家族的一些成员可以在人类中引起严重疾病和死亡。在过去的20年中，冠状病毒在人类中引起了三次重大爆发，分别由严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)和SARS-CoV-2导致。截至2021年1月，SARS-CoV-2已经在全球范围内感染了超过8400万人，导致近200万死亡。尽管几种SARS-CoV-2疫苗已被批准在美国和其他国家使用，但仍然需要有效的诱导粘膜免疫且能快速大量生产的SARS-CoV-2疫苗。
发明内容
本文公开了免疫原性组合物，包含具有复制能力的4型腺病毒(adenovirus type4,Ad4)，其表达SARS-CoV-2刺突(S)蛋白(“Ad4-刺突”)，如来自原始武汉株或来自SARS-CoV-2变体，如beta(B.1.351)变体、delta(B.1.617.2)变体、gamma(P.1)变体、delta plus变体，或omicron(B.1.1.529)变体的野生型或修饰版本的S蛋白。在所公开的Ad4载体中，编码SARS-CoV-2 S蛋白的基因被克隆进入Ad4疫苗株的E3区。为了容纳S蛋白的插入，E3区的至少一部分被删除。所公开的Ad4-刺突疫苗与其他已提出的和被许可的SARS-CoV-2疫苗平台相比具有几个重要的优势。特别是，作为复制型载体，Ad4-刺突能够诱导持久性的免疫反应，包括粘膜免疫，这是抑制病毒感染和传播的一个重要因素。而且，Ad4-刺突疫苗能以相对较低的成本快速生产至高滴度。
本文提供了表达SARS-CoV-2 S蛋白的重组的、具有复制能力的Ad4。该重组的Ad4的基因组包括腺病毒E3区中的缺失和SARS-CoV-2 S蛋白编码序列的插入。该SARS-CoV-2 S蛋白可以是天然的S蛋白或是被修饰的S蛋白，如稳定化的或被截短的S蛋白。此外，S蛋白可以来自SARS-CoV-2的武汉株或其变体，如关注的变体(variant of concern,VOC)。
本文还提供了重组的、具有复制能力的Ad4载体，该载体具有腺病毒E3区中的缺失和SARS-CoV-2 S蛋白编码序列的插入。该SARS-CoV-2 S蛋白可以是天然的S蛋白或是修饰的S蛋白，如稳定化的或截短的S蛋白，其衍生自武汉株或SARS-CoV-2变体，如VOC。
本文进一步提供了免疫原性组合物，其包括本文所公开的重组Ad4或重组Ad4载体，和药学上可接受的载体(carrier)。
本文还提供了在受试者中诱发针对SARS-CoV-2的免疫反应的方法和通过向受试者施用治疗有效量的本文所公开的重组Ad4、重组Ad4载体或免疫原性组合物以使受试者针对SARS-CoV-2感染免疫的方法。在一些实施方案中，该重组Ad4、重组Ad4载体或免疫原性组合物被施用于上呼吸道，如鼻内施用。
本公开的前述的和其他的目的和特征将会通过以下参照附图进行的具体描述变得更加明显。
附图说明
图1：转染的A549细胞中稳定化和截短设计的SARS-CoV-2刺突的表达。用含有武汉株SARS-CoV-2刺突蛋白(nCoV)基因的穿梭载体质粒转染A549细胞。制备了四种刺突蛋白构建体：野生型(WT)、稳定型(PP)、尾部截短型(TT)和内吞基序截短型(noEndo)。对照组包括未转染(unTF)细胞和用表达HIV-1包膜(Env)蛋白(FDE3)的质粒转染的细胞。刺突和Env的表达分别使用SARS-CoV-2刺突蛋白特异性抗体和HIV-1Env特异性抗体(VRC01)通过流式细胞术测量。相对于野生型刺突蛋白，转染的A549细胞中的SARS-CoV-2刺突蛋白表达随着稳定化突变、尾部的截短和内吞基序的截短而减少。
图2A-2B：感染的A549细胞中稳定化和截短设计的SARS-CoV-2刺突的表达。携带SARS-CoV-2蛋白基因的复制型腺病毒用于感染A549细胞。测试了基于武汉株的三种刺突蛋白设计在A549细胞表面的表达：野生型(nCoV-WT)、PP稳定型(nCoV-PP)和尾部截短型(nCoV-TT)刺突蛋白。表达HIV-1Env蛋白(FDE3)的复制型腺病毒被用作感染的阳性对照，未感染(unIF)细胞被用作阴性对照。刺突蛋白的表达使用SARS-CoV-2刺突蛋白特异性抗体通过流式细胞术测量。抗体VRC01用于检测HIV Env的表达。nCoV-WT的刺突表达如图2A所示；FDE3、nCoV-PP和nCoV-TT的刺突表达如图2B所示。如图2A-2B所示，nCoV-WT和nCoV-PP构建体的刺突蛋白的表达都很高。
图3：用含有SARS-CoV-2刺突蛋白基因的复制型Ad4进行免疫，以在兔中诱导中。在第0天和第28天(箭头所示)，新西兰白兔用1.29×109个感染单位(IFU)的纯化的复制型Ad4nCoV-WT进行免疫。使用荧光素酶测定法，在免疫后4周(第二剂之前)检测到针对武汉型SARS-CoV-2假病毒的血清中和，并持续增加达免疫后12周。
图4：nCoV-PP、nCoV-WT、nCoV-尾部截短型和nCoV-No-Endo刺突蛋白的氨基酸比对。比对显示了SARS-Cov-2野生型(武汉型)刺突蛋白中引入的三个突变的位置。nCoV-PP含有在第986位和第987位氨基酸的双脯氨酸稳定化取代；nCoV-尾部截短型包括胞质尾部末端的24个氨基酸的缺失；nCoV-No-Endo包含末端的内吞信号基序的缺失(末端的五个残基)。氨基酸编号参考如本文SEQ ID NO:2所述的野生型刺突蛋白。
图5A-5B：仓鼠鼻内Ad4-SARS-CoV-2的剂量滴定中对武汉型假病毒的血清中和作用。叙利亚黄金仓鼠被鼻内施用102-107个感染形成单位(IFU)的PP稳定化的Ad4-SARS-CoV-2武汉型刺突(Ad4-SARS-CoV-2WuPP)。在第4周(图5A)和第8周(图5B)测量针对武汉型假病毒的血清中和作用。对于最高剂量的Ad4-SARS-CoV-2WuPP，在两个时间点都观察到强中和作用。
图6A-6E：仓鼠鼻内的表达所述VOC刺突的Ad4-SARS-CoV-2的血清中和作用。叙利亚黄金仓鼠用鼻内Ad4进行免疫，该Ad4表达稳定化的刺突蛋白，来自武汉株(Ad4-CoV2-武汉型)、beta变体(Ad4-CoV2-SA)、delta变体(Ad4-CoV2-印度型)或gamma变体(Ad4-CoV2-巴西型)，或是表达具有beta变体RBD的稳定化的嵌合刺突蛋白(Ad-CoV2-Wu/RBD-SA)。表达H5流感病毒血凝素的Ad4(Ad4-H5)和假接种作为阴性对照。鼻内施用28天后，测定针对武汉型假病毒(图6A)或delta假病毒(图6B)的血清中和作用。另外，鼻内施用56天后，测定针对武汉型假病毒(图6C)、delta假病毒(图6D)和omicron假病毒(图6E)的血清中和作用。
序列表
随附的序列表中列出的核酸和氨基酸序列，使用标准字母缩写来表示核苷酸碱基，使用三个字母的代码来表示氨基酸，如37C.F.R.1.822所定义。仅显示每个核酸序列的一条链，但互补的链被理解为包括在对显示的链的任何引用中。序列表以ASCII文本文件的形式提交，创建于2022年1月14日，大小为199KB，其通过引用并入本文。在随附的序列表中：
SEQ ID NO:1是Ad4-SARS-CoV-2刺突载体的核苷酸序列。
TAAATTTAAATGAATTCCGTCAAGGGCGACACAAAAGGTATTCTAAATGCATAATAAATACTGATAACATCTTATAGTTTGTATTATATTTTGTATTATCGTTGACATGTATAATTTTGATATCAAAAACTGATTTTCCCTTTATTATTTTCGAGATTTATTTTCTTAATTCTCTTTAACAAACTAGAAATATTGTATATACAAAAAATCATAAATAATAGATGAATAGTTTAATTATAGGTGTTCATCAATCGAAAAAGCAACGTATCTTATTTAAAGTGCGTTGCTTTTTTCTCATTTATAAGGTTAAATAATTCTCATATATCAAGCAAAGTGACAGGCGCCCTTAAATATTCTGACAAATGCTCTTTCCCTAAACTCCCCCCATAAAAAAACCCGCCGAAGCGGGTTTTTACGTTATTTGCGGATTAACGATTACTCGTTATCAGAACCGCCCAGGATGCCTGGCAGTTCCCTACTCTCGCCGCTGCGCTCGGTCGTTCGGCTGCGGGACCTCAGCGCTAGCGGAGTGTATACTGGCTTACTATGTTGGCACTGATGAGGGTGTCAGTGAAGTGCTTCATGTGGCAGGAGAAAAAAGGCTGCACCGGTGCGTCAGCAGAATATGTGATACAGGATATATTCCGCTTCCTCGCTCACTGACTCGCTACGCTCGGTCGTTCGACTGCGGCGAGCGGAAATGGCTTACGAACGGGGCGGAGATTTCCTGGAAGATGCCAGGAAGATACTTAACAGGGAAGTGAGAGGGCCGCGGCAAAGCCGTTTTTCCATAGGCTCCGCCCCCCTGACAAGCATCACGAAATCTGACGCTCAAATCAGTGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGCGGCTCCCTCGTGCGCTCTCCTGTTCCTGCCTTTCGGTTTACCGGTGTCATTCCGCTGTTATGGCCGCGTTTGTCTCATTCCACGCCTGACACTCAGTTCCGGGTAGGCAGTTCGCTCCAAGCTGGACTGTATGCACGAACCCCCCGTTCAGTCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGAAAGACATGCAAAAGCACCACTGGCAGCAGCCACTGGTAATTGATTTAGAGGAGTTAGTCTTGAAGTCATGCGCCGGTTAAGGCTAAACTGAAAGGACAAGTTTTGGTGACTGCGCTCCTCCAAGCCAGTTACCTCGGTTCAAAGAGTTGGTAGCTCAGAGAACCTTCGAAAAACCGCCCTGCAAGGCGGTTTTTTCGTTTTCAGAGCAAGAGATTACGCGCAGACCAAAACGATCTCAAGAAGATCATCTTATTAAGCTTAGAAAAACTCATCGAGCATCAAATGAAATTGCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATGAAGGAGAAAACTCACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTCGTCCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGAGTGACGACTGAATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCCATTACGCTCGTCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGCGAGGCGAAATACGCGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAGTGCAACCGGCGCAGGAACACTGCCAGCGCATCAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACCTGGAACGCTGTTTTTCCGGGGATCGCAGTGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGTGGCATAAATTCCGTCAGCCAGTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGTTTCAGAAACAACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCGCACCTGATTGCCCGACATTATCGCGAGCCCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTCCCGTTGAATATGGCTCATATTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTCAGTGTTACAACCAATTAACCAATTCTGAACATTATCGCGAGCCCATTTATACCTGAATATGGCTCATAACACCCCTTGTTTGCCTGGCGGCAGTAGCGCGGTGGTCCCACCTGACCCCATGCCGAACTCAGAAGTGAAACGCCGTAGCGCCGATGGTAGTGTGGGGACTCCCCATGCGAGAGTAGGGAACTGCCAGGCATCAAATAAAACGAAAGGCTCAGTCGAAAGACTGGGCCTTTCGCCCGGGCTAATTAGGGGGTGTCGCCCTTATCGCTGAGGATCCATTTAAATTTAATTAACATCATCAATAATATACCTTATTTTTTTTGTGTGAGTTAATATGCAAATAAGGCGTGAAAATTTGGGGATGGGGCGCGCTGATTGGCTGTGACAGCGGCGTTCGTTAGGGGCGGGGCAGGTGACGTTTTGATGACGCGACTATGAGGAGGAGTTAGTTTGCAAGTTCTGGTGGGGAAAAGTGACGTCAAACGAGGTGTGGTTTAAACACGGAAATACTCAATTTTCCCACGCTGTCTAACAGGAAATGAGGTGTTTTTGGGCGGATGCAAGTGAAAACGGACCATTTTCGCGCGAAAACTGAATGAGGAAGTGAAATCTGAGTAATTTAGTGTTTATGACAGGGAGGAGTATTTGCCGAGGGCCGAGTAGACTTTGACCGTTTACGTGGGGGTTTCGATTACCGTGTTTTTCACCTAAAGTTCCGCGTACGGTGTCAAAGTCCGGTGTTTTTACGTAGGTGTCAGCTGATCGTCAGGGTATTTAAACCTGCGCTCTGCAGTCAAGAGGCCACTCTTGAGTGCCAGCGAGAAGAGTTTTCTCCTCCGCGCCGCGAGTCAGATCTACACTTTGAAATATGAGGCACCTAAGAGACCTGCCCGATGAGGAAATTATCATCGCTTCCGGGAGCGAGATTCTGGAACTGGTGGTAAATGCTATGATGGGCGACGACCATCCGGAACCCCCCACCCCATTTGAGACACCTTCGCTGCACGATTTGTATGATCTGGAGGTGGATGTGCCCGAGGACGACCCCAACGAGAAGGCGGTAAATGATTTATTTAGCGATGCCGCGCTGCTAGCTGCCGAGGAGGCTTCAAGCCCTAGCTCAGACAGCGACTCTTCACTGCATACCCCTAGACACGACAGAGGTGAGAAAGAGATCCCCGGGCTTAAATGGGAAAAGATGGACTTGCGTTGCTATGAGGAATGCCTGCCCCCAAGCGATGATGAGGACGAGCAGGCGATTCAGAACGCAGCGAGCCATGGAGTGCAAGCCGTCAGCGAGAGCTTTGCACTGGACTGCCCGCCTTTGCCCGGACACGGCTGTAAGTCTTGTGAATTTCATCGCATCAATACTGGAGATAAAGCTGTGTTATGTGCACTTTGCTATATGAGAGCGTACAACCATTGTGTTTACAGTAAGTGTGATTAAGTGAACTTTAAAGGGAGGCAAAGAGTAGGGTGACTGGGTGATGACTGGTTTATTTATGTATATCTGTTTTTTATATAGGTCCCGTTTCTGACGCAGATGATGAGACCCCCACTACAGAGTCCACTTTGTCACCCCCTGAAATTGGCACGTCTCCATCTGACAATATTGTTAGACCAGTTCCTGTAAGAGCCACTGGGAGGAGAGCAGCTGTAGAATGTTTGGATGATTTGCTTCAGGGTGGAGATGAACCTTTGGACTTGTGTACCCGGAAACGCCCCAGGCATTAAGTGCCACACATGTGTGTTTACTTGAGGTGATGTCAGTATTTATAGGGTGTGGAGTGCAATAAAATATGTGTTGACTTTAAGTGCGTGGTTTATGACTCAGGGGAGGGGACTTTGGGTATATAAGCAGGTGCAGACCTGTGTGGTTAGCTCAGAGCGGTATGGAGATTTGGACGGTTTTGGAAGACTTTCACAAGACTAGGCAGCTGCTAGAGAACGCCTCGAACGGAGTCTCTTACCTGTGGAGATTCTGCTTCGGCGGTGACCTAGCTAAGCTAGTCTATAGGGCCAAACAGGATTATAGGGAACAATTTGAGGATATTTTGAGAGAGTGTCCTGGTCTTTTTGACGCTCTTAACTTGGGCCATCAGTCTCACTTTAACCAGAGAATTTCAAGAGCCCTTGACTTTACTACTCCTGGCAGAACCACTGCAGCAGTAGCCTTTTTTGCTTTTATTTTTGACAAATGGAGTCAAGAAACCCATTTCAGCAGGGATTACCAGCTGGATTTCTTAGCAGTAGCTTTGTGGAGAACATGGAAGTGCCAGCGCCTGAATGCAATCTCCGGCTACTTGCCGGTACAGCCGCTAGACACTCTGAGGATCCTGAGTCTCCAGCAGCAGGAGGATCAAGAAGAGAATCCGAGAGCCGGCCTGGACCCTCCGGCGGAGGAGTAGCTGACCTGTTTCCTGAACTGCACCGGGTGCTGACTAGGTCTTCGAGTGGTCGGGAGAGGGGTATTAAGCGGGAGAGGCATGATGAGACTAATCACAGAATTGAACTGACTGTGGGTCTGATGAGCCGCAAGCGTCCAGAAACAGTGTGGTGGTATGAGGTGCAGTCAACTGGCACAGATGAGGTGTCAGTCATGCATGAGAGATTTTCCCTAGAACAAGTCAAGACTTGTTGGTTGGAGCCTGAGGATGATTGGGAGGTAGCCATCAGGAATTATGCCAAGCTGGCTCTGAGGCCAGATAGAAAGTACAAGATTACTAAGCTGATAAATATCAGAAATGCCTGCTACATCTCAGGGAATGGGGCTGAAGTGGAGATCTGTCTCCAGGATAGAGTGGCTTTCAGATGCTGCATGATGAATATGTACCCGGGAGTGGTGGACATGGATGGGGTCACCTTTATGAACATGAGGTTCAGGGGAGATGGGTATAATGGGACGGTCTTTATGGCCAATACCAAGCTGACAGTGCATGGATGCTCCTTCTTTGGGTTTAATAACACCTGCATCGAGGCTTGGGGTCAGGTCGGTGTTAAGGGGTGCAGTTTTTCAGCCAACTGGATGGGGGTAGTGGGCAGGACCAAGAGTATGCTGTCTGTGAAGAAATGCTTGTTTGAGAGGTGCCACCTGGGGGTGATGAGCGAGGGCGAAGCCAGAATCCGCCACTGTGCCTCTACCGAGACGGGCTGTTTTGTGCTGTGCAAGGGCAATGCCAAGATCAAGCATAATATGATCTGTGGAGCCTCGGACGAGCGCGGCTACCAGATGCTGACCTGCGCCGGTGGGAACAGTCATATGCTGGCCGCCGTGCATGTGGCTTCCCATTCCCGCAAGCCCTGGCCTGAGTTCGAGCACAATGTCATGACCAGGTGCAATATGCATCTGGGGGCTCGCCGAGGCATGTTTATGCCCTACCAGTGCAACCTGAATTATGTAAAGGTGCTCCTGGAGCCCGATGTCATGTCCAGAGTGAGCCTGACGGGGGTGTTTGACATGAATGTGGAAGTGTGGAAGATTCTAAGATATGATGAATACAAGACCAGGTGTCGAGCCTGCGAGTGCGGAGGGAAGCATGCCAGGTTCCAGCCCGTGTGTGTGGATGTGACGGAGGACCTGCGACCCGATCATTTGGTGTTGTCCTGCACCGGGACGGAGTTCGGCTCCAGTGGGGAAGAATCTGACTAGAGTGAGTAGTGTTTTGGGGAGGGAGAGGACCTGCATAAGGGGCAGAATGATTAAAATCTGTGCTTTTCTGTGTGTTGCAGCAGCATGAGCGGAAACGGCTCCTTTGAGGGAGGGGTATTCAGCCCTTATCTGACGGGGCGTCTCCCCTCCTGGGCGGGAGTGCGTCAAAATGTGATGGGATCCACGGTGGACGGCCGGCCCGTACAGCCCGCGAACTCTTCAACCCTGACCTATGCAACCCTGAGCTCCTCGTCGGTGGACGCAGCTGCCGCCGCAGCTGCTGCTTCTGCCGCCAGCGCCGTGCGCGGAATGGCCATGGGCGCCGGCTATTACGGCACTCTGGTGGCCAACTCGAGTTCCACTAATAATCCCGCCAGCCTGAACGAGGAGAAGCTGCTGCTGTTGATGGCCCAGCTCGAGGCCTTGACCCAGCGCCTGGGCGAGCTGACCCAGCAGGTGGCTCAGCTGCAGGAGCAGACGCGGGCCGCGGTTGCCACGGTGAAATCCAAATAAAAAATGAATCAATAAATAAACGGAGACGGTTGTTGATTTTAAAAATCAGAGTCTGAATCTTTATTTGATTTTTCGCGCACGGTAGGCCCTGGACCACCGGCCTCGATCATTGAGCACCCGGTGGATCTTTTCCAAGACCCGGTAGAGGTGGGATTGGATATTGAGGTACATGGGCATGAGCCCGTCCCGGGGGTGAAGGTAGCTCCATTGCAGGGCCTCGTGCTCGGGGGTGGTGTTGTAAATCACCCAGTCATAGCAGGGACGCAGGGCGTGGTGTTGCACAATATCTTTGAGGAGGAGACTGATGGCCACGGGCAGCCCTTTGGTGTAGGTGTTTACAAACCTGTTGAGCTGGGAGGGATGCATGCGGGGGGAGATGAGGTGCATCTTAGCCTGGATCTTCAGATTGGCGATGTTACCGCCCAGATCCCGCCTGGGATTCATGTTGTGCAGGACCACCAGCACGGTGTATCCGGTGCACTTGGGGAATTTGTCATGCAACTTGGAAGGGAAGGCATGAAAGAATTTGGAGACGCCCTTGTGGCCGCCCAGGTTTTCCATGCACTCATCCATGATAATGGCTATGGGCCCGTGGGCGGCGGCTTGGGCAAAGACGTTTCGGGGGTCGGACACATCGTAGTTGTGGTCCTGGGTGAGATCTTCATAGGCCATTTTAATGAATTTGGGGCGGAGGGTGCCCGATTGGGGGACGAAGGTACCCTCAATCCCGGGGGCGTAGTTTCCCTCACAGATCTGCATCTCCCAGGCCTTAAGCTCCGAGGGGGGGATCATGTCCACCTGCGGGGCGATAAAGAAAACGGTTTCCGGGGCGGGGGAGATGAGCTGGGCGGAAAGCAGGTTGCGGAGTAGCTGGGACTTACCGCAGCCGGTGGGGCCGTAGATAACCCCAATGACCGGCTGCAGGTGGTAGTTGAGGGAGACACAGCTGCCGTCCTCCCTAAGAAGGGGGGCCACCTCGTTCATCATTTGGCGCACGTGCATGTTCTCGCGCACCAGTTCCGCCAGGAGTCGCTCTCCGCCCAGCGAGAGGAGCTCCTGGAGCGAGGCGAAGTTTTTCAGCGGCTTGAGCCCGTCGGCCATGGGCATTTTGGAAAGGGTCTGTTGCAGGAGTTCCAAGCGGTCCCAGAGCTCGGTGATGTGCTCTACGGCATCTCGATCCAGCAGACCTCCTCGTTTCGCGGGTTGGGGCGACTGCGGGAGTAGGGCGCCAGACGATGGGCGTCCAGCGCGGCCAGGGTCCGGTCCTTCCAGGGTCGCAGCGTCCGCGTCAGGGTGGTCTCCGTCACGGTAAAGGGGTGCGCGCCGGGCTGGGCGCTTGCGAGGGTGCGCTTCAGGCTCATCCGGCTGGTCGAGAACCGCTCCCGATCGGCGCCCTGTGCGTCGGCCAGGTAGCAATTGACCATGAGTTCGTAGTTGAGCGCCTCGGCCGCGTGGCCTTTGGCGCGGAGCTTACCTTTGGAAGTCTGCCCACAGGCGGGACAGAGGAGGGACTTGAGGGCGTAGAGCTTGGGGGCGAGGAAGACGGACTCGGGGGCGTAGGCGTCCGCGCCGCAGTGGGCGCAGACGGTCTCGCACTCCACGAGCCAGGTGAGGTCGGGCTGATTGGGATCAAAAACCAGTTTTCCGCCGTTCTTTTTGATGCGTTTCTTACCTCTGGTCTCCATGAGCTCGTGTCCCCGCTGGGTGACAAAGAGGCTGTCCGTGTCCCCGTAAACCGACTTTATGGGTCGGTCCTCGAGTGGGACGCCGCGGTCCTCGTCGTAGAGGAAACCCGACCACTCTGAGACGAAGGCCCGGGTCCAAGCCAGCACGAAGGAGGCCACGTGGGAGGGATAGCGGTCGTTATCCACCAGCGGGTCCACCTTCTCCAGTGTATGCAAACACATGTCCCCCTCGTCCACATCCAGGAAGGTGATTGGCTTGTAAGTGTAGGCCACGTGACCGGGGGTCCCGGCCGGGGGGGTATAAAAGGGGGCGGGCCGCTGCTCGTCTTCACTGTCTTCCGGATCGCTGTCCAGGAGCGCCAGCTGTTGGGGTAGGTATTCCCTCTCAAAGGCGGGCATGACCTCCGCACTCAGGTTGTCAGTTTCTAGAAACGAGGAGGATTTGATATTGACGGTGCCGGCGGAGATGCCTTTCAAGAGCCCCTCGTCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCGAGTTTGGTGGCGAAGGAGCCGTAGAGGGCGTTGGAGAGGAGCTTGGCGATGGAGCGCATGGTCTGGTTCTTTTCCTTGTCGGCGCGCTCCTTGGCGGCGATGTTGAGCTGCACGTACTCGCGCGCCACGCACTTCCATTCGGGGAAGACGGTGGTTAGCTCGTCTGGCACGATTCTGACCTGCCAGCCCCGGTTATGCAGGGTGATGAGGTCAACGCTGGTGGCCACCTCGCCGCGCAGGGGCTCGTTGGTCCAGCAGAGGCGGCCGCCCTTGCGCGAGCAGAAGGGGGGCAGGGGGTCCAGCATAAGCTCGTCGGGGGGGTCAGCATCGATGGTGAAGATGCCTGGCAGGAGGTCGGGGTCGAAGTAGCTTATGCAGGTGCCCAGATCGTCCAGAGAAGCTTGCCATTCGCGCACGGCCAGCGCGCGCTCGTAGGGACTAAGGGGCGTGCCCCAGGGCATGGGGTGGGTGAGCGCGGAGGCGTACATGCCGCAGATGTCGTAGACGTAGAGGGGCTCATCAAGGATGCCAATGTAGGTGGGGTAGCAGCGGCCCCCGCGGATGCTGGCGCGCACGTAGTCATACAACTCGTGCGAGGGGGCGAGGAGCCCGGCTCCGAGATTGGCGCGGCTGGGTTTTTCGGCGCGGTAGACGATCTGACGGAAGATGGCGTGGGAGTTGGAGGAGATGGTGGGTCTTTGGAAGATGTTGAAGTGGGCGTGGGGCAGGCCGACCGAGTCGCGGATGAAGTGGGCGTAGGAGTCTTGCAGCTTGGCGACAAGCTCGGCGGTGACGAGGACGTCCAGGGCGCAGTAGTCAAGGGTCTCTTGGATGATGTCATACTTGAGCTGGCCCTTTTGTTTCCACAGCTCGCGGTTGAGAAGGAACTCTTCGCGGTCCTTCCAGTACTCTTCAAGGGGGAACCCGTCCTGGTCGGCACGGTAAGAGCCTAGCATGTAGAACTGGTTAACGGCCTTGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCATAGGCCTGGGCGGCCTTGCGCAGGGAGGTGTGCGTGAGGGCGAAGGTGTCCCTGACCATGACCTTTAGGAACTGGTGCTTGAAGTCGATATCGTCGCAGCCCCCCTGCTCCCAGAGCTGGAAGTCCGTGCGCTTCTTGTAGGCGGGGTTGGGCAAAGCGAAAGTAACATCGTTGAAGAGGATCTTGCCCGCGCGGGGCATAAAGTTGCGAGTGATGCGGAAAGGCTGGGGCACCTCGGCCCGGTTGTTGATGACCTGGGCGGCGAGCACGATCTCGTCGAAGCCGTTAATGTTGTGGCCCACAATGTATAGTTCCACGAACCGCGGGCGGCCCTTGACGTGGGGCAGTTTCTTGAGCTCCTCGTAGGTGAGCTCGTCGGGGTCGCTGAGCCCGTGCTGCTCGAGGGCCCAGTCGGCGAGATGGGGGTTGGCGCGGAGGAAGGAAGTCCAGAGATCCACGGCCAGGGCGGTTTGCAGACGATCCCGGTACTGGCGGAACTGCTGACCCACGGCCATTTTTTCGGGGGTGACGCAGTAGAAGGTGCGGGGGTCGCCGTGCCAACGGTCCCATTTTAGCTGGAGGGCGAGATCAAGGGCGAGCTCAACGAGCCGGTCGTCCCCGGAGAGTTTCATGACCAGCATGAAGGGGACGAGCTGCTTGCCGAAGGACCCCATCCAGGTGTAGGTTTCCACATCGTAGGTGAGGAAGAGCCTTTCGGTGCGAGGATGCGAGCCGATGGGGAAGAACTGGATCTCCTGCCACCAGTTGGAGGAATGGCTGTTGATGTGATGGAAGTAGAAATGCCGACGGCGCGCCGAACATTCGTGCTTGTGTTTATACAAGCGGCCACAGTGCTCGCAACGCTGCACGGGATGCACGTGCTGCACGAGCTGTACCTGGGTTCCTTTGACGAGGAATTTCAGTGGGAAGTGGAGTCGTGGCGCCTGCATCTGGTGCTGTACTACGTCGTGGTGGTCGGCCTGGCCCTCTTCTGCCTCGATGGTGGTCATGCTGACGAGCCCGCGCGGGAGGCAGGTCCAGACCTCGGCGCGAACGGGTCGGAGAGCGAGGACGAGGGCGCGCAGGCCGGAGCTGTCCAGGGTCCTGAGACGCTGCGGAGTCAGGTCAGTGGGCAGCGGCGGCGCGCGGTTGACTTGCAGGAGTTTTTCAAGGGCGCGCGGGAGGTCCAGATGGTACTTGATCTCCACCGCGCCGTTGGTGGCGACGTCGATGGCTTGCAGTGTCCCGTGCCCCTGGGGAGTGACCACCGTCCCCCGTTTCTTCTTGGCGGGCGGAAGCGGTTTGGCTTCCATGGTTAAAAGCGGCGGCGAGGACGCGCGCCGGGCGGTAGGGGCGGCTCGGGACCCGGAGGCAGTGGTGGCAGGGGCACGTCGGCGCCGCGCGCGGGCAGGTTCTGGTACTGCGCCCGGAGAAGACTGGCGTGAGCGACGACGCGACGGTTGACGTCCTGGATCTGACGCCTCTGGGTGAAGGCCACGGGACCCGTGAGTTTGAACCTGAAAGACAGTTCGACAGAATCAATCTCGGTATCATTGACGGCGGCCTGCCGCAGAATCTCTTGCACGTCGCCCGAGTTGTCCTGGTAGGCAATCTCGGTCATGAACTGCTCGATCTCCTCCTCCTGAAGGTCTCCGCGGCCGGCGCGCTCCACGGTGGCCGCGAGGTCGTTGGAGATGCGGCCCATGAGCTGCGAGAAGGCGTTCATGCCCGCCTCGTTCCAGACGCGGCTGTAAACCACGGCGCCCTCGGGATCGCGGGCGCGCATGACCACCTGGGCGAGGTTGAGCTCCACGTGGCGCGCAAAAACCGCGTAGTTGCAGAGGCGCTGGTAGAGGTAGTTGAGCGTGGTGGCAATGTGCTCAGTGACAAAGAAGTACATAATCCAGCGGCGGAGCGGCATTTCGCTGACGTCGCCCAGGGCTTCCAAGCGCTCCATGGCCTCGTAAAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGTGCAGATACGGTCAAGTCCTCCTCCAGAAGACGGATGAGCTCGGCGATGGTGGCGCGCACCTCGCGCTCGAAGGCTCCCGTGAGTTCCTCCACTTCCTCCTCTTCATCCACTAACATCTCTTCTACTTCCTCCTCAGGCGGTGGTGGCGGGGGAGGGGGCCTGCGTCGCCGGCGGCGCACGGGCAGACGGTCGATGAAACGCTCGATGGTCTCGCCGCGCCGGCGTCGCATGGTCTCGGTGACGGCGCGCCCGTCCTCGCGGGGTCGCAGCGTAAAGACGCCGCCGCGCATCTCCAGGTGGCCCGGGGGGTCCCCGTTGGGCAGGGAGAGTGCGCTGACGATGCATCTTATCAATTGCCCCGTAGGGACTCCGCGCAAGGACCTAAGCGTCTCTAGATCCACGGGATCTGAAAACCGTTGAACGAAGGCTTCGAGCCAGTCGCAGTCGCAAGGTAGGCTGAGCACGGTTTCTTCTGGCGGCGGTGGGGTGTGGGCGGGGGCGATGCTGCTGGTGATGAAGTTGAAATAGGCGGTTCTGAGACGGCGGATGGTGGCGAGGAGCACCAGGTCTTTGGGCCCGGCTTGCTGGATGCGCAGACGGTCGGCCATGCCCCAGGCGTGGTCCTGACACCTGGCCAGGTCCTTGTAGTAGTCCTGCATGAGCCGCTCCACGGGCACCTCCTCCTCGCCCGCGCGGCCGTGCATACGCGTGAGCCCAAACCCGCGCTGCGGCTGGACGAGCGCCAGGTCAGCGACGACGCGCTCGGCGAGGATGGCCTGCTGGATCTGGGTGAGGGTGGTCTGGAAGTCGTCAAAGTCGACGAAGCGGTGGTAGGCTCCGGTGTTAATGGTGTAGGAGCAGTTGGCCATGACGGACCAGTTGACAGTCTGGTGACCGGGCCGCGCGAGCTCGTGGTACTTGAGGCGCGAGTAGGCGCGCGAGTCGAAGATGTAGTCGTTGCAGGTGCGCACCAGGTACTGGTAGCCGATGAGGAAGTGCGGCGGCGGCTGGCGGTAGAGCGGCCATCGCTCGGTGGCGGGGGCGCCGGGCGCTAGGTCCTCGAGCATGGTGCGGTGGTAGCCGTAGATGTACCTTGACATCCAGGTGATGCCGGCGGCGGTGGTGGAGGCGCGAGGGAACTCGCGGACGCGGTTCCAGATGTTGCGCAGCGGCAGGAAGTAGTTCATGGTGGGCACGGTCTGGCCCGTGAGGCGCGCGCAGTCGTTGATGCTCTAGACATACGGGCAAAAACGAAAGCGGTCAGCGGCTCGACTCCGTGGCCTGGAGGCTAAGCGAACGGGTTGGGCTGCGCGTGTACCCCGGTTCGAATCTCGAATCAGGCTGGAGCCGCAGCTAACGTGGTACTGGCACTCCCGTCTCGACCCAGGCCTGCACAAAACCTCCAGGATACGGAGGCGGGTCGTTTTGCAAATTTTTGGCGGTCGAAAAAAGCTAGTAAGCGCGGAAAGCGGCCGACCGCAATGGCTCACTGCCGTAGATTGGAGAAGAATCGCCAGGGTTGCGTTGCGGTGTGCCCCGGTTCGAGACCGCTCGGGTCGGCCGAATTCCGCGGCTAACGAGGGCGTGGCTGCCCCGTCGTTTCCAAGACCCCATAAGCCAGCCGACTTCTCCAGTTACGGAGCGAGCCCCTCTTTTGTTTTGTTTTTTGCCAGATGCATCCCGTACTGCGGCAGATGCGCCCCCACCCTCCACCGCAACAGCAGCCCCCTCCTACGCAACAGCCGGCGCTTCTGCCTCCGCCCCAGCAGCAGCAACTTCCAGCCACTACCGCCGCGGCCGCCGTGAGCGGGGCCGGGCAGAGTCAGTATGACCTGGCTTTGGAAGAGGGCGAGGGGCTGGCGCGCCTGGGGGCGTCGTCGCCGGAGCGGCACCCGCGCGTGCAGATGAAAAGGGACGCTCGCGAGGCCTACGTGCCCAAGCAGAACCTGTTCAGAGACAGGAGCGGCGAGGAGCCCGAGGAGATGCGCGCAGCCCGTTTCCACGCGGGGCGGGAGCTGCGGCGCGGCCTGGACAGAAAGAGGGTGCTGAGGGACGAGGATTTCGAGGCGGACGAGCTGACGGGGATCAGCCCTGCGCGCGCGCACGTGGCCGCGGCCAACCTGGTCACGGCGTACGAGCAGACCGTGAAGGAGGAGAGCAACTTCCAAAAATCCTTCAACAACCACGTGCGCACCCTGATCGCGCGCGAGGAGGTGACCCTGGGCCTGATGCACCTGTGGGACCTGCTGGAGGCCATTGTGCAGAACCCCACCAGCAAACCGCTGACGGCGCAGCTGTTCCTGGTGGTGCAGCACAGTCGGGACAACGAGACTTTTAGGGAGGCGCTGCTGAATATCACCGAGCCCGAGGGCCGCTGGCTTCTGGACCTGGTGAATATTCTGCAGAGCATCGTGGTGCAGGAGCGCGGGCTGCCGCTGTCCGAGAAGCTGGCGGCCATCAACTTTTCGGTGCTGAGTTTGGGCAAGTACTACGCTAGGAAGATCTACAAGACCCCGTACGTGCCCATAGACAAGGAGGTGAAGATCGACGGGTTTTACATGCGCATGACCCTGAAAGTGCTGACCCTGAGCGACGATCTGGGGGTGTACCGCAACGACAGGATGCGCCGCGCGGTAAGCGCCAGCAGGCGGCGCGAGCTGAGCGATCAGGAGCTGATGCACAGCCTGCAGCGGGCCCTGACCGGGGCCGGGACCGAGGGGGAGAGCTACTTTGACATGGGCGCGGACCTGCACTGGCAGCCCAGCCGCCGGGTCTTGGAAGCCGCGGCGGTCCCTTACGTAGAAGAGGTGGACGATGAGGATGAGGGCGAGTACCTGGAAGACTGATGGCGCGACCGTATTTTTGCTAGATGCAGCAACAGCCACCTCCTGATCCCGCAATGCGGGCGGCGCTGCAGAGCCAGCCGTCCGGCATTAACTCCTCGGACGATTGGACCCAGGCCATGCAACGCATCATGGCGCTGACGACCCGCAACCCCGAAGCCTTTAGACAGCAGCCCCAGGCCAACCGGCTCTCGGCCATCCTGGAGGCCGTGGTGCCCTCGCGCTCCAACCCCACGCACGAGAAGGTGCTGGCCATCGTGAACGCGCTGGTTGAGAACAAGGCCATTCGCGGCGACGAGGCCGGGCTGGTGTACAACGCACTGCTGGAGCGCGTGGCCCGCTACAACAGCACCAACGTGCAGACCAACCTGGACCGCATGGTGACCGACGTGCGCGAAGCCGTGGCCCAGCGCGAACGGTTCCACCGCGAGTCCAACCTGGGATCCATGGTGGCACTGAACGCCTTCCTCAGCACGCAGCCCGCCAACGTGCCCCGGGGCCAGGAGGACTACACCAACTTCATTAGCGCCCTGCGGCTAATGGTGACCGAGGTGCCCCAGAGCGAGGTGTACCAGTCGGGCCCGGACTACTTCTTCCAGACCAGTCGCCAGGGCTTGCAGACCGTGAACCTGAGTCAGGCTTTCAAGAACTTGCAGGGACTGTGGGGCGTGCAGGCTCCGGTCGGGGACCGCGCGACGGTGTCGAGCCTGCTGACGCCGAACTCGCGCCTGCTGCTGCTGCTGGTGGCGCCCTTCACGGACAGCGGTAGTATCAACCGCAACTCGTACCTGGGCTACCTGATTAACCTGTACCGCGAGGCCATTGGCCAGGCGCACGTGGACGAGCAGACCTACCAGGAGATTACCCACGTGAGCCGCGCCCTTGGCCAGGACGACCCGGGCAATCTGGAAGCCACCCTGAACTTCTTGCTGACCAACCGGTCGCAGAAGATCCCGCCCCAGTACGCGCTGAGCGCCGAGGAGGAGCGTATATTGAGATACGTGCAGCAAAGTGTGGGACTGTTCCTGATGCAGGAGGGGGCCACCCCCAGCGCCGCGCTCGACATGACCGCGCGCAACATGGAGCCCAGCATGTACGCCAGTAATCGCCCGTTTATTAATAAGCTGATGGACTACCTGCATCGGGCGGCCGCCATGAACTCTGACTATTTCACCAACGCCATCCTGAACCCCCACTGGCTCCCGCCGCCGGGGTTCTACACGGGCGAGTACGACATGCCCGACCCCAATGACGGGTTTCTGTGGGACGACGTGGACAGCAGCGTGTTCTCCCCCCGACCGGGTGCTAACGAGCGCCCCTTGTGGAAGAAAGAGGGCAGCGACCGGCGCCCGTCCTCGGCGCTGTCCGGCCGCACGGGTGCTGCCGCAGCGGTGCCCGAGGCCGCCAGTCCCTTTCCGAGCTTGTCACTGAACAGCGTCCGCAGTAGCGAGCTGGGCAGGATCACGCGCCCGCGCTTGCTGGGCGAGGAGGAGTACTTAAATAACTCGCTGTTGAGGCCCGAGCGGGAGAAGAACTTCCCCAATAACGGGATAGAGAGTCTGGTGGATAAGATGAGCCGCTGGAAGACGTACGCGCATGAGCACAGGGACGATCCCCGGGCAACGCAGGGGGCCACCAGCCGGGGCAGTGCCGCCCGTAAACGCCGCTGGCACGACAGGCAGCGGGGACTGATGTGGGACGATGAGGATTCCGCCGACGACAGCAGCGTGTTGGACTTGGGCGGGAGTGGTGGTGGTAACCCGTTCGCTCACCTGCGCCCCCGCGTCGGGCGCCTGATGTAAAAAGAAACCAAAAATAAATGGTACTCACCAAGGCCATGGCGACCAGCGTGCGTTCGTTTCTTCTCTGTTGTATCTAGTATGATGAGGCGTGCGTACCCGGAGGGTCCTCCTCCCTCGTACGAGAGCGTGATGCAGCAGGCAATGGCGGCGGCGGCGGCGATGCAGCCCCCGCTGGAGGCTCCTTACGTGCCACCGCGGTACCTGGCGCCTACGGAGGGGCGAAACAGCATTCGTTACTCGGAGCTGGCACCCTTGTACGATACCACCCGGTTGTACCTGGTGGACAACAAGTCGGCGGACATCGCCTCGCTGAACTACCAGAACGACCACAGCAACTTTCTGACCACCGTGGTGCAGAACAACGATTTCACCCCCACGGAGGCCAGCACCCAGACCATCAACTTTGACGAGCGCTCGCGGTGGGGCGGTCAGCTGAAAACCATCATGCATACCAACATGCCCAACGTGAACGAGTTCATGTACAGCAACAAGTTCAAGGCGCGGGTCATGGTCTCCCGCAAGACCCCCAACGGGGTGACAGTAGGGGATGATTATGATGGTAGTCAGGATGAGCTGAAATACGAGTGGGTGGAGTTTGAGCTGCCCGAAGGCAACTTCTCGGTGACCATGACCATTGACCTGATGAACAACGCCATCATCGACAATTACTTGGCAGTGGGGCGGCAGAACGGGGTGCTGGAGAGCGACATCGGCGTGAAGTTCGACACCCGGAACTTCAGGCTGGGTTGGGACCCCGTGACCGAGCTGGTCATGCCCGGGGTGTACACCAACGAGGCCTTCCACCCCGACATCGTGCTGTTGCCCGGCTGCGGGGTGGACTTTACCGAGAGCCGCCTCAGTAATATGCTGGGCATCCGCAAGAGGCAGCCCTTCCAGGAGGGTTTCCAGATCATGTACGAGGACCTGGATGGAGGTAACATCCCCGCGCTCTTGGATGTCGAGGCCTATGAGAAAAGCAAGGAGGAGAGCGTCGCCGCGTCAACCGCAGCCGTAGCCACCGCCTCTACCGAGGTCCGGGGCGATAATTTTGCTAGCGCCGCAGCAGTGGCGGCGGCCAAGGCTGATGAAACCGAAAGTAAGATAGTTATTCAGCCGGTGGAGAAGGATAGCAAGGATAGGAGCTACAACGTGCTCTCGGACAAGAAAAACACCGCCTACCGCAGCTGGTACCTGGCCTACAACTATGGCGACCACGAGAAGGGCGTGCGCTCCTGGACGCTGCTCACCACCTCGGACGTCACCTGCGGCGTGGAGCAAGTCTACTGGTCGCTGCCCGACATGATGCAAGACCCGGTCACCTTCCGCTCCACGCGTCAAGTTAGCAACTACCCGGTGGTGGGCGCCGAGCTCATGCCCGTCTACTCCAAGAGCTTCTTCAACGAGCAGGCCGTCTACTCGCAGCAGCTGCGCGCCTTCACCTCGCTCACGCACGTCTTCAACCGCTTCCCTGAGAACCAGATCCTCGTCCGCCCGCCCGCGCCCACCATTACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACCCTGCCGCTGCGCAGCAGTATCCGGGGAGTCCAGCGCGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTCTACAAGGCCCTGGGCATAGTCGCGCCGCGCGTCCTCTCGAGCCGCACCTTCTAAAAAATGTCCATTCTCATCTCGCCCAGTAATAACACCGGTTGGGGTCTGCGCGCGCCCAGCAAGATGTACGGAGGCGCTCGCCAACGCTCCACGCAACACCCCGTGCGCGTGCGCGGGCACTTCCGCGCTCCCTGGGGCGCCCTCAAGGGCCGCGTGCGGTCGCGCACCACCGTCGACGACGTGATCGACCAGGTGGTGGCCGACGCTCGCAACTACACCCCCGCCGCCGCGCCCGTCTCCACCGTGGACGCCGTCATTGACAGCGTGGTGTCCGACGCGCGCCGGTACGCCCGCGCCAAGAGCCGGCGGCGGCGCATCGCCCGGCGGCACCGTAGCACCACCGCCATGCGTGCGGCGCGAGCCTTGCTGCGCAGGGCCAGGCGCACGGGACGCAGGGCCATGCTCAGGGCGGCCAGACGCGCGGCTTCAGGCGCCAGCGCCGGCAGGACTCGGAGACGCGCGGCCACGGCGGCGGCAGCGGCCATAGCCAGCATGTCCCGCCCGCGGCGAGGGAACGTGTACTGGGTGCGCGACGCCGCCACCGGTGTGCGCGTGCCCGTGCGCACCCGCCCCCCTCGCACTTGAAGATGTTCACTTCGCGATGTTGATGTGTCCCAGCGGCGAGGAGAAGGATGTCCAAGCGCAAATTCAAGGAAGAGATGCTCCAGGTCATCGCGCCTGAGATCTACGGCCCCGCGGCGGCGGTGAAGGATGAAAGAAATCCCCGCAAAATCAAGCGGGTCAAAAAGGACAAAAAGGAAGAAGATGATGTGGACGATATGGTAGAGTTTGTGCGCGAGTTTGCCCCCCGGAGGCGCGTGCAGTGGCGCGGGCGGAAAGTGCGTCCGGTGCTGAGACCCGGCACCACGGTGGTTTTCGCGCCTGGCGAGCGGTCCGGCACGACATCCAAGCGCTCCTACGATGAGGTGTACGGGGACGAGGATATTCTCGAGCAGGCGGCCGAGCGCCTGGGCGAGTTTGCTTACGGCAAGCGCAACCGCCTTGCGCCCCTGAAGGAAGAGGTGGTGTCCATCCCGCTGGACCACGGCAACCCCACGCCGAGTCTTAAGCCCGTGACCCTGCAGCAGGTGCTGCCGAGCGCGGCGCCGCGTCGGGGCTTGAAGCGCGAGGGCGAGGATGTGTACCCCACCATGCAGCTGATGGTGCCCAAGCGCCAGAAGCTGGAAGACGTGCTGGAGACCATGAAGGTGGACCCGGACGTGCAGCCCGAGGTCAAGGTGAGGCCCATCAAGCAGGTGGCCCCGGGCCTTGGCGTGCAGACCGTGGACATCAAGATCCCCACGGAGCCCATGGAAACGCAGACCGAGGTCGTGAAGCCCATCACCAGCACCATGGAGGTGCAGACGGATCCTTGGATGCCGGCGGCGCCCCGAAAACCCCGGCGCAAGTACGGCGCGGCCAGCCTGCTGATGCCCAACTACGCGCTGCATCCTTCCATCATCCCCACGCCGGGCTACCGCGGCACGCGCTTCTACCACGGCTATACCGGCTCCCGCCGCCGCAAGACCACCACCCGCCGCCGTCGTCGCCGCACAGCTGCAACTCCCGCTGCCGCCCTGGTGCGGAGAGTGTACCGCCGCGGCCGCGCGCCTCTGACCCTGCCGCGGGCGCGCTACCACCCGAGCATTACCATTTAACTTTGCCGTCGCCTTTGCAGATATGGCTCTCACATGCCGCATTCGCGTCCCCATTACGGGCTACCGAGGAAGAAAACCGCGCCGTAGAAGGCTGGCGGGAAGCGGGATGCGCCGCCACCCCCACCGGCGGCGGCGCGCCATCAGCAAGCGGTTGGGGGGAGGCTTCCTGCCCGCGCTGATCCCCATCATCGCCGCGGCGATCGGGGCGATCCCCGGCATTGCTTCCGTGGCGGTGCAGGCCTCTCAGCGCCACTGAGACACACACTTGGAAATTGTAATAAACCCGAATGGACTCTGACGCTCCTGGTCCTGTGATGTGTTTTTGTAGACAGATGGAAGACATCAATTTTTCGTCCCTGGCTCCGCGACACGGCACGCGGCCGTTTATGGGCACCTGGAGCGACATCGGCACCAGCCAACTGAACGGGGGCGCCTTCAATTGGAGCAGTCTCTGGAGCGGGCTTAAGAATTTTGGGTCCACGCTTAAAACCTATGGCAGCAAGGCGTGGAACAGCACCACAGGGCAGGCGCTGAGAGATAAGCTGAAAGAGCAGAACTTCCAGCAGAAGGTAGTCGATGGCCTCGCCTCAGGCATCAACGGGGTGGTGGACCTGGCCAATCAGGCCGTGCAGCGGCAGATCAACAGCCGCCTGGACCCGGTTCCCCCCGCCGGCTCCGTGGAGATGCCGCAGGTGGAGGAGGAGCTGCCTCCCCTGGACAAGCGGGGCGACAAGCGTCCCCGTCCCGACGCGGAGGAGACGCTGCTGACGCACACGGACGAACCGCCCCCGTACGAGGAGGCGGTGAAACTGGGCCTGCCCACCACGCGTCCCATTGCGCCTCTAGCTACCGGGGTGCTGAAACCCGAGAGTAGTAAGCCCGCGACCTTGGACTTGCCTCCTCCGCCCACTCCCCGCCCCTCCACAGTGGCTAAGCCCCTGCCGCCGGTGGCCGTGGCCCGCGCGCGACCGGGGGCTCGCCCTCAGGCGAACTGGCAGAGCACTCTGAACAGCATCGTGGGTCTGGGAGTGCAGAGTGTGAAGCGCCGCCGCTGTTATTAAAAAACACTGTAGCGCTTAACTTGCTTGTCTGTGTATATGTGTATGTCCGCCGCCGCTGCTGTCCAGAAGGAGGAGTGAAGAGAAAGGCGCGTCGTCGAGTTGCAAGATGGCCACCCCATCGATGCTGCCCCAGTGGGCGTACATGCACATCGCCGGACAGGACGCTTCGGAGTACCTGAGTCCGGGTCTGGTGCAGTTCGCCCGCGCCACAGACACCTACTTCAGTCTGGGGAACAAGTTTAGGAACCCCACGGTGGCGCCTACCCACGATGTGACCACCGACCGCAGCCAGCGGCTGACGCTGCGCTTTGTGCCCGTGGACCGGGAGGACAACACCTACTCGTACAAAGTGCGCTACACGCTGGCCGTGGGCGACAACCGCGTGCTGGACATGGCCAGCACCTACTTTGACATCCGCGGCGTGCTGGATCGGGGCCCTAGCTTCAAACCCTACTCCGGCACTGCCTACAACAGCCTGGCTCCCAAGGGAGCGCCCAACACCTGCCAGTGGAAGGATTCTGACAGCAAAATGCATACCTTTGGGGCAGCTGCCATGCCCGGTGTTACTGGGAAAAAGATAGAAGCTGATGGGCTGCCTATTAGAATAGATTCAACTTCTGGAACTGACACAGTAATTTATGCTGATAAAACTTTCCAACCAGAACCACAAGTTGGAAATGACAGTTGGGTTGACACCAATGGTGCAGAGGAAAAATATGGAGGCAGAGCTCTAAAGGACACTACAAAAATGAAACCCTGTTATGGTTCATTCGCCAAGCCTACCAACAAAGAAGGTGGTCAGGCTAACTTAAAAGATTCAGAACCCGCCGCCACCACTCCTAACTATGATATAGACCTGGCTTTCTTTGACAGCAAAACTATTGTTGCTAACTACGATCCAGATATTGTAATGTACACAGAAAATGTTGACTTGCAGACTCCAGATACTCATATTGTATACAAACCTGGAACAGAGGACACCAGCTCTGAATCCAATTTGGGTCAGCAGGCCATGCCTAACAGACCCAACTACATTGGCTTCAGAGACAATTTTATCGGGCTCATGTACTACAACAGCACTGGCAATATGGGGGTGCTGGCCGGTCAGGCCTCTCAGCTGAATGCTGTGGTTGACTTGCAAGACAGAAACACTGAACTGTCCTACCAGCTCTTGCTTGACTCTCTGGGTGACAGAACCCGGTATTTCAGTATGTGGAATCAGGCGGTGGACAGCTATGATCCTGATGTGCGCATTATTGAAAACCATGGTGTGGAGGATGAATTGCCAAACTATTGCTTTCCGTTGAATGGTGTGGGATTGACAGACACTTACCAGGGTGTTAAAGTTAAAACAGATGCAGGTTCTGAAAAGTGGGACAAAGATGACACCACAGTTAGTAATGCTAATGAAATCCATGTAGGCAATCCTTTTGCCATGGAAATCAACATCCAAGCCAACCTGTGGAGGAACTTCCTCTATGCCAATGTTGCCCTCTATTTGCCTGATAAATACAAATACACACCGGCCAACATCACCCTGCCCACCAACACCAACACCTACGAGTACATGAACGGCCGGGTGGTGGCGCCCTCGCTGGTGGACGCCTACATTAACATTGGGGCGCGCTGGTCGCTGGACCCCATGGACAACGTAAATCCCTTCAACCACCACCGCAATGCGGGCTTGCGCTACCGCTCCATGCTCCTGGGCAACGGGCGCTACGTGCCATTCCACATCCAGGTGCCCCAGAAATTTTTTGCCATTAAGAGCCTCCTGCTCCTGCCCGGGTCCTACACCTACGAGTGGAACTTCCGCAAGGACGTCAACATGATCCTGCAGAGTTCCCTTGGCAACGACCTGCGCACAGACGGGGCCTCCATCACCTTCACCAGCATTAACCTCTACGCCACCTTCTTCCCCATGGCGCACAACACCGCCTCCACGCTTGAGGCCATGCTGCGCAACGACACCAATGACCAATCCTTCAACGACTACCTCTCGGCGGCCAACATGCTCTATCCCATCCCGGCCAACGCCACCAACGTGCCCATCTCCATCCCCTCGCGCAACTGGGCCGCCTTTCGCGGCTGGTCCTTCACGCGTCTCAAGACCAAAGAGACGCCCTCGCTGGGCTCCGGGTTCGACCCCTACTTCGTCTACTCGGGCTCCATCCCCTACCTCGACGGCACCTTCTACCTCAACCACACCTTCAAGAAGGTCTCCATCACCTTCGACTCTTCCGTCAGCTGGCCCGGCAACGACCGGCTCCTGACGCCCAACGAGTTCGAAATCAAGCGCACCGTCGACGGCGAGGGATACAACGTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCCACTACAACATCGGCTACCAGGGCTTCTACGTGCCCGAGGGCTACAAGGACCGCATGTACTCCTTCTTCCGCAACTTCCAGCCCATGAGCCGCCAGGTGGTGGACGAGGTTAACTACAAGGACTACCAGGCCGTCACCCTGGCCTACCAACACAACAACTCGGGCTTCGTTGGATACCTCGCGCCCACTATGCGCCAGGGCCAGCCCTACCCCGCCAACTACCCCTACCCGCTCATCGGCAAGAGCGCCGTTACCAGCGTCACCCAGAAAAAGTTCATCTGCGACAGGGTCATGTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGCGCGCTCACCGACCTCGGCCAGAACATGCTCTATGCTAACTCCGCCCACGCGCTAGACATGAATTTCGAAGTCGACCCCATGGATGAGTCCACCCTTCTCTATGTTGTCTTCGAAGTCTTCGACGTCGTCCGAGTGCACCAGCCCCACCGCGGCGTCATTGAGGCCGTCTACCTGCGCACCCCCTTCTCAGCCGGTAACGCCACCACATAAATTCTTGCTTCTTGCAAGAAGCCATGGCCGCGGGCTCCGGCGAGCAGGAGCTCAGGGCCATCATCCGCGACCTGGGGTGCGGGCCCTACTTCCTGGGCACCTTCGATAAGCGATTCCCGGGATTCATGGCCCCGCACAAGGTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGAGCATTGGCTGGCCTTCGCCTGGAACCCGCGCTCGAACACCTGCTACCTCTTCGACCCCTTCGGGTTCTCGGACCAGCGCCTCAAGCAAATCTACCAGTTCGAGTACGAGGGACTGCTGCGCCGCAGCGCCCTGGCCACCAAGGACCGCTGCGTTACCCTGGAAAAGTCCACCCAGACCGTGCAGGGTCCGCGTTCGGCCGCCTGCGGGCTTTTCTGCTGCATGTTCCTACACGCCTTCGTGCACTGGCCCAACCGCCCCATGGACAAAAATCCCACCATGAACTTGCTGACGGGGGTGCCCAACGGCATGCTCCAGTCGCCCCAGGTGGAACCTACCCTGCGCCGCAACCAGGAGGCACTCTACCGCTTCCTCAACTCCCACTCTGCATACTTTCGCTCTCACCGCGCGCGCATTGAGAAGGCCACCGCCTTCGACCGCATGAATCAAGACATGTAACAGTGTGTTTTAAAATATGTTTAATAAACAGCACTTTTTATGTGACACATGCATTTGAGATAATTTTATTCTTAAAAATCGAAGGGGTTCTGCCGGGAGGTTTCGGCATGGCCCGCGGGCAGGGACACGTTGCGGAACTGGTACTTGGCCAGCCACTTGAACTCGGGGATCAGCAGTTTCGGCAGCAGGGTGTCGGGGAACGAGTCGGTCCACAGCTTCCGCGTCAGTTGCAGGGCGCCCAGCAGGTCGGGCGCGGAGATCTTGAAATCGCAGTTGGGACCCGCGTTTTGCGCGCGAGAGTTGCGGTACACAGGGTTGCAGCACTGGAACACCATCAGGGCCGGATGCTTCACGCTCGCCAGCACCGTAGCGTCGGTGATCCCGTCCACGTCGAGGTCTTCGGCGTTGGCCATCCCGAAGGGGGTCATCTTGCAGGTCTGCCGGCCCATGGTGGGCACGCAGCCGGGCTTGTGGTTGCAATCGCAGTGCAGGGGGATCAGCATCATCTGGGCCTGGTCGGCGTTCATCCCCGGGTACATGGCCTTCATGAAAGCCTCCAGCTGCTTAAACGCCTGCTGGGCCTTGGCTCCCTCGGTGAAGAAGACCCCGCAGGACTTGCTAGAAAACTGGTTGGTAGCGCACCCGGCGTCGTGCACGCAGCAGCGCGCGTCGTTGTTGGCCAGCTGCACCACGCTGCGCCCCCAGCGGTTCTGGGTAATCTTGGCCCGGTCGGGGTTCTCCTTTAGCGCGCGTTGCCCGTTCTCGCTTGCCACATCCATCTCGATCATGTGCTCCTTCTGGATCATGGTGGTCCCGTGCAGGCACCGCAGCTTGCCCTCGACTTCGGTACAGCCGTGCAGCCACAGCGCGCACCCCGTGCTCTCCCAGTTCTTGTGGGCGATCTGGGAATGCGCATGCACGAACCCCTGCAGGAAGCGGCCCATCATGGTCGTCAGGGTCTTGTTACTGGTAAAGGTCAGCGGAATGCCGCGGTGCTCCTCGTTGATGTACAGGTGGCAGATGCGGCGATACACCTCGCCCTGCTCGGGCATCAGTTGGAAGTTGGATTTTAGGTCGCTTTCCACACGGTAGCGCTCCATCAGCATATTCATGATTTCCATGCCCTTCTCCCAGGCCGATACAATGGGCAGGCTCAGGGGGTTCGTCACCGCCATCTTAGCGCTAGCAGCCTTCGTCAGCGGGTCGTTCTCATTGAGAGTCTCAAAGCTCCGCTTGCCGTCCTTCTCGGTGATCCGCACGGGGGGGTAGCTGAAGCCCACGGCCGCCAGCTCCTCCTCGGCCTCTCTTTCGTCCTCGCTGTCCTGGCTGACGTCCTGCAGGGGCACATGCTTCGTTTTGCGGGGTTTCTTTTTGGGCGGCTGCTGCGGCGGCGGTGGTTGTTCCTGAGGCGAGGGGGAGCGCGAGTTCTCGCTCACCACTACTATCTCTTCTTCTTGGTCCGAGGCCACGCGGCGGTAGGTATGTCTCTTCAGGGGCAGAGGCGGAGGCGACGGGCTCTCGCGGCCCGGCGGGTGGCTGGCAGAGCCCCTTCCGCGATCGGGGGTGCGCTCCCGGCGGCGCTCTAACTGACTTCCTCCGCGGCCGGCCATTGTGTTCTCCTAGGGAACAACAACAAGCATGGAGACTCAGCCATCGTCGCCAACCTCGCCATCTGCCCCCACCGCCGACAAGAAGCAGCAGCAGAATGAGAGCTTAACCGCCCCGCCGCCCAGCCCCGCCACCTTTGTCGCGGCCCCAGACATGCAAGAGATGGAGGAATCCATTCAGATTGACCTGGGCTATGTGACGCCCGCGGAGCACGAGGAGGAGCTTGCAGTGCGCTTTTCAACCCAGGAAGAGATACACCAAGAACAGCCAGAGCAGGAAGCAAAGAGCGAGCATGACTACCTCCACCAGAGCGGGGGGGAGGACGCCCTCATCAAGCATCTGGCCCGGCAGGCCATCATCGTCAAGGACGCGCTGCTTGACCGCACCGAGGTGCCCCTCAGCGTGGAGGAGCTCAGCCGCGCCTACGAGCTCAACCTCTTCTCGCCGCGCGTGCCCCCCAAGCGCCAGCCCAACGGCACCTGCGAGCCCAACCCACGCCTCAACTTCTACCCGGTCTTCGCGGTGCCCGAGGCCCTGGCCACCTACCACATCTTTTTCAAGAACCAAAGGATCCCTGTCTCCTGTCGCGCCAACCGCACCCGCGCCGACTCCCTTTTCAACCTGGGCCCCGGTGCCCGCCTACCTGATATCGCCTCCTTGGAAGAGGTTCCCAAGATCTTCGAGGGTCTGGGCAGCGACGAGACTCGGGCCGCAAACGCTCTGCAAGGAGAAGGAGGAGATCATGAGCACCACAGCGCCCTGGTGGAGTTGGAAGGCGACAACGCGCGTCTGGCGGTGCTCAAGCGCACGATCGAGCTGACCCATTTCGCCTACCCGGCGCTTAACCTGCCCCCCAAAGTCATGAGCACGGTTATGGATCAGGTGCTCATCAAGCGCGCGTCGCCCATCTCCAAGGAGATGCAAGACCCCGAGAGCTCCGAGGAGGGCAAGCCCGTGGTCAGCGACGAGCAGCTGGCGCGGTGGCTGGGACCCCAAGCTAGTCCCCAGAGCTTGGAAGAGCGGCGCAAGCTCATAATGGCCGTGGTCCTGGTGACCGCGGAGCTGGAGTGTCTGCGCCGCTTCTTCGCCGACGCAGAAATTCTGCGCAAGGTCGAGGAGAACCTGCACTACATCTTCAGGCACGGGTTCGTACGCCAGGCCTGCAAGATCTCCAACGTGGAGCTGACCAACCTGGTCTCCTACATGGGCATCTTGCACGAGAACCGCCTGGGGCAGAACGTGCTGCACACCACCCTGCGCGGGGAGGCCCGCCGCGACTACATCCGCGACTGCGTTTACCTCTACCTCTGCCACACCTGGCAGACAGCCATGGGCGTGTGGCAGCAGTGTCTGGAGGAGCAGAACCTAAAAGAGCTCTGCAAGCTCCTGCAGAAGAACCTCAAGGCCCTGTGGACCGGGTTCGACGAGCGCACCACCGCCTCGGACCTGGCAGACCTCATTTTCCCCGAGCGTCTCAGGCTGACGCTGCGCAACGGTTTGCCCGACTTTATGAGTCAAAGCATGTTGCAAAACTTTCGCTCTTTCATCCTCGAACGCTCCGGGATCCTGCCGGCCACCTGCTCCGCGCTGCCCTCGGACTTCGTGCCGCTGACCTTCCGCGAGTGCCCCCCGCCGCTGTGGAGCCACTGCTACCTGCTGCGCTTGGCCAACTACCTGGCCTACCACTCGGACGTGATCGAGGACGTCAGCAGCGAGGGCCTGCTCGAGTGCCACTGCCGCTGCAACCTCTGCACGCCGCACCGCTCCCTGGCCTGCAACCCCCAGCTGCTGAGCGAGACCCAGATCATCGGCACCTTCGAGTTGCAAGGGCCCGGCGATGAGGGTTCTGCCGCCAAGGGGGGTCTGAAACTCACCCCGGGGCTGTGGACCTCGGCCTACTTGCGCAAGTTCGTGCCCGAGGACTACCATCCCTTCGAGATCAGGTTCTACGAGGACCAATCCCAGCCGCCCAAGGCCGAGCTGTCGGCCTGCGTCATCACCCAGGGGGCGATCCTGGCCCAATTGCAAGCTATCCAGAAATCCCGCCAAGAATTCTTGCTGAAAAAGGGCCGCGGGGTCTACCTTGATCCCCAGACCGGTGAGGAGCTTAACCCCGGCTTCCCCCAGGATGCCCCGAGGAAGCAGCAAGAAGCTGAAAGTGGAGCTGCCGCCCGTGGAGGATTTGGAGGAAGACTGGGAGAGCAGTCAGGCAGAGGAGGAGGAGATGGAAGACTGGGACAGCACTCAGGCAGAGGACAGCCTGCAAGACAGTCTGGAAGACGAGGAGGAGGCAGAGGAGGTGGAAGAAGTAGCCGCCGCCGCCAGACCGTCGTCCTCGGCGGAGAAAGCAAGCAGCACGGATACCATCTCCGCTCCGGGTCGGGGTCCCGCTCGACCCCACAGTAGATGGGACGAGACCGGGCGATTCCCGAACCCCACCACCCAGACCGGTAAGAAGGAGCGGCAGGGATACAAGTCCTGGCGGGGGCACAAAAACGCCATCGTCTCCTGCTTGCAAGCTTGCGGGGGCAACATCTCATTCACCCGGCGCTACCTGCTCTTTCACCGCGGGGTGAACTTCCCCCGCAACATCTTGCATTACTACCGTCACCTCCACAGCCCCTACTACTTCCAAGAAGAGGCAGAAAAAGACAAAACCAGCAGCTAGAAAATCCACAGCGGCGGCGGCGGCAGGTGGACTGAGGATCGCGGCGAACGAGCCGGCGCAGACCCGGGAACTGAGGAACCGGATCTTTCCCACCCTCTATGCCATCTTCCAGCAGAGTCGGGGGCAGGAGCAGGAACTGAAAGTCAAGAACCGTTCTCTGCGCTCGCTCACCCGCAGTTGTCTGTATCACAAGAGCGAAGACCAACTTCAGCGCACGCTTGAGGACGCCGAGGCTCTCTTCAACAAGTACTGCGCACTCACTCTTAAAGAGTAGCCCGCGCCCGCCCACACACGGAAAAAGGCGGGAATTACGTCACCTGTGCACCCCCACCCAGCACCGCTATGAGCAAAGAAATTCCCACGCCTTACATGTGGAGCTACCAGCCCCAGATGGGCCTGGCCGCCGGCGCCGCCCAGGACTACTCCACCCGCATGAATTGGCTCAGCGCCGGGCCCGGGATGATCTCACGGGTGAATGACATCCGCGCCCACCGAAACCAGATACTCCTAGAACAGTCAGCGCTCACCGCCACGCCCCGCAATCACCTCAATCCGCGTAATTGGCCCGCCGCCCTAGTGTACCAGGAAATTCCCCAGCCCACGACCGTACTACTTCCGCGAGACGCCCAGGCCGAAGTCCAGCTGACTAACTCAGGTGTCCAGCTGGCGGGCGGCGCCACCCTGTGTCGTCACCACCCCGCTCAGGGTATAAAGCGGCTGGTGATCCGGGGCAGAGGCACACAGCTCAACGACGAGGTGGTGAGCTCTTCACTGGGTTTGCGACCTGACGGAGTCTTCCAACTCGCCGGATCGGGAAGATCTTTTCGGGGCAACATCTCATTCACCCGGCGCTACCTGCTCTTTCACCGCGGGGTGAACTTCCCCCGCAACATCTTGCATTACTACCGTCACCTCCACAGCCCCTACTACTTCCAAGAAGAGGCAGAAAAAGACAAAACCAGCAGCTAGAAAATCCACAGCGGCGGCGGCGGCAGGTGGACTGAGGATCGCGGCGAACGAGCCGGCGCAGACCCGGGAACTGAGGAACCGGATCTTTCCCACCCTCTATGCCATCTTCCAGCAGAGTCGGGGGCAGGAGCAGGAACTGAAAGTCAAGAACCGTTCTCTGCGCTCGCTCACCCGCAGTTGTCTGTATCACAAGAGCGAAGACCAACTTCAGCGCACGCTTGAGGACGCCGAGGCTCTCTTCAACAAGTACTGCGCACTCACTCTTAAAGAGTAGCCCGCGCCCGCCCACACACGGAAAAAGGCGGGAATTACGTCACCTGTGCACCCCCACCCAGCACCGCTATGAGCAAAGAAATTCCCACGCCTTACATGTGGAGCTACCAGCCCCAGATGGGCCTGGCCGCCGGCGCCGCCCAGGACTACTCCACCCGCATGAATTGGCTCAGCGCCGGGCCCGGGATGATCTCACGGGTGAATGACATCCGCGCCCACCGAAACCAGATACTCCTAGAACAGTCAGCGCTCACCGCCACGCCCCGCAATCACCTCAATCCGCGTAATTGGCCCGCCGCCCTAGTGTACCAGGAAATTCCCCAGCCCACGACCGTACTACTTCCGCGAGACGCCCAGGCCGAAGTCCAGCTGACTAACTCAGGTGTCCAGCTGGCGGGCGGCGCCACCCTGTGTCGTCACCACCCCGCTCAGGGTATAAAGCGGCTGGTGATCCGGGGCAGAGGCACACAGCTCAACGACGAGGTGGTGAGCTCTTCACTGGGTTTGCGACCTGACGGAGTCTTCCAACTCGCCGGATCGGGAAGATCTTCCTTCACGCCTCGTCAGGCCGTGCTGACTTTGGAGAGTTCTTCCTCGCAACCTCGCTCGGGCGGCATCGGCACTCTCCAGTTTGTGGAGGAGTTCACTCCCTCGGTCTACTTCAACCCCTTCTCCGGCTCCCCCGGCCACTATCCGGACGAGTTCATCCCGAACTTCGATGCCATCAGCGAATCGGTAGACGGCTACGATTGAATGTCCCATGGTGGCGCGGCTGACCTAGCTCGGCTTCGACACCTGGACCACTGCCGCCGCTTTCGCTGCTTCGCTCGGGACCTCGCCGAGTTTACCTACTTTGAGCTGTCCGAGGAGCACCCTCAGGGCCCGGCCCACGGAGTGCGGATCGTCGTCGAAGGGGGCCTAGACTCCCACCTGCTTCGTATCTTCAGCCAGCGCCCGATCCTGGTCCAGCGCCAACAGGGCAACACCCTCCTGACCCTTTACTGCATCTGCAACCACCCCGGCCTGCACGAAAGTCTTTGTTGTCTGCTGTGTACTGAGTATAATAAAAGCTGAGATCAGCGACTACTCCGGACTCGATTGTGTTCCAGCAGTCTGGCGATACCAAGGGTTGCATCCACTGCTCCTGCGACTCCCCCGAGTGCGTTCACACCCTCATCAAGACCCTATGCGGCCTCCGCGACCTCCTCCCCATGAACTAATCAACTAACCCCTTACCCCATTACCCATCCAGTAAAAAAAATAAAGATTAAAGAGACGATGATTTTGAATTACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCACTGTCTTCCGGATCGCTGTCCAGGAGCGCCAGCTGTTGGGCTCGCGGTTGAGAAGGAACTCTTCGCGGTCCTTCCAGTACTCTTCAAGGGGGAACCCGTCCTGGTCGGCACGGGACTCCGCGCAAGGACCTAAGCGTCTCCAGATCCACGGGATCTGAAAACCGTTGAACGAAGGCTTCGAGCCAGTCGCAGTCGCAAGTCTAGAGCCACCATGTTCGTCTTCCTGGTCCTGCTGCCCCTGGTCTCATCTCAGTGCGTGAATCTGACTACAAGAACTCAGCTGCCTCCCGCCTACACCAATTCCTTCACCCGGGGCGTGTACTATCCTGACAAGGTGTTTAGAAGCTCCGTGCTGCACTCTACACAGGATCTGTTTCTGCCATTCTTTAGCAACGTGACCTGGTTCCACGCCATCCACGTGAGCGGCACCAATGGCACAAAGCGGTTCGACAATCCCGTGCTGCCTTTTAACGATGGCGTGTACTTCGCCTCTACCGAGAAGAGCAACATCATCAGAGGCTGGATCTTTGGCACCACACTGGACTCCAAGACACAGTCTCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATGATCCCTTCCTGGGCGTGTACTATCACAAGAACAATAAGAGCTGGATGGAGTCCGAGTTTAGAGTGTATTCTAGCGCCAACAATTGCACATTTGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGAGGGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCTAAGCACACCCCCATCAACCTGGTGCGCGACCTGCCTCAGGGCTTCAGCGCCCTGGAGCCACTGGTGGATCTGCCTATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCTGCACAGAAGCTACCTGACACCCGGCGACTCCTCTAGCGGATGGACCGCAGGAGCAGCAGCCTACTATGTGGGCTATCTGCAGCCTAGGACCTTCCTGCTGAAGTACAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGAGCGAGACAAAGTGTACACTGAAGTCCTTTACCGTGGAGAAGGGCATCTATCAGACATCCAATTTCAGGGTGCAGCCAACCGAGTCTATCGTGCGCTTTCCTAATATCACAAACCTGTGCCCATTTGGCGAGGTGTTCAACGCAACCAGGTTCGCAAGCGTGTACGCATGGAATAGGAAGCGCATCTCTAACTGCGTGGCCGACTATAGCGTGCTGTACAACTCCGCCTCTTTCAGCACCTTTAAGTGCTATGGCGTGTCCCCCACAAAGCTGAATGACCTGTGCTTTACCAACGTGTACGCCGATTCTTTCGTGATCAGGGGCGACGAGGTGCGCCAGATCGCACCTGGACAGACAGGCAAGATCGCCGACTACAATTATAAGCTGCCAGACGATTTCACCGGCTGCGTGATCGCCTGGAACAGCAACAATCTGGATTCCAAAGTGGGCGGCAACTACAATTATCTGTACCGGCTGTTTAGAAAGAGCAATCTGAAGCCCTTCGAGAGGGACATCTCTACAGAGATCTACCAGGCCGGCAGCACCCCTTGCAATGGCGTGGAGGGCTTTAACTGTTATTTCCCACTGCAGTCCTACGGCTTCCAGCCCACAAACGGCGTGGGCTATCAGCCTTACCGCGTGGTGGTGCTGAGCTTTGAGCTGCTGCACGCACCAGCAACAGTGTGCGGACCCAAGAAGTCCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGCCTGACCGGAACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCATTTCAGCAGTTCGGCAGGGACATCGCAGATACCACAGACGCCGTGCGCGACCCACAGACCCTGGAGATCCTGGATATCACACCCTGCTCTTTCGGCGGCGTGAGCGTGATCACACCAGGAACCAATACAAGCAACCAGGTGGCCGTGCTGTATCAGGACGTGAATTGTACCGAGGTGCCTGTGGCCATCCACGCCGATCAGCTGACCCCAACATGGCGGGTGTACAGCACCGGCTCCAACGTGTTCCAGACAAGAGCAGGATGCCTGATCGGAGCAGAGCACGTGAACAATTCCTATGAGTGCGACATCCCAATCGGCGCCGGCATCTGTGCCTCTTACCAGACCCAGACAAACTCTCCAAGGAGAGCACGGAGCGTGGCATCCCAGTCTATCATCGCCTATACCATGTCCCTGGGCGCCGAGAATTCTGTGGCCTACTCTAACAATAGCATCGCCATCCCAACCAACTTCACAATCTCTGTGACCACAGAGATCCTGCCCGTGTCCATGACCAAGACATCTGTGGACTGCACAATGTATATCTGTGGCGATTCTACCGAGTGCAGCAACCTGCTGCTGCAGTACGGCAGCTTTTGTACCCAGCTGAATAGAGCCCTGACAGGCATCGCCGTGGAGCAGGATAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCCCCTATCAAGGACTTTGGCGGCTTCAATTTTTCCCAGATCCTGCCTGATCCATCCAAGCCTTCTAAGCGGAGCTTTATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTATGGCGATTGCCTGGGCGACATCGCAGCACGGGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCACCCCTGCTGACAGATGAGATGATCGCACAGTACACAAGCGCCCTGCTGGCAGGAACCATCACATCCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTTTGCCATGCAGATGGCCTATAGGTTCAACGGCATCGGCGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACAGCCTGTCCTCTACAGCCTCCGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGAGCTCCAACTTCGGCGCCATCTCTAGCGTGCTGAATGATATCCTGAGCCGGCTGGACAAGGTGGAGGCAGAGGTGCAGATCGACCGGCTGATCACAGGCAGACTGCAGTCTCTGCAGACCTATGTGACACAGCAGCTGATCAGGGCAGCAGAGATCAGGGCAAGCGCCAATCTGGCAGCAACCAAGATGTCCGAGTGCGTGCTGGGCCAGTCTAAGAGAGTGGACTTTTGTGGCAAGGGCTATCACCTGATGTCCTTCCCTCAGTCTGCCCCACACGGCGTGGTGTTTCTGCACGTGACCTACGTGCCCGCCCAGGAGAAGAACTTCACCACAGCCCCTGCCATCTGCCACGATGGCAAGGCCCACTTTCCAAGGGAGGGCGTGTTCGTGTCCAACGGCACCCACTGGTTTGTGACACAGCGCAATTTCTACGAGCCCCAGATCATCACCACAGACAATACCTTCGTGAGCGGCAACTGTGACGTGGTCATCGGCATCGTGAACAATACCGTGTATGATCCACTGCAGCCCGAGCTGGACAGCTTTAAGGAGGAGCTGGATAAGTACTTCAAGAATCACACCTCCCCTGACGTGGATCTGGGCGACATCAGCGGCATCAATGCCTCCGTGGTGAACATCCAGAAGGAGATCGACCGCCTGAACGAGGTGGCCAAGAATCTGAACGAGAGCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCATGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACATCCTGCTGTTCTTGCCTGAAGGGCTGCTGTAGCTGTGGCTCCTGCTGTAAGTTTGATGAGGACGATTCCGAACCCGTGCTGAAGGGAGTGAAGCTGCATTACACCTGAGGATCCCTCGAGCTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGTGATCAATAAAGAATCACTTACTTGAAATCTGAAACCAGGTCTCTGTCCATGTTTTCTGTCAGCAGCACTTCGCTCCCCTCTTCCCAGCTCTGGTACTGCAGGCCCCGGCGGGCTGCAAACTTCCTCCACACTCTGAAGGGGATGTCAAATTCCTCCTGTCCCTCAATCTTCATTTTTTATTTCTATTAGATGTCCAAAAAGCGCGCGCGGGTGGATGATGGCTTCGACCCCGTGTATCCCTACGATGCAGACAACGCACCGACCGTGCCCTTCATCAACCCTCCCTTCGTCTCTTCAGATGGATTCCAAGAAAAGCCCCTGGGGGTGTTGTCCCTTAGGCTGGCCGACCCTGTCACCACCAAGAATGGGGAAATTACCCTCAAGCTGGGGGAGGGGGTGGACCTTGACGACTCGGGAAAACTCATTGCAAACACAGTAAACAAGGCCATTGCCCCTCTCAGTTTTTCCAACAACACCATTTCCCTTAACATGGATACCCCTTTATACACCAAAGATGGAAAACTATCCTTACAAGTTTCTCCACCATTAAGTATATTAAAATCAACAATTTTGAATACATTAGCTCTAGCTTTTGGCTCAGGTTTAGGACTCAGTGGCAGCGCCCTGGCAGTACAGTTAGCCTCTCCACTTACATTTGATGATAAAGGGAATATAAAGATTACCCTAAACAGGGGATTGCATGTTACAACAGGAGATGCAATTGAAAGCAACATCAGTTGGGCTAAAGGTATAAAATTTGAAGATGGTGCCATAGCTACAAACATTGGTAAGGGGCTAGAGTTCGGAACCAGTAGTACAGAAACAGGAGTTAATAATGCTTATCCAATCCAAGTTAAACTTGGCTCTGGTCTCAGCTTTGACAGCACAGGAGCCATAATGGCTGGCAATAAAGACTATGATAAATTAACTTTGTGGACAACGCCTGACCCATCACCAAACTGTCAAATACTTGCAGAAAATGATGCAAAACTAACACTTTGCTTAACTAAGTGTGACAGTCAAATACTGGCCACTGTATCAGTTTTGGTTGTTAGAAGTGGAAACTTAAACCCAATTACTGGCACAGTAAGCAGTGCTCAAGTTTTTCTACGTTTTGATGCAAATGGTGTTCTTTTAACAGAACACTCTACACTAAAAAAATACTGGGGCTACAAGCAAGGAGATAGCATAGATGGCACTCCATACACCAATGCTGTTGGTTTTATGCCAAATTCAACAGCTTATCCAAAGACCCAAAGTTCTACTACTAAAAATAATATAGTGGGTCAAGTATACATGAATGGAGATGTTTCAAAACCCATGCTTCTTACTATAACTCTTAATGGTACTGATGACACCACCAGTGCATACTCAATGTCATTTTCATACACCTGGACTAACGGAAGCTATATCGGAGCAACATTTGGAGCTAACTCATACACCTTCTCCTACATAGCCCAACAATAATCCCACCCTGCATGCCAACCCACCTTTTCCCTCTATTTATAAATGGAAACTGAAACAAAAATAAAGTTCAAGTGTTTTATTGATTCAACAGTTTTTCACAGGATTCGAGTAGTTATTTTCCCTCCACCCTCCCATCTCATGGAATACACTATCCTCTCCCCACGCACAGCCTTAAACATCTGAATGCTATTGGTAATGGACATGGTTTTGATCTCCACATTCCACACAGTTTCAGAGCGAGACAGTCTCGGGTCGGTCAAGGAGATGAAACCCTCCGGGCACTCCTGCATCTGCACCTCACAGTTCAACAGCTGAGGGCTGTCCTCGGTGATTGGAATCACAGTTATCTGGAATAAGAGCGATGAGAATCATAATCCGCAAACGGGATCGGGCGGTTGTGGCGCATCAGGCCCCGCAGCAGTCGCTGTCTGCGCCGCTCCGTCAAGCTGCTACTCAAGGGGTCCGGGTCCAGGGACTCCCTGCGCATGATGCCAATGGCCCTGAGCATCAGTCGCCTGGTACGGCGGGCGCAGCAGCGGATGCGGATCTCACTCAGGTCGGAGCAGTACGTGCAGCACAGCACCACCAAGTTGTTCAACAGTCCATAGTTCAACGTGCTCCAGCCAAAACTCATTTGTGGAACTATGCTGCCCACATGTCCATCGTACCAGATCCTGATGTAAATCAGGTGGCGTCCCCTCCAGAACACACTGCCCATGTACATGATCTCCTTGGGCATGTGCAGGTTCACCACCTCCCGGTACCACATCACCCGCTGGTTGAACATGCAGCCCTGGATAATTCTGCGGAACCAGATGGCAAGTACCGTCCCGCCCGCCATGCAGCGCAGGGACCCCGGGTTCTGGCAATGGCAGTGGATCACCCACCGCTCGCGACCGTGGATCAACTGGGAACTAAACAAGTCTATGTTGGCACAGCACAGGCACACGCTCATGCATGTCTTCAGCACTCTCAATTCCTCGGGGGTCAGGACCATATCCCAGGGCACAGGGAACTCTTGCAGGACAGTGAACCCGGCCGAACAGGGCAATCCTCGCACGGAACTTACATTGTGCATGGACAGGGTATCGCAATCAGGCAGCACCGGATGATCCTCCACCAGAGAAGCGCGGCTCTCGGTCTCCTCACAGCGAGGTAAGGTGGCCGGCGGTTGGTACGGATGATGGCGAGATAACGCTAATCGTGTTCTGGATCGTGTCATGATGGAGCTGTTTCCGGACATTTTCGTATTTCACAAAGCAGAACCTGGTCCGGGCACTGCACACCGCTCGTCGGCGACGGTCTCGGCGCTTCGAGCGCTCAATGTTGAAGTTATAGAACAGCCACTCCCTCAGAACGTGCAGTATCTCCTGAGCCTCTTGGGTGATGAAAATCCCATCCGCCCTGATGGCTCTGATTACATCAACCACGGTGGAATGGGCCAAACCCAGCCAGATGATGCAATTTTGTTGGGTTTCGGTGACGGCGGGGGAGGGAAGAACAGGAAGAACCATGATTAACTTTATTCCAAACGGTCTCGGAACACTTCAAAATGCAGGTCCCGGAGGTGGCACCTCTCGCCCCCACTGTGTTGGTGGAAAATAACAGCCAGGTCAAAGGTAACACGGTTCTCGAGATGTTCCACGGTGGCTTCCAGCAAAGCCTCCACGCGCACATCCAGAAACAAGAGGACAGCGAAAGCGGGAGCGTTTTCTAATTCCTCAATCATCATATTACACTCCTGCACCATGCCTAGATAATTTTCATTTTTCCAGCCTTGAATGATTCGTATTAGTTCCTGAGGTAAATCCAAGCCAGCCATGATAAAAAGCTCGCGCAGAGCGCCCTCCACCGGCATTCTTAAGCACACCCTCATAATTCCAACAGATTCTGCTCCTGGTTCACCTGTAGTAGATTAACAAGTGGAATATCAATTGCTCTGCCGCAATCCCTAAGCTCCTCCCTTAGCAGTAACTGTATGTACTCATTCATATCTTCTCCGAAATTTTTAGCCATAGGACCACCAGGAACAAGAGAAGGGCAAGCCACATTACAGATAAAGCGAAGTCCTCCCCAGTGAGCATTGCCAAATGTAAGATTGAAATAAGCATGCTGGCTAGACCCGGTGATATCTTCCAGATAACTGGACAGAAAATCAGGCAAGCAATTTTTAAGAAAATTAACAAAAGAAAAGTCGTCTAGGTGCACGTTTAGAGCCTCAGGAACAACGATGGAATAAGTGCAAGGAGTACGTTCCAGCATGGTTAGTGTTTTTGGTGATCTGTAGAACAAAAAATAAACATGCAATATTAAACCATGCTAGCCTGGCGAACAGGTGGATAAATCACTCTTTCCAACACCAGGCAGGCTACAGGGTCTCCGGCGCGACCATTGTAGAAGCTGACATTATGATTAAAAAGCATCACCGACAGACCTTCCCGGTGGCCGGCATGGATGATTCGAGAAGAAGCATACACTCCGGGAACATTGGCGTCCGTGAGTGAAAAAAAGCGACCTATAAAGCCTTGAGGCACTACAATGCTTAATCTTAATTCCAGCAAAGCGACCCCATGCGGATGAAGCACAAAATTGGCAGGTGCGTAAAAAATGTAATTACTCCCCTTCTGCACAGGCAGCAAAGCCCCCGCTCCCTCCAGAAACACATACAAAACCTGAGCGTCCATAGCTTACCGAGCACGGCAGGCGCAAGAGTCAGAGAAAAAGCTGAGCTCTAACCTAACTGCCCGCTTCTGTACTCAATATATAGCCCTAACCTCACTGACGTAAAGGCCAAGGTCTAAAAATACCCGCCAACACGCCCAGAAACCGGTGACACACTAAAAAAATACGTGCACTTCCTCAAACGCCCAAACTGGCGTCATTTCCGGTTTCCCACGCTACGTCACCTCTCAACGACTTTCAAATTCCGTCGACCGTTAAACACATCAGTTACCCCGCCCCTAACGAACGCCGCTGTCACAGCCAATCAGCGCGCCCCATCCCCAAATTTTCACGCCTTATTTGCATATTAACTCACACAAAAAAAATAAGGTATATTATTGATGATGAAGCTTTTAAT
SEQ ID NO:2是在GenBank登录号YP_009724390.1下的野生型Ad4-SARS-CoV-2(武汉株)刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:3是具有双脯氨酸取代的稳定化的SARS-CoV-2刺突蛋白(nCoV-PP)的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:4是尾部截短的SARS-CoV-2刺突蛋白(nCoV-TT)的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCS
SEQ ID NO:5是缺少C端内吞基序的SARS-CoV-2刺突蛋白(nCoV-noEndo)的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGV
SEQ ID NO:6是编码SARS-CoV-2刺突蛋白的核酸序列。
ATGTTTGTTTTTCTTGTTTTATTGCCACTAGTCTCTAGTCAGTGTGTTAATCTTACAACCAGAACTCAATTACCCCCTGCATACACTAATTCTTTCACACGTGGTGTTTATTACCCTGACAAAGTTTTCAGATCCTCAGTTTTACATTCAACTCAGGACTTGTTCTTACCTTTCTTTTCCAATGTTACTTGGTTCCATGCTATACATGTCTCTGGGACCAATGGTACTAAGAGGTTTGATAACCCTGTCCTACCATTTAATGATGGTGTTTATTTTGCTTCCACTGAGAAGTCTAACATAATAAGAGGCTGGATTTTTGGTACTACTTTAGATTCGAAGACCCAGTCCCTACTTATTGTTAATAACGCTACTAATGTTGTTATTAAAGTCTGTGAATTTCAATTTTGTAATGATCCATTTTTGGGTGTTTATTACCACAAAAACAACAAAAGTTGGATGGAAAGTGAGTTCAGAGTTTATTCTAGTGCGAATAATTGCACTTTTGAATATGTCTCTCAGCCTTTTCTTATGGACCTTGAAGGAAAACAGGGTAATTTCAAAAATCTTAGGGAATTTGTGTTTAAGAATATTGATGGTTATTTTAAAATATATTCTAAGCACACGCCTATTAATTTAGTGCGTGATCTCCCTCAGGGTTTTTCGGCTTTAGAACCATTGGTAGATTTGCCAATAGGTATTAACATCACTAGGTTTCAAACTTTACTTGCTTTACATAGAAGTTATTTGACTCCTGGTGATTCTTCTTCAGGTTGGACAGCTGGTGCTGCAGCTTATTATGTGGGTTATCTTCAACCTAGGACTTTTCTATTAAAATATAATGAAAATGGAACCATTACAGATGCTGTAGACTGTGCACTTGACCCTCTCTCAGAAACAAAGTGTACGTTGAAATCCTTCACTGTAGAAAAAGGAATCTATCAAACTTCTAACTTTAGAGTCCAACCAACAGAATCTATTGTTAGATTTCCTAATATTACAAACTTGTGCCCTTTTGGTGAAGTTTTTAACGCCACCAGATTTGCATCTGTTTATGCTTGGAACAGGAAGAGAATCAGCAACTGTGTTGCTGATTATTCTGTCCTATATAATTCCGCATCATTTTCCACTTTTAAGTGTTATGGAGTGTCTCCTACTAAATTAAATGATCTCTGCTTTACTAATGTCTATGCAGATTCATTTGTAATTAGAGGTGATGAAGTCAGACAAATCGCTCCAGGGCAAACTGGAAAGATTGCTGATTATAATTATAAATTACCAGATGATTTTACAGGCTGCGTTATAGCTTGGAATTCTAACAATCTTGATTCTAAGGTTGGTGGTAATTATAATTACCTGTATAGATTGTTTAGGAAGTCTAATCTCAAACCTTTTGAGAGAGATATTTCAACTGAAATCTATCAGGCCGGTAGCACACCTTGTAATGGTGTTGAAGGTTTTAATTGTTACTTTCCTTTACAATCATATGGTTTCCAACCCACTAATGGTGTTGGTTACCAACCATACAGAGTAGTAGTACTTTCTTTTGAACTTCTACATGCACCAGCAACTGTTTGTGGACCTAAAAAGTCTACTAATTTGGTTAAAAACAAATGTGTCAATTTCAACTTCAATGGTTTAACAGGCACAGGTGTTCTTACTGAGTCTAACAAAAAGTTTCTGCCTTTCCAACAATTTGGCAGAGACATTGCTGACACTACTGATGCTGTCCGTGATCCACAGACACTTGAGATTCTTGACATTACACCATGTTCTTTTGGTGGTGTCAGTGTTATAACACCAGGAACAAATACTTCTAACCAGGTTGCTGTTCTTTATCAGGATGTTAACTGCACAGAAGTCCCTGTTGCTATTCATGCAGATCAACTTACTCCTACTTGGCGTGTTTATTCTACAGGTTCTAATGTTTTTCAAACACGTGCAGGCTGTTTAATAGGGGCTGAACATGTCAACAACTCATATGAGTGTGACATACCCATTGGTGCAGGTATATGCGCTAGTTATCAGACTCAGACTAATTCTCCTCGGCGGGCACGTAGTGTAGCTAGTCAATCCATCATTGCCTACACTATGTCACTTGGTGCAGAAAATTCAGTTGCTTACTCTAATAACTCTATTGCCATACCCACAAATTTTACTATTAGTGTTACCACAGAAATTCTACCAGTGTCTATGACCAAGACATCAGTAGATTGTACAATGTACATTTGTGGTGATTCAACTGAATGCAGCAATCTTTTGTTGCAATATGGCAGTTTTTGTACACAATTAAACCGTGCTTTAACTGGAATAGCTGTTGAACAAGACAAAAACACCCAAGAAGTTTTTGCACAAGTCAAACAAATTTACAAAACACCACCAATTAAAGATTTTGGTGGTTTTAATTTTTCACAAATATTACCAGATCCATCAAAACCAAGCAAGAGGTCATTTATTGAAGATCTACTTTTCAACAAAGTGACACTTGCAGATGCTGGCTTCATCAAACAATATGGTGATTGCCTTGGTGATATTGCTGCTAGAGACCTCATTTGTGCACAAAAGTTTAACGGCCTTACTGTTTTGCCACCTTTGCTCACAGATGAAATGATTGCTCAATACACTTCTGCACTGTTAGCGGGTACAATCACTTCTGGTTGGACCTTTGGTGCAGGTGCTGCATTACAAATACCATTTGCTATGCAAATGGCTTATAGGTTTAATGGTATTGGAGTTACACAGAATGTTCTCTATGAGAACCAAAAATTGATTGCCAACCAATTTAATAGTGCTATTGGCAAAATTCAAGACTCACTTTCTTCCACAGCAAGTGCACTTGGAAAACTTCAAGATGTGGTCAACCAAAATGCACAAGCTTTAAACACGCTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGATATCCTTTCACGTCTTGACAAAGTTGAGGCTGAAGTGCAAATTGATAGGTTGATCACAGGCAGACTTCAAAGTTTGCAGACATATGTGACTCAACAATTAATTAGAGCTGCAGAAATCAGAGCTTCTGCTAATCTTGCTGCTACTAAAATGTCAGAGTGTGTACTTGGACAATCAAAAAGAGTTGATTTTTGTGGAAAGGGCTATCATCTTATGTCCTTCCCTCAGTCAGCACCTCATGGTGTAGTCTTCTTGCATGTGACTTATGTCCCTGCACAAGAAAAGAACTTCACAACTGCTCCTGCCATTTGTCATGATGGAAAAGCACACTTTCCTCGTGAAGGTGTCTTTGTTTCAAATGGCACACACTGGTTTGTAACACAAAGGAATTTTTATGAACCACAAATCATTACTACAGACAACACATTTGTGTCTGGTAACTGTGATGTTGTAATAGGAATTGTCAACAACACAGTTTATGATCCTTTGCAACCTGAATTAGACTCATTCAAGGAGGAGTTAGATAAATATTTTAAGAATCATACATCACCAGATGTTGATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCGCCTCAATGAGGTTGCCAAGAATTTAAATGAATCTCTCATCGATCTCCAAGAACTTGGAAAGTATGAGCAGTATATAAAATGGCCATGGTACATTTGGCTAGGTTTTATAGCTGGCTTGATTGCCATAGTAATGGTGACAATTATGCTTTGCTGTATGACCAGTTGCTGTAGTTGTCTCAAGGGCTGTTGTTCTTGTGGATCCTGCTGCAAATTTGATGAAGACGACTCTGAGCCAGTGCTCAAAGGAGTCAAATTACATTACACATAA
SEQ ID NO:7是具有双脯氨酸取代的稳定化的SARS-CoV-2beta变体刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNFTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFANPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRGLPQGFSALEPLVDLPIGINITRFQTLHISYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGNIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQPTYGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGVENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:8是稳定化的、双脯氨酸取代的嵌合SARS-CoV-2刺突蛋白的氨基酸序列，该刺突蛋白包括beta变体的RBD和来自武汉株的剩余序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGNIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQPTYGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:9是具有双脯氨酸取代的稳定化的SARS-CoV-2delta变体刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTTTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLDVYYHKNNKSWMKSEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPHGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYRYRLFRKSNLKPFERDISTEIYQAGSTPCNGVQGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSRRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTDWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:10是具有双脯氨酸取代的稳定化的SARS-CoV-2gamma变体刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNFTNRTQLPSAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNYPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLSEFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGTIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQPTYGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEYVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAAIKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASFVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:11是具有双脯氨酸取代的稳定化的SARS-CoV-2delta变体刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNLRTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLDVYYHKNNKSWMESGVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGNIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYRYRLFRKSNLKPFERDISTEIYQAGSKPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSRRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQNVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:12是具有双脯氨酸取代的稳定化的SARS-CoV-2omicron变体刺突蛋白的氨基酸序列。
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHVISGTNGTKRFDNPVLPFNDGVYFASIEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLDHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPIIVEPERDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFDEVFNATRFASVYAWNRKRISNCVADYSVLYNLAPFFTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGNIADYNYKLPDDFTGCVIAWNSNKLDSKVSGNYNYLYRLFRKSNLKPFERDISTEIYQAGNKPCNGVAGFNCYFPLRSYSFRPTYGVGHQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLKGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEYVNNSYECDIPIGAGICASYQTQTKSHRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLKRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKYFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFKGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNHNAQALNTLVKQLSSKFGAISSVLNDIFSRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO:13是编码具有双脯氨酸取代的稳定化的SARS-CoV-2beta变体刺突蛋白的密码子优化的核酸序列。
ATGTTCGTGTTTCTGGTGCTGCTGCCTCTGGTGAGCTCCCAGTGCGTGAACTTCACCACAAGAACCCAGCTGCCCCCTGCCTACACCAATTCCTTCACAAGGGGCGTGTACTATCCCGACAAGGTGTTTCGCTCTAGCGTGCTGCACTCCACACAGGATCTGTTTCTGCCTTTCTTTTCTAACGTGACCTGGTTCCACGCCATCCACGTGAGCGGCACCAATGGCACAAAGCGGTTCGCCAATCCAGTGCTGCCCTTTAACGACGGCGTGTACTTCGCCTCCACCGAGAAGTCTAACATCATCAGAGGCTGGATCTTTGGCACCACACTGGATAGCAAGACACAGTCCCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATGACCCATTCCTGGGCGTGTACTATCACAAGAACAATAAGTCTTGGATGGAGAGCGAGTTTAGGGTGTACTCCTCTGCCAACAATTGCACATTTGAGTACGTGAGCCAGCCCTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGCGCGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCCAAGCACACCCCAATCAACCTGGTGAGGGGACTGCCACAGGGCTTCTCTGCCCTGGAGCCACTGGTGGACCTGCCCATCGGCATCAACATCACCCGCTTTCAGACACTGCACATCAGCTACCTGACACCAGGCGATAGCTCCTCTGGATGGACCGCAGGAGCAGCAGCCTACTATGTGGGCTACCTGCAGCCCAGGACCTTCCTGCTGAAGTATAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGTCTGAGACCAAGTGTACACTGAAGAGCTTTACCGTGGAGAAGGGCATCTACCAGACAAGCAATTTCCGGGTGCAGCCTACCGAGTCCATCGTGAGATTTCCCAATATCACAAACCTGTGCCCTTTTGGCGAGGTGTTCAACGCCACCCGCTTCGCCAGCGTGTATGCCTGGAATAGGAAGCGCATCTCCAACTGCGTGGCCGACTATTCTGTGCTGTACAACAGCGCCTCCTTCTCTACCTTTAAGTGCTACGGCGTGAGCCCCACAAAGCTGAATGACCTGTGCTTTACCAACGTGTATGCCGATTCCTTCGTGATCAGGGGCGACGAGGTGCGCCAGATCGCACCAGGCCAGACAGGCAATATCGCCGACTACAACTATAAGCTGCCTGACGATTTCACCGGCTGCGTGATCGCCTGGAACAGCAACAATCTGGATAGCAAAGTGGGCGGCAACTACAATTATCTGTACCGGCTGTTTAGAAAGTCTAACCTGAAGCCATTCGAGAGGGACATCTCCACAGAGATCTACCAGGCCGGCTCTACCCCCTGCAATGGCGTGAAGGGCTTTAACTGTTATTTCCCTCTGCAGAGCTACGGCTTCCAGCCAACCTACGGCGTGGGCTATCAGCCCTACCGCGTGGTGGTGCTGTCTTTTGAGCTGCTGCACGCACCTGCAACAGTGTGCGGCCCAAAGAAGAGCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGACTGACCGGCACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCTTTTCAGCAGTTCGGCCGGGACATCGCCGATACCACAGACGCCGTGAGAGACCCTCAGACCCTGGAGATCCTGGATATCACACCATGCTCCTTCGGCGGCGTGTCTGTGATCACACCAGGCACCAATACAAGCAACCAGGTGGCCGTGCTGTACCAGGGCGTGAATTGTACCGAGGTGCCCGTGGCAATCCACGCAGACCAGCTGACCCCTACATGGAGGGTGTATTCTACCGGCAGCAACGTGTTCCAGACACGCGCCGGATGCCTGATCGGAGCAGAGCACGTGAACAATAGCTACGAGTGCGATATCCCTATCGGCGCCGGCATCTGTGCCTCCTATCAGACCCAGACAAACTCCCCACGGAGAGCCCGGTCTGTGGCAAGCCAGTCCATCATCGCCTACACCATGAGCCTGGGCGTGGAGAACAGCGTGGCCTATTCCAACAATTCTATCGCCATCCCTACCAACTTCACAATCTCCGTGACCACAGAGATCCTGCCAGTGAGCATGACCAAGACATCCGTGGACTGCACAATGTACATCTGTGGCGATTCCACCGAGTGCTCTAACCTGCTGCTGCAGTATGGCTCTTTTTGTACCCAGCTGAATAGAGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCACCCATCAAGGACTTTGGCGGCTTCAACTTCAGCCAGATCCTGCCCGATCCTAGCAAGCCATCCAAGCGGTCTTTTATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTACGGCGATTGCCTGGGCGACATCGCAGCCAGAGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCTCCACTGCTGACAGATGAGATGATCGCCCAGTATACATCTGCCCTGCTGGCAGGAACCATCACAAGCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTTTGCCATGCAGATGGCCTACAGGTTCAACGGCATCGGCGTGACCCAGAATGTGCTGTATGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACTCTCTGAGCTCCACAGCAAGCGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGTCTAGCAACTTCGGCGCCATCTCCTCTGTGCTGAATGATATCCTGAGCCGGCTGGACCCTCCTGAGGCAGAGGTGCAGATCGACCGGCTGATCACAGGCAGACTGCAGTCCCTGCAGACCTACGTGACACAGCAGCTGATCAGGGCAGCAGAGATCAGGGCATCTGCCAATCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTGGGCCAGTCCAAGAGAGTGGACTTTTGTGGCAAGGGCTACCACCTGATGAGCTTCCCACAGTCCGCCCCTCACGGCGTGGTGTTTCTGCACGTGACCTATGTGCCAGCCCAGGAGAAGAACTTCACCACAGCACCAGCCATCTGCCACGATGGCAAGGCACACTTTCCTCGGGAGGGCGTGTTCGTGAGCAACGGCACCCACTGGTTTGTGACACAGAGAAATTTCTACGAGCCACAGATCATCACCACAGACAATACCTTCGTGAGCGGCAACTGTGACGTGGTCATCGGAATCGTGAACAATACCGTGTACGATCCTCTGCAGCCAGAGCTGGACTCTTTTAAGGAGGAGCTGGATAAGTATTTCAAGAATCACACCAGCCCCGACGTGGATCTGGGCGACATCTCTGGCATCAATGCCAGCGTGGTGAACATCCAGAAGGAGATCGACCGCCTGAACGAGGTGGCCAAGAATCTGAACGAGTCCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCCTGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACAAGCTGCTGTTCCTGCCTGAAGGGCTGCTGTTCTTGTGGCAGCTGCTGTAAGTTTGATGAGGACGATAGCGAGCCTGTGCTGAAGGGCGTGAAGCTGCACTATACCTGA
SEQ ID NO:14是编码稳定化的、双脯氨酸取代的嵌合SARS-CoV-2刺突蛋白的密码子优化的核酸序列，该刺突蛋白包含beta变体的RBD和来自武汉株的剩余序列。
ATGTTCGTGTTTCTGGTGCTGCTGCCTCTGGTGAGCTCCCAGTGCGTGAACCTGACCACAAGGACCCAGCTGCCCCCTGCCTACACCAATTCCTTCACACGGGGCGTGTACTATCCCGACAAGGTGTTTAGATCTAGCGTGCTGCACTCCACACAGGATCTGTTTCTGCCTTTCTTTTCTAACGTGACCTGGTTCCACGCCATCCACGTGAGCGGCACCAATGGCACAAAGCGGTTCGACAATCCAGTGCTGCCCTTTAACGATGGCGTGTACTTCGCCTCCACCGAGAAGTCTAACATCATCAGAGGCTGGATCTTTGGCACCACACTGGACAGCAAGACACAGTCCCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATGATCCATTCCTGGGCGTGTACTATCACAAGAACAATAAGTCTTGGATGGAGAGCGAGTTTCGCGTGTACTCCTCTGCCAACAATTGCACATTTGAGTACGTGAGCCAGCCCTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGAGGGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCCAAGCACACCCCAATCAACCTGGTGCGCGACCTGCCACAGGGCTTCTCTGCCCTGGAGCCACTGGTGGATCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCTGCACAGAAGCTACCTGACACCAGGCGACAGCTCCTCTGGATGGACCGCAGGAGCAGCAGCCTACTATGTGGGCTACCTGCAGCCCAGGACCTTCCTGCTGAAGTATAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGTCTGAGACCAAGTGTACACTGAAGAGCTTTACCGTGGAGAAGGGCATCTACCAGACAAGCAATTTCAGGGTGCAGCCTACCGAGTCCATCGTGCGCTTTCCCAATATCACAAACCTGTGCCCTTTTGGCGAGGTGTTCAACGCCACCCGCTTCGCCAGCGTGTATGCCTGGAATAGGAAGCGCATCTCCAACTGCGTGGCCGACTATTCTGTGCTGTACAACAGCGCCTCCTTCTCTACCTTTAAGTGCTACGGCGTGAGCCCCACAAAGCTGAATGACCTGTGCTTTACCAACGTGTATGCCGATTCCTTCGTGATCAGGGGCGACGAGGTGCGCCAGATCGCACCAGGCCAGACAGGCAATATCGCCGACTACAACTATAAGCTGCCTGACGATTTCACCGGCTGCGTGATCGCCTGGAACAGCAACAATCTGGATAGCAAAGTGGGCGGCAACTACAATTATCTGTACCGGCTGTTTAGAAAGTCTAACCTGAAGCCATTCGAGAGGGACATCTCCACAGAGATCTACCAGGCCGGCTCTACCCCCTGCAATGGCGTGAAGGGCTTTAACTGTTATTTCCCTCTGCAGAGCTACGGCTTCCAGCCAACCTACGGCGTGGGCTATCAGCCCTACCGCGTGGTGGTGCTGTCTTTTGAGCTGCTGCACGCACCTGCAACAGTGTGCGGCCCAAAGAAGAGCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGACTGACCGGCACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCTTTTCAGCAGTTCGGCAGGGACATCGCAGATACCACAGACGCCGTGCGCGACCCTCAGACCCTGGAGATCCTGGATATCACACCATGCTCCTTCGGCGGCGTGTCTGTGATCACACCAGGCACCAATACAAGCAACCAGGTGGCCGTGCTGTACCAGGGCGTGAATTGTACCGAGGTGCCCGTGGCAATCCACGCAGACCAGCTGACCCCTACATGGCGGGTGTATTCTACCGGCAGCAACGTGTTCCAGACAAGAGCCGGATGCCTGATCGGAGCAGAGCACGTGAACAATAGCTACGAGTGCGATATCCCTATCGGCGCCGGCATCTGTGCCTCCTATCAGACCCAGACAAACTCCCCACGGAGAGCCCGGTCTGTGGCAAGCCAGTCCATCATCGCCTACACCATGAGCCTGGGCGCCGAGAACAGCGTGGCCTATTCCAACAATTCTATCGCCATCCCTACCAACTTCACAATCTCCGTGACCACAGAGATCCTGCCAGTGAGCATGACCAAGACATCCGTGGACTGCACAATGTACATCTGTGGCGATTCCACCGAGTGCTCTAACCTGCTGCTGCAGTATGGCTCTTTTTGTACCCAGCTGAATAGAGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCACCCATCAAGGACTTTGGCGGCTTCAACTTCAGCCAGATCCTGCCCGATCCTAGCAAGCCATCCAAGCGGTCTTTTATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTACGGCGATTGCCTGGGCGACATCGCAGCCAGAGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCTCCACTGCTGACAGATGAGATGATCGCCCAGTATACATCTGCCCTGCTGGCAGGAACCATCACAAGCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTTTGCCATGCAGATGGCCTACAGATTCAACGGCATCGGCGTGACCCAGAATGTGCTGTATGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACTCTCTGAGCTCCACAGCAAGCGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGTCTAGCAACTTCGGCGCCATCTCCTCTGTGCTGAATGATATCCTGAGCCGGCTGGACCCACCAGAGGCAGAGGTGCAGATCGACCGGCTGATCACAGGCAGACTGCAGTCCCTGCAGACCTACGTGACACAGCAGCTGATCAGGGCAGCAGAGATCAGGGCATCTGCCAATCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTGGGCCAGTCCAAGAGAGTGGACTTTTGTGGCAAGGGCTACCACCTGATGAGCTTCCCACAGTCCGCCCCTCACGGCGTGGTGTTTCTGCACGTGACCTATGTGCCAGCCCAGGAGAAGAACTTCACCACAGCACCAGCCATCTGCCACGATGGCAAGGCACACTTTCCCCGGGAGGGCGTGTTCGTGAGCAACGGAACCCACTGGTTTGTGACACAGCGCAATTTCTACGAGCCACAGATCATCACCACAGACAATACATTCGTGTCCGGCAACTGTGACGTGGTCATCGGAATCGTGAACAATACCGTGTACGATCCTCTGCAGCCAGAGCTGGACTCTTTTAAGGAGGAGCTGGATAAGTATTTCAAGAATCACACCAGCCCCGACGTGGATCTGGGCGACATCTCTGGCATCAATGCCAGCGTGGTGAACATCCAGAAGGAGATCGACAGGCTGAACGAGGTGGCCAAGAATCTGAACGAGTCCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCCTGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACAAGCTGCTGTTCCTGCCTGAAGGGCTGCTGTTCTTGTGGCAGCTGCTGTAAGTTTGATGAGGACGATAGCGAGCCTGTGCTGAAGGGCGTGAAGCTGCACTATACCTGA
SEQ ID NO:15是编码具有双脯氨酸取代的稳定化的SARS-CoV-2delta变体刺突蛋白的密码子优化的核酸序列。
ATGTTCGTGTTTCTGGTGCTGCTGCCTCTGGTGAGCTCCCAGTGCGTGAACCTGACCACAACCACACAGCTGCCCCCTGCCTATACCAATTCCTTCACACGCGGCGTGTACTATCCTGACAAGGTGTTTCGGTCTAGCGTGCTGCACTCCACACAGGATCTGTTTCTGCCATTCTTTTCTAACGTGACCTGGTTCCACGCCATCCACGTGAGCGGCACCAATGGCACAAAGCGGTTCGACAATCCAGTGCTGCCCTTTAACGATGGCGTGTACTTCGCCTCCACCGAGAAGTCTAACATCATCCGGGGCTGGATCTTTGGCACCACACTGGACAGCAAGACACAGTCCCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATGATCCCTTCCTGGACGTGTACTATCACAAGAACAATAAGTCTTGGATGAAGAGCGAGTTTAGAGTGTATTCCTCTGCCAACAATTGCACATTTGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGAGAGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCCAAGCACACCCCAATCAACCTGGTGAGGGACCTGCCACACGGCTTCTCTGCCCTGGAGCCACTGGTGGATCTGCCCATCGGCATCAACATCACCAGATTTCAGACACTGCTGGCCCTGCACAGGAGCTACCTGACACCCGGCGACAGCTCCTCTGGATGGACCGCCGGCGCTGCCGCCTACTATGTGGGCTATCTGCAGCCTCGCACCTTCCTGCTGAAGTACAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGTCTGAGACCAAGTGTACACTGAAGAGCTTTACCGTGGAGAAGGGCATCTATCAGACAAGCAATTTCCGCGTGCAGCCAACCGAGTCCATCGTGCGGTTTCCCAATATCACAAACCTGTGCCCTTTTGGCGAGGTGTTCAACGCAACCAGGTTCGCAAGCGTGTACGCATGGAATCGCAAGCGGATCTCCAACTGCGTGGCCGACTATTCTGTGCTGTACAACAGCGCCTCCTTCTCTACCTTTAAGTGCTATGGCGTGAGCCCAACAAAGCTGAATGACCTGTGCTTTACCAACGTGTACGCCGATTCCTTCGTGATCCGGGGCGACGAGGTGCGGCAGATCGCACCAGGACAGACAGGCAAGATCGCAGACTACAATTATAAGCTGCCTGACGATTTCACCGGCTGCGTGATCGCCTGGAACTCTAACAATCTGGATAGCAAAGTGGGCGGCAACTACAATTATAGATACAGGCTGTTTAGAAAGTCTAATCTGAAGCCATTCGAGAGGGACATCTCCACAGAGATCTACCAGGCCGGCTCTACCCCCTGCAATGGCGTGCAGGGCTTTAACTGTTATTTCCCTCTGCAGAGCTACGGCTTCCAGCCAACCAACGGCGTGGGCTATCAGCCCTACCGGGTGGTGGTGCTGTCTTTTGAGCTGCTGCACGCACCTGCAACAGTGTGCGGACCAAAGAAGAGCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGACTGACCGGAACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCATTTCAGCAGTTCGGCAGAGACATCGCCGATACCACAGACGCCGTGAGGGACCCTCAGACCCTGGAGATCCTGGATATCACACCATGCTCCTTCGGCGGCGTGTCTGTGATCACACCCGGCACCAATACAAGCAACCAGGTGGCCGTGCTGTATCAGGGCGTGAATTGTACCGAGGTGCCAGTGGCAATCCACGCAGACCAGCTGACCCCTACATGGCGCGTGTACTCTACCGGCAGCAACGTGTTCCAGACAAGGGCAGGATGCCTGATCGGAGCAGAGCACGTGAACAATAGCTATGAGTGCGATATCCCCATCGGCGCCGGCATCTGTGCCTCCTACCAGACCCAGACAAACTCCCGGAGAAGGGCCAGATCTGTGGCCAGCCAGTCCATCATCGCCTATACCATGAGCCTGGGCGCCGAGAACAGCGTGGCCTACTCCAACAATTCTATCGCCATCCCTACCAACTTCACAATCTCCGTGACCACAGAGATCCTGCCAGTGAGCATGACCAAGACATCCGTGGACTGCACAATGTATATCTGTGGCGATTCCACCGAGTGCTCTAACCTGCTGCTGCAGTACGGCTCTTTTTGTACCCAGCTGAATAGGGCCCTGACAGGAATCGCAGTGGAGCAGGACAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCACCCATCAAGGACTTTGGCGGCTTCAACTTCAGCCAGATCCTGCCCGATCCTAGCAAGCCCTCCAAGCGGAGCTTCATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTATGGCGATTGCCTGGGCGACATCGCAGCAAGGGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCTCCACTGCTGACAGATGAGATGATCGCCCAGTACACATCTGCCCTGCTGGCAGGAACCATCACAAGCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCTTTTGCCATGCAGATGGCCTATCGCTTCAACGGCATCGGCGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACTCTCTGAGCTCCACAGCAAGCGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGTCTAGCAACTTCGGCGCCATCTCCTCTGTGCTGAATGATATCCTGAGCAGACTGGACCCCCCCGAGGCCGAGGTGCAGATCGACAGACTGATCACAGGCAGGCTGCAGTCCCTGCAGACCTACGTGACACAGCAGCTGATCAGGGCCGCCGAGATCAGGGCCTCTGCCAATCTGGCCGCCACCAAGATGAGCGAGTGCGTGCTGGGCCAGTCCAAGAGGGTGGATTTTTGTGGCAAGGGCTATCACCTGATGAGCTTCCCACAGTCCGCCCCTCACGGAGTGGTGTTTCTGCACGTGACCTACGTGCCAGCCCAGGAGAAGAACTTCACCACAGCACCAGCAATCTGCCACGACGGCAAGGCACACTTTCCAAGAGAGGGCGTGTTCGTGAGCAACGGCACCGATTGGTTTGTGACACAGAGGAATTTCTACGAGCCCCAGATCATCACCACAGACAATACATTCGTGTCCGGCAACTGTGACGTGGTCATCGGCATCGTGAACAATACCGTGTATGATCCTCTGCAGCCAGAGCTGGACTCTTTTAAGGAGGAGCTGGATAAGTACTTCAAGAATCACACCAGCCCCGACGTGGATCTGGGCGACATCTCTGGCATCAATGCCAGCGTGGTGAACATCCAGAAGGAGATCGACCGGCTGAACGAGGTGGCCAAGAATCTGAACGAGTCCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCTTGGTATATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACAAGCTGCTGTTCCTGCCTGAAGGGCTGCTGTTCTTGTGGCAGCTGCTGTAAGTTTGATGAGGACGATAGCGAGCCAGTGCTGAAGGGCGTGAAGCTGCACTACACCTGA
SEQ ID NO:16是编码具有双脯氨酸取代的稳定化的SARS-CoV-2gamma变体刺突蛋白的密码子优化的核酸序列。
ATGTTCGTGTTTCTGGTGCTGCTGCCTCTGGTGAGCTCCCAGTGCGTGAATTTCACCAACAGAACACAGCTGCCTTCTGCCTACACCAATAGCTTCACACGGGGCGTGTACTATCCAGACAAGGTGTTTAGATCTAGCGTGCTGCACAGCACACAGGATCTGTTTCTGCCATTCTTTTCCAACGTGACCTGGTTCCACGCCATCCACGTGTCCGGCACCAATGGCACAAAGCGGTTCGACAATCCCGTGCTGCCTTTTAACGATGGCGTGTACTTCGCCTCCACCGAGAAGTCTAACATCATCAGAGGCTGGATCTTTGGCACCACACTGGACAGCAAGACACAGTCCCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATTATCCCTTCCTGGGCGTGTACTATCACAAGAACAATAAGTCTTGGATGGAGAGCGAGTTTAGGGTGTACTCCTCTGCCAACAATTGCACATTTGAGTATGTGAGCCAGCCTTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGAGCGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCCAAGCACACCCCCATCAACCTGGTGCGCGACCTGCCTCAGGGCTTCTCTGCCCTGGAGCCCCTGGTGGATCTGCCTATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCTGCACAGAAGCTACCTGACACCCGGCGACAGCTCCTCTGGATGGACCGCCGGCGCTGCCGCCTACTATGTGGGCTACCTGCAGCCTAGGACCTTCCTGCTGAAGTATAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGTCCGAGACCAAGTGTACACTGAAGTCTTTTACCGTGGAGAAGGGCATCTACCAGACATCTAATTTCAGGGTGCAGCCAACCGAGAGCATCGTGCGCTTTCCTAATATCACAAACCTGTGCCCATTTGGCGAGGTGTTCAACGCCACCCGCTTCGCCAGCGTGTATGCCTGGAATAGGAAGCGCATCAGCAACTGCGTGGCCGACTATTCCGTGCTGTACAACAGCGCCTCCTTCTCTACCTTTAAGTGTTACGGCGTGTCTCCTACAAAGCTGAATGACCTGTGCTTTACCAACGTGTATGCCGATAGCTTCGTGATCAGGGGCGACGAGGTGCGCCAGATCGCACCAGGACAGACCGGAACAATCGCAGACTACAATTATAAGCTGCCTGACGATTTCACCGGCTGCGTGATCGCCTGGAACTCCAACAATCTGGATTCTAAAGTGGGCGGCAACTACAATTATCTGTACCGGCTGTTTAGAAAGTCCAACCTGAAGCCATTCGAGCGGGACATCAGCACAGAGATCTACCAGGCAGGCTCCACCCCATGCAATGGAGTGAAGGGCTTTAACTGTTATTTCCCACTGCAGAGCTACGGCTTCCAGCCCACATATGGCGTGGGCTATCAGCCTTACAGAGTGGTGGTGCTGTCCTTTGAGCTGCTGCACGCACCAGCAACAGTGTGCGGACCCAAGAAGTCTACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGACTGACCGGAACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCATTTCAGCAGTTCGGCAGGGACATCGCAGATACCACAGACGCCGTGCGCGACCCACAGACCCTGGAGATCCTGGATATCACACCCTGCAGCTTCGGCGGCGTGTCCGTGATCACACCAGGAACCAATACAAGCAACCAGGTGGCCGTGCTGTACCAGGGCGTGAATTGTACCGAGGTGCCTGTGGCAATCCACGCAGACCAGCTGACCCCAACATGGCGGGTGTATTCTACCGGCAGCAACGTGTTCCAGACAAGAGCCGGCTGCCTGATCGGCGCCGAGTATGTGAACAATTCTTACGAGTGCGATATCCCTATCGGCGCCGGCATCTGTGCCAGCTACCAGACCCAGACAAACAGCCCACGGAGAGCACGGTCCGTGGCAAGCCAGTCCATCATCGCCTACACCATGTCTCTGGGCGCCGAGAATAGCGTGGCCTATTCCAACAATTCTATCGCCATCCCAACCAACTTCACAATCTCCGTGACCACAGAGATCCTGCCCGTGTCTATGACCAAGACAAGCGTGGACTGCACAATGTACATCTGTGGCGATTCCACCGAGTGCTCTAACCTGCTGCTGCAGTATGGCAGCTTTTGTACCCAGCTGAATAGAGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCCCCTATCAAGGACTTTGGCGGCTTCAACTTCAGCCAGATCCTGCCTGATCCAAGCAAGCCATCCAAGAGGTCTTTTATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTACGGCGATTGCCTGGGCGACATCGCAGCAAGGGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCACCCCTGCTGACAGATGAGATGATCGCCCAGTATACATCCGCCCTGCTGGCCGGCACCATCACATCTGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTTTGCCATGCAGATGGCCTACAGGTTCAACGGCATCGGCGTGACCCAGAATGTGCTGTATGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACTCCCTGAGCTCCACAGCCTCTGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGTCTAGCAACTTCGGCGCCATCTCCTCTGTGCTGAATGATATCCTGAGCCGGCTGGACCCCCCCGAGGCAGAGGTGCAGATCGACCGGCTGATCACCGGCAGACTGCAGAGCCTGCAGACCTACGTGACACAGCAGCTGATCAGGGCCGCCGAGATCAGGGCATCCGCCAATCTGGCCGCCATCAAGATGTCTGAGTGCGTGCTGGGCCAGAGCAAGAGAGTGGACTTTTGTGGCAAGGGCTACCACCTGATGAGCTTCCCTCAGTCCGCCCCACACGGAGTGGTGTTTCTGCACGTGACCTATGTGCCCGCCCAGGAGAAGAACTTCACCACAGCCCCTGCCATCTGCCACGATGGCAAGGCCCACTTTCCAAGGGAGGGCGTGTTCGTGTCCAACGGCACCCACTGGTTTGTGACACAGCGCAATTTCTACGAGCCCCAGATCATCACCACAGACAATACCTTCGTGAGCGGCAACTGTGACGTGGTCATCGGCATCGTGAACAATACCGTGTACGATCCACTGCAGCCCGAGCTGGACTCCTTTAAGGAGGAGCTGGATAAGTATTTCAAGAATCACACCTCTCCCGACGTGGATCTGGGCGACATCTCCGGCATCAATGCCTCTTTCGTGAACATCCAGAAGGAGATCGACCGCCTGAACGAGGTGGCCAAGAATCTGAACGAGTCCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCCTGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACAAGCTGCTGTTCCTGCCTGAAGGGCTGCTGTTCTTGTGGCAGCTGCTGTAAGTTTGATGAGGACGATAGCGAGCCTGTGCTGAAGGGCGTGAAGCTGCACTATACCTGA
SEQ ID NO:17是编码具有双脯氨酸取代的稳定化的SARS-CoV-2delta plus变体刺突蛋白的密码子优化的核酸序列。
ATGTTTGTGTTTCTGGTGCTGCTGCCACTGGTGAGTAGCCAGTGTGTGAACCTGAGAACCCGAACACAGCTGCCTCCTGCCTATACCAACAGCTTCACCAGAGGCGTGTACTACCCTGACAAGGTGTTCCGATCTAGCGTGCTCCATAGCACCCAGGACCTGTTCTTGCCTTTTTTCTCTAACGTGACATGGTTCCACGCCATTCACGTGTCTGGCACCAACGGAACAAAAAGATTCGACAACCCTGTGCTGCCCTTCAACGACGGTGTCTATTTTGCCAGCACCGAGAAGAGCAACATCATCAGAGGCTGGATCTTCGGAACCACCCTGGACAGCAAGACCCAGAGCCTGCTGATCGTCAATAACGCAACAAATGTGGTGATCAAGGTGTGCGAGTTCCAATTTTGCAACGATCCTTTCCTGGATGTGTACTACCACAAGAACAACAAAAGCTGGATGGAAAGTGGAGTTTATAGCAGCGCCAACAACTGCACCTTCGAGTACGTGAGCCAACCTTTCCTGATGGACCTCGAAGGGAAACAGGGCAACTTCAAGAACCTTAGAGAGTTCGTCTTTAAGAACATCGACGGCTACTTTAAAATCTACTCCAAGCACACCCCCATCAACCTGGTGCGGGACCTGCCTCAGGGCTTTAGCGCGCTGGAACCCTTGGTTGACCTGCCCATCGGCATCAACATCACTAGATTCCAGACCCTTCTGGCCCTCCACCGGTCTTACCTGACACCTGGCGACAGTAGTTCTGGCTGGACAGCCGGCGCCGCTGCCTACTACGTGGGCTATCTGCAGCCTAGAACCTTCCTGCTGAAGTACAACGAGAACGGCACCATCACCGACGCTGTGGATTGCGCCCTGGACCCTCTGTCCGAAACCAAGTGCACACTGAAGTCCTTCACCGTGGAAAAGGGCATCTACCAGACCTCTAACTTCCGGGTGCAGCCTACTGAAAGCATCGTGCGGTTCCCAAACATTACAAACCTGTGCCCTTTCGGAGAAGTTTTCAACGCCACTCGCTTCGCCTCTGTCTATGCCTGGAACAGAAAGCGGATCAGCAATTGTGTGGCCGATTACAGCGTGCTGTACAACAGCGCCAGCTTTTCTACATTCAAGTGCTACGGCGTGTCTCCCACCAAGCTGAATGATCTGTGCTTCACCAACGTGTACGCCGACTCGTTTGTGATCCGGGGAGACGAAGTGCGCCAGATCGCCCCTGGGCAGACAGGAAACATCGCCGATTACAATTACAAACTGCCTGACGATTTTACAGGATGTGTGATAGCTTGGAACTCCAACAACCTCGACAGCAAAGTGGGCGGCAACTACAATTACCGGTACAGACTGTTTAGAAAGAGCAACCTAAAACCCTTCGAGAGAGATATCTCTACCGAGATCTACCAGGCCGGCAGCAAGCCTTGTAATGGCGTTGAGGGCTTCAACTGTTACTTCCCTCTGCAGAGCTACGGCTTCCAGCCCACCAACGGCGTCGGGTACCAGCCTTACAGAGTTGTGGTTCTGAGCTTCGAGCTGCTCCACGCTCCTGCCACCGTGTGTGGTCCTAAGAAAAGCACCAACCTGGTGAAGAACAAGTGCGTGAATTTCAATTTCAACGGCCTGACAGGCACAGGCGTGCTGACCGAGAGCAACAAAAAGTTCCTGCCCTTCCAGCAGTTCGGCAGAGATATTGCCGATACCACAGACGCCGTGCGGGACCCTCAAACCCTGGAAATCTTGGACATCACACCTTGCAGCTTCGGCGGAGTGTCTGTGATCACTCCCGGGACCAACACCAGCAACCAGGTTGCCGTGCTGTACCAGGGCGTCAACTGCACCGAAGTGCCAGTGGCTATACACGCCGACCAGCTGACCCCTACATGGCGGGTGTACAGCACCGGCAGCAACGTGTTCCAGACCAGAGCCGGCTGCCTGATCGGCGCAGAGCACGTGAACAACTCTTATGAATGCGACATCCCCATCGGAGCCGGCATTTGCGCCAGCTACCAGACACAGACCAATAGCAGAAGACGGGCTAGAAGCGTGGCCTCGCAGAGCATAATCGCATACACAATGAGCCTGGGAGCCGAGAACAGCGTGGCCTACAGCAACAATAGTATCGCCATCCCCACAAATTTTACCATCAGCGTGACAACCGAAATCCTGCCAGTGAGCATGACAAAGACCAGCGTCGACTGCACAATGTACATATGTGGCGATAGCACGGAGTGCAGCAATCTGCTGCTCCAATACGGCAGCTTCTGCACCCAGCTGAATCGGGCACTGACCGGCATCGCCGTGGAACAGGATAAAAATACCCAGGAGGTGTTTGCCCAGGTGAAGCAGATATATAAGACCCCTCCGATCAAGGACTTCGGAGGCTTCAATTTCAGCCAGATCCTGCCCGATCCAAGCAAGCCTAGCAAGCGGTCCTTCATCGAGGATCTGCTGTTCAATAAGGTGACCCTGGCCGACGCCGGATTCATCAAACAGTACGGCGACTGCCTGGGCGACATCGCCGCCAGAGATCTGATCTGTGCTCAAAAGTTCAACGGACTGACAGTCCTGCCACCTCTGTTGACAGATGAAATGATCGCTCAGTACACCTCCGCCCTCCTGGCCGGGACGATCACCTCTGGATGGACCTTCGGCGCCGGCGCTGCACTGCAGATCCCTTTCGCCATGCAGATGGCCTACAGATTCAACGGCATCGGAGTGACCCAAAACGTCCTGTACGAGAACCAGAAGCTGATCGCCAACCAGTTCAACTCTGCTATCGGCAAGATCCAGGACAGCCTCAGCAGCACCGCCAGCGCCCTGGGCAAACTCCAGAACGTGGTGAACCAGAACGCACAGGCCCTGAATACCCTGGTGAAGCAGCTGAGCAGCAACTTCGGCGCTATCAGCTCTGTGCTGAACGACATCCTGAGCAGACTGGACCCTCCCGAGGCCGAGGTGCAGATTGACAGGCTGATCACAGGCAGACTGCAGTCGCTGCAAACTTACGTGACCCAGCAACTGATCCGGGCCGCCGAAATCAGGGCCAGCGCCAACCTGGCTGCTACAAAGATGTCCGAATGCGTGTTGGGCCAGTCCAAGAGAGTGGACTTCTGCGGCAAGGGATACCACCTGATGAGCTTCCCTCAGTCCGCTCCCCACGGCGTCGTGTTCCTGCATGTGACATACGTGCCCGCCCAGGAGAAGAATTTCACCACCGCCCCTGCCATCTGCCACGACGGCAAGGCCCACTTCCCCAGAGAGGGCGTGTTCGTGTCCAACGGCACCCACTGGTTCGTGACCCAGCGGAACTTCTACGAGCCTCAGATCATCACCACCGATAACACATTCGTGTCCGGCAACTGCGACGTGGTTATCGGCATCGTGAACAATACCGTGTACGACCCTCTGCAGCCAGAACTGGATTCTTTTAAGGAAGAGCTGGACAAATACTTTAAGAACCACACATCTCCTGATGTGGACCTGGGCGACATCAGCGGCATCAACGCCTCCGTGGTCAACATCCAAAAGGAGATCGATAGACTGAACGAGGTGGCCAAGAACCTCAACGAGTCTCTGATTGACCTGCAGGAGCTGGGCAAGTACGAGCAGTACATCAAGTGGCCTTGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCTATCGTCATGGTGACCATCATGCTGTGCTGTATGACCTCCTGCTGCAGCTGTCTGAAAGGCTGCTGTTCTTGCGGCAGCTGTTGCAAGTTTGACGAGGACGACTCCGAGCCCGTGCTGAAGGGGGTGAAGCTGCACTACACGTGA
SEQ ID NO:18是编码具有双脯氨酸取代的稳定化的SARS-CoV-2omicron变体刺突蛋白的密码子优化的核酸序列。
ATGTTCGTGTTCCTGGTGCTGCTGCCCCTGGTGTCTAGCCAATGTGTGAACCTGACAACAAGGACCCAGCTTCCCCCAGCTTACACCAATTCATTTACAAGAGGCGTGTATTACCCCGATAAGGTGTTCCGAAGCAGCGTGCTGCACAGCACCCAGGATCTCTTCCTGCCTTTTTTCAGCAATGTGACTTGGTTCCACGTGATCAGCGGAACCAACGGCACCAAGCGGTTTGACAATCCTGTGCTGCCCTTCAACGACGGCGTGTACTTCGCCAGCATCGAGAAGAGCAACATTATCCGGGGCTGGATCTTCGGCACCACCCTCGATAGCAAGACCCAGAGCTTACTGATCGTAAACAACGCCACCAATGTCGTAATCAAGGTCTGTGAATTTCAGTTCTGCAACGACCCCTTTCTGGACCACAAGAACAACAAGTCGTGGATGGAAAGCGAGTTCAGAGTGTACAGCTCCGCTAACAATTGTACATTCGAGTACGTGTCTCAGCCTTTCCTGATGGACCTGGAAGGCAAGCAGGGAAACTTCAAGAATCTGAGGGAGTTCGTGTTCAAAAACATCGACGGCTACTTCAAGATCTACAGCAAGCATACCCCCATCATCGTTGAACCTGAGAGAGACCTGCCACAGGGTTTCAGCGCTCTGGAGCCTCTGGTTGACCTGCCCATCGGCATCAACATCACCCGGTTTCAGACACTGTTAGCCCTGCATAGATCTTACCTGACCCCAGGCGATTCTTCCTCTGGCTGGACCGCCGGAGCCGCAGCCTACTACGTGGGATATCTGCAGCCCAGAACCTTCCTGCTGAAATACAACGAGAACGGAACCATCACCGATGCCGTGGACTGCGCCCTGGACCCTCTGTCTGAAACCAAGTGCACCCTGAAGAGCTTCACCGTGGAAAAGGGCATCTACCAGACCAGCAACTTTCGGGTGCAGCCCACCGAGAGCATCGTGAGATTTCCAAACATCACCAACCTGTGTCCTTTCGACGAGGTGTTTAATGCCACAAGATTCGCCAGCGTGTACGCCTGGAATAGAAAAAGAATCTCCAACTGCGTGGCTGATTACTCAGTGCTTTACAACCTGGCCCCATTCTTCACCTTCAAGTGCTACGGCGTTAGCCCTACCAAGCTCAATGATCTGTGCTTCACGAACGTGTACGCCGACAGCTTCGTGATCCGGGGCGACGAAGTCAGACAGATCGCCCCTGGACAGACCGGTAATATCGCCGACTACAATTACAAGCTGCCTGATGATTTCACAGGTTGCGTGATCGCCTGGAACTCCAACAAGCTGGACAGCAAGGTGTCCGGCAACTACAACTACCTGTATAGACTTTTCAGAAAGTCCAACCTGAAGCCATTCGAGCGGGACATCAGCACTGAGATCTACCAGGCCGGCAACAAACCCTGCAACGGAGTTGCCGGATTCAACTGCTATTTCCCTCTGAGATCTTACTCCTTCAGACCTACATACGGCGTGGGACACCAGCCTTACAGAGTAGTGGTGCTCAGCTTCGAGCTTCTGCACGCTCCTGCCACCGTGTGCGGCCCTAAGAAGAGCACGAACCTGGTGAAGAACAAATGTGTTAATTTTAACTTCAACGGCCTGAAGGGCACAGGAGTCCTGACCGAGAGCAATAAAAAATTCTTGCCCTTCCAGCAGTTCGGAAGAGACATCGCCGACACCACAGATGCTGTGAGAGACCCTCAGACCCTGGAAATCCTCGACATCACCCCTTGCAGCTTCGGCGGCGTCAGCGTGATCACCCCGGGCACCAACACCTCTAACCAGGTGGCCGTGCTGTACCAGGGCGTGAATTGCACCGAGGTTCCTGTGGCCATCCACGCGGACCAGCTGACACCAACATGGCGGGTGTACAGCACCGGCTCCAACGTGTTTCAGACCAGAGCCGGCTGTCTGATCGGCGCCGAATATGTGAACAACAGCTACGAATGCGACATCCCAATCGGCGCCGGCATTTGCGCCAGCTACCAGACACAGACCAAAAGTCACCGGAGAGCTCGGAGCGTGGCCTCTCAGAGCATTATCGCCTATACCATGAGCCTGGGGGCCGAGAACAGCGTGGCCTATTCCAACAACAGCATCGCCATCCCTACCAATTTCACCATCTCTGTGACCACCGAGATCCTGCCAGTGTCCATGACAAAGACAAGCGTGGACTGCACCATGTACATCTGCGGCGACTCTACCGAGTGCAGCAACCTGCTGCTGCAGTACGGCAGCTTTTGCACACAGCTGAAACGGGCGCTGACAGGAATTGCCGTTGAGCAGGACAAGAACACTCAGGAGGTGTTTGCCCAAGTGAAGCAGATATATAAGACCCCTCCTATCAAATACTTCGGCGGCTTTAACTTCAGCCAGATCCTCCCTGATCCTTCTAAGCCTAGCAAGCGCAGCTTCATCGAGGACCTGCTGTTCAACAAGGTAACCCTGGCTGACGCCGGCTTCATCAAGCAGTACGGTGATTGCCTGGGCGACATCGCAGCCCGGGACCTGATCTGTGCCCAAAAATTCAAGGGCCTGACTGTTCTGCCTCCTCTGCTGACAGATGAAATGATCGCCCAGTACACCTCCGCCCTGCTGGCTGGCACAATCACCAGCGGCTGGACATTCGGCGCCGGCGCCGCGCTGCAGATCCCTTTCGCCATGCAGATGGCCTACAGATTCAACGGCATCGGAGTGACTCAGAACGTGCTGTACGAAAACCAGAAACTGATTGCAAATCAGTTTAACAGCGCAATCGGCAAGATCCAGGATAGCCTGTCCAGCACCGCCTCCGCTCTGGGCAAGCTGCAAGACGTGGTGAACCACAATGCCCAGGCTCTGAACACCTTGGTGAAGCAGCTGAGCAGCAAGTTCGGCGCCATTTCTTCCGTGCTGAACGACATCTTCAGCAGACTCGATCCTCCCGAGGCCGAGGTGCAGATCGACAGACTGATCACGGGCAGACTGCAGTCTCTGCAGACATACGTGACACAGCAACTGATCAGAGCCGCTGAAATCAGGGCCTCTGCCAACCTGGCCGCCACCAAGATGTCTGAGTGCGTGCTCGGCCAGTCTAAAAGAGTGGACTTCTGCGGCAAAGGCTACCACCTGATGAGCTTCCCCCAGAGCGCCCCCCACGGCGTGGTGTTCCTACACGTTACCTACGTGCCGGCTCAAGAAAAGAACTTTACCACCGCCCCTGCCATCTGCCACGACGGAAAGGCCCACTTCCCTCGGGAGGGTGTGTTTGTCAGCAACGGCACACACTGGTTCGTGACACAGCGGAACTTCTACGAGCCCCAAATCATCACAACAGATAACACCTTCGTCAGCGGCAACTGTGACGTGGTGATCGGCATCGTGAACAACACCGTGTATGACCCTCTGCAGCCTGAGCTGGACAGCTTTAAGGAAGAGCTGGACAAGTACTTCAAGAATCACACAAGTCCTGACGTGGATCTGGGCGATATCAGTGGCATCAACGCCTCTGTGGTGAACATACAAAAGGAGATCGACAGACTGAACGAGGTGGCAAAGAACCTGAATGAAAGCCTGATCGACCTGCAAGAACTGGGCAAGTACGAGCAGTACATCAAGTGGCCTTGGTACATTTGGCTGGGATTTATCGCAGGCCTCATCGCCATCGTGATGGTGACAATCATGCTGTGTTGCATGACCAGCTGTTGCAGCTGCCTGAAAGGCTGTTGTAGCTGCGGCAGCTGCTGCAAGTTCGATGAGGACGACAGCGAGCCTGTCCTGAAGGGGGTGAAGCTGCACTACACATGA
SEQ ID NO:19是编码具有双脯氨酸取代的稳定化的SARS-CoV-2武汉株刺突蛋白的密码子优化的核酸序列。
ATGTTCGTCTTCCTGGTCCTGCTGCCCCTGGTCTCATCTCAGTGCGTGAATCTGACTACAAGAACTCAGCTGCCTCCCGCCTACACCAATTCCTTCACCCGGGGCGTGTACTATCCTGACAAGGTGTTTAGAAGCTCCGTGCTGCACTCTACACAGGATCTGTTTCTGCCATTCTTTAGCAACGTGACCTGGTTCCACGCCATCCACGTGAGCGGCACCAATGGCACAAAGCGGTTCGACAATCCCGTGCTGCCTTTTAACGATGGCGTGTACTTCGCCTCTACCGAGAAGAGCAACATCATCAGAGGCTGGATCTTTGGCACCACACTGGACTCCAAGACACAGTCTCTGCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAATGATCCCTTCCTGGGCGTGTACTATCACAAGAACAATAAGAGCTGGATGGAGTCCGAGTTTAGAGTGTATTCTAGCGCCAACAATTGCACATTTGAGTACGTGTCCCAGCCTTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAACCTGAGGGAGTTCGTGTTTAAGAATATCGATGGCTACTTCAAGATCTACTCTAAGCACACCCCCATCAACCTGGTGCGCGACCTGCCTCAGGGCTTCAGCGCCCTGGAGCCACTGGTGGATCTGCCTATCGGCATCAACATCACCCGGTTTCAGACACTGCTGGCCCTGCACAGAAGCTACCTGACACCCGGCGACTCCTCTAGCGGATGGACCGCAGGAGCAGCAGCCTACTATGTGGGCTATCTGCAGCCTAGGACCTTCCTGCTGAAGTACAACGAGAATGGCACCATCACAGACGCAGTGGATTGCGCCCTGGACCCCCTGAGCGAGACAAAGTGTACACTGAAGTCCTTTACCGTGGAGAAGGGCATCTATCAGACATCCAATTTCAGGGTGCAGCCAACCGAGTCTATCGTGCGCTTTCCTAATATCACAAACCTGTGCCCATTTGGCGAGGTGTTCAACGCAACCAGGTTCGCAAGCGTGTACGCATGGAATAGGAAGCGCATCTCTAACTGCGTGGCCGACTATAGCGTGCTGTACAACTCCGCCTCTTTCAGCACCTTTAAGTGCTATGGCGTGTCCCCCACAAAGCTGAATGACCTGTGCTTTACCAACGTGTACGCCGATTCTTTCGTGATCAGGGGCGACGAGGTGCGCCAGATCGCACCTGGACAGACAGGCAAGATCGCCGACTACAATTATAAGCTGCCAGACGATTTCACCGGCTGCGTGATCGCCTGGAACAGCAACAATCTGGATTCCAAAGTGGGCGGCAACTACAATTATCTGTACCGGCTGTTTAGAAAGAGCAATCTGAAGCCCTTCGAGAGGGACATCTCTACAGAGATCTACCAGGCCGGCAGCACCCCTTGCAATGGCGTGGAGGGCTTTAACTGTTATTTCCCACTGCAGTCCTACGGCTTCCAGCCCACAAACGGCGTGGGCTATCAGCCTTACCGCGTGGTGGTGCTGAGCTTTGAGCTGCTGCACGCACCAGCAACAGTGTGCGGACCCAAGAAGTCCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTTCAACGGCCTGACCGGAACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCATTTCAGCAGTTCGGCAGGGACATCGCAGATACCACAGACGCCGTGCGCGACCCACAGACCCTGGAGATCCTGGATATCACACCCTGCTCTTTCGGCGGCGTGAGCGTGATCACACCAGGAACCAATACAAGCAACCAGGTGGCCGTGCTGTATCAGGACGTGAATTGTACCGAGGTGCCTGTGGCCATCCACGCCGATCAGCTGACCCCAACATGGCGGGTGTACAGCACCGGCTCCAACGTGTTCCAGACAAGAGCAGGATGCCTGATCGGAGCAGAGCACGTGAACAATTCCTATGAGTGCGACATCCCAATCGGCGCCGGCATCTGTGCCTCTTACCAGACCCAGACAAACTCTCCAAGGAGAGCACGGAGCGTGGCATCCCAGTCTATCATCGCCTATACCATGTCCCTGGGCGCCGAGAATTCTGTGGCCTACTCTAACAATAGCATCGCCATCCCAACCAACTTCACAATCTCTGTGACCACAGAGATCCTGCCCGTGTCCATGACCAAGACATCTGTGGACTGCACAATGTATATCTGTGGCGATTCTACCGAGTGCAGCAACCTGCTGCTGCAGTACGGCAGCTTTTGTACCCAGCTGAATAGAGCCCTGACAGGCATCGCCGTGGAGCAGGATAAGAACACACAGGAGGTGTTCGCCCAGGTGAAGCAGATCTACAAGACCCCCCCTATCAAGGACTTTGGCGGCTTCAATTTTTCCCAGATCCTGCCTGATCCATCCAAGCCTTCTAAGCGGAGCTTTATCGAGGACCTGCTGTTCAACAAGGTGACCCTGGCCGATGCCGGCTTCATCAAGCAGTATGGCGATTGCCTGGGCGACATCGCAGCACGGGACCTGATCTGTGCCCAGAAGTTTAATGGCCTGACCGTGCTGCCACCCCTGCTGACAGATGAGATGATCGCACAGTACACAAGCGCCCTGCTGGCAGGAACCATCACATCCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTTTGCCATGCAGATGGCCTATAGGTTCAACGGCATCGGCGTGACCCAGAATGTGCTGTACGAGAACCAGAAGCTGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACAGCCTGTCCTCTACAGCCTCCGCCCTGGGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAATACCCTGGTGAAGCAGCTGAGCTCCAACTTCGGCGCCATCTCTAGCGTGCTGAATGATATCCTGAGCCGGCTGGACCCCCCCGAGGCAGAGGTGCAGATCGACCGGCTGATCACAGGCAGACTGCAGTCTCTGCAGACCTATGTGACACAGCAGCTGATCAGGGCAGCAGAGATCAGGGCAAGCGCCAATCTGGCAGCAACCAAGATGTCCGAGTGCGTGCTGGGCCAGTCTAAGAGAGTGGACTTTTGTGGCAAGGGCTATCACCTGATGTCCTTCCCTCAGTCTGCCCCACACGGCGTGGTGTTTCTGCACGTGACCTACGTGCCCGCCCAGGAGAAGAACTTCACCACAGCCCCTGCCATCTGCCACGATGGCAAGGCCCACTTTCCAAGGGAGGGCGTGTTCGTGTCCAACGGCACCCACTGGTTTGTGACACAGCGCAATTTCTACGAGCCCCAGATCATCACCACAGACAATACCTTCGTGAGCGGCAACTGTGACGTGGTCATCGGCATCGTGAACAATACCGTGTATGATCCACTGCAGCCCGAGCTGGACAGCTTTAAGGAGGAGCTGGATAAGTACTTCAAGAATCACACCTCCCCTGACGTGGATCTGGGCGACATCAGCGGCATCAATGCCTCCGTGGTGAACATCCAGAAGGAGATCGACCGCCTGAACGAGGTGGCCAAGAATCTGAACGAGAGCCTGATCGATCTGCAGGAGCTGGGCAAGTATGAGCAGTACATCAAGTGGCCATGGTACATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATGGTGACCATCATGCTGTGCTGTATGACATCCTGCTGTTCTTGCCTGAAGGGCTGCTGTAGCTGTGGCTCCTGCTGTAAGTTTGATGAGGACGATTCCGAACCCGTGCTGAAGGGAGTGAAGCTGCATTACACCTGA
具体实施方式
I.缩写
Ad(adenovirus)：腺病毒
CoV(coronavirus)：冠状病毒
COVID-19(coronavirus disease 2019)：2019冠状病毒疾病
Env(envelope)：包膜
GI(gastrointestinal)：胃肠的
HIV(human immunodeficiency virus)：人类免疫缺陷病毒
IFU(infection forming units)：感染形成单位
IM(intramuscular)：肌肉内
IN(intranasal)：鼻内
OPV(oral poliovirus)：口服脊髓灰质炎病毒
PP(double protein substitution)：双蛋白取代
S(spike protein)：刺突蛋白
SARS(severe acute respiratory syndrome)：严重急性呼吸综合征
TT(tail truncated)：尾部截短
URT(upper respiratory tract)：上呼吸道
VOC(variant of concern)：关注的变体
Wu(Wuhan strain)：武汉株
II.术语
除非另有说明，否则按照常规用法使用技术术语。分子生物学中常用术语的定义可见于Benjamin Lewin,Genes X,由Jones&Bartlett Publishers出版,2009；和Meyers etal.(eds.),The Encyclopedia of Cell Biology and Molecular Medicine,由Wiley-VCH出版，共16卷，2008；和其他类似参考资料。
本文中使用的单数形式的“a”、“an”和“the”，除非上下文另有明确说明，否则既指单数也指复数。例如，术语“an antigen”包括单个或多个抗原，可以认为等同于短语“至少一个抗原”。本文中使用的术语“包含”意指“包括”。还应理解，对于核酸或多肽给出的任何和所有碱基大小或氨基酸大小，以及所有分子量或分子质量值均是近似的，并且是出于描述目的而提供，除非另有说明。尽管可以使用许多与本文描述的方法和材料相似或等同的方法和材料，但本文描述了特别合适的方法和材料。如有冲突，以本说明书(包括术语解释)为准。此外，这些材料、方法和实施例仅是说明性的而不是限制性的。为了便于查看各种实施方案，提供以下术语解释：
腺病毒：一种非包膜病毒，具有线性双链DNA基因组和二十面体衣壳。人类腺病毒至少有68种已知的血清型，被分为七个种类(A、B、C、D、E、F和G种)。不同血清型的腺病毒与不同类型的疾病相关联，其中一些血清型引起呼吸道疾病(主要是B种和C种)、结膜炎(B种和D种)和/或胃肠炎(F种和G种)。4型腺病毒(Ad4)是E种病毒，可以引起急性呼吸道疾病和眼部疾病。基于腺病毒的载体通常用于多种治疗应用，包括疫苗和基因治疗载体。在本文的一些实施方案中，所述腺病毒载体是E3区全部缺失或部分缺失的人的具有复制能力的Ad4。
佐剂：免疫原性组合物的成分，用于增强抗原性。在一些实施方案中，佐剂可以包括吸附抗原的矿物质(明矾、氢氧化铝或磷酸盐)的悬浮液；或油包水乳液，例如，在其中抗原溶液乳化在矿物油(弗氏不完全佐剂)中，有时包含灭活的分枝杆菌(弗氏完全佐剂)以进一步增强抗原性(抑制抗原降解和/或引起巨噬细胞汇集)。在一些实施方案中，在所公开的免疫原性组合物中使用的佐剂是卵磷脂和卡波姆均聚物的组合(如可以从AdvancedBioAdjuvants,LLC获得的ADJUPLEXTM佐剂；也参见Wegmann,Clin Vaccine Immunol 22(9):1004-1012,2015)。用于所公开的免疫原性组合物的其他佐剂包括QS21纯化的植物提取物、Matrix M、AS01、MF59和ALFQ佐剂。免疫刺激寡核苷酸(如那些包括CpG基序的)也可以用作佐剂。佐剂包括生物分子(“生物佐剂”)，如共刺激分子。示例性的佐剂包括IL-2、RANTES、GM-CSF、TNF-α、IFN-γ、G-CSF、LFA-3、CD72、B7-1、B7-2、OX-40L、4-1BBL和toll样受体(TLR)激动剂，如TLR-9激动剂。本领域普通技术人员熟悉佐剂(参见例如Singh(ed.)VaccineAdjuvants and Delivery Systems.Wiley-Interscience,2007)。
施用：通过选定的途径将组合物引入受试者。施用可以是局部的或全身的。例如，如果选定的途径是静脉内的，则通过将组合物引入受试者的静脉中来施用组合物。示例性的施用途径包括但不限于鼻内、吸入、口服、注射(如皮下、肌内、皮内、腹膜内和静脉内)、舌下、直肠、透皮(例如，外用)和阴道途径。
密码子优化：核酸序列被改变，以使密码子在特定的系统(如特定的物种或物种的组)中最适于表达。例如，核酸序列可以被优化为在哺乳动物细胞中或在特定的哺乳动物物种(如人类细胞)中表达。密码子优化不改变所编码的蛋白的氨基酸序列。
保守变体：含有不会显著影响或降低蛋白质功能的保守氨基酸取代的蛋白质，如冠状病毒刺突蛋白。“保守”氨基酸取代是那些不会显著影响或降低蛋白质功能的取代，如当施用于受试者时蛋白质诱发免疫反应的能力。术语保守变异还包括使用取代的氨基酸代替未取代的亲本氨基酸。此外，改变、添加或缺失编码序列中的单个氨基酸或低百分比的氨基酸(例如小于5％，在一些实施方案中小于1％)的单个取代、缺失或添加是保守变异，其中该改变导致氨基酸被化学上相似的氨基酸取代。
以下六组是被认为是彼此保守取代的氨基酸的实例：
1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T)；
2)天冬氨酸(D)、谷氨酸(E)；
3)天冬酰胺(N)、谷氨酰胺(Q)；
4)精氨酸(R)、赖氨酸(K)；
5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V)；和
6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
非保守取代是那些降低蛋白质(如重组Env蛋白)活性或功能的取代，如施用于受试者时诱发免疫反应的能力。例如，如果氨基酸残基对于蛋白质的功能是必需的，那么即使在其他情况下保守的取代也可能破坏该活性。因此，保守取代不改变感兴趣蛋白质的基本功能。
冠状病毒：一大类正义单链RNA病毒家族，可以感染人类和非人类动物。冠状病毒的名字来自于其表面上的冠状刺突。病毒包膜由包含病毒膜(M)、包膜(E)和刺突(S)蛋白的脂质双层组成。大多数冠状病毒引起轻度到中度的上呼吸道疾病，如普通感冒。然而，已经出现了三种冠状病毒，可以引起更严重的疾病和死亡：严重急性呼吸综合征冠状病毒(SARS-CoV)、SARS-CoV-2和中东呼吸综合征冠状病毒(MERS-CoV)。其他感染人类的冠状病毒包括人类冠状病毒HKU1(HKU1-CoV)、人类冠状病毒OC43(OC43-CoV)、人类冠状病毒229E(229E-CoV)，以及人类冠状病毒NL63(NL63-CoV)。
COVID-19：由冠状病毒SARS-CoV-2引起的疾病。
简并变体：编码多肽的多核苷酸，其包括因遗传密码而简并的序列。有20种天然氨基酸，其中大多数由一个以上的密码子指定。因此，只要多肽的氨基酸序列不变，就会包括所有简并的核苷酸序列。
E3区：是指腺病毒早期3区(E3)基因，其含有多个开放阅读框(ORF)。人类4型腺病毒(Ad4)的E3区包括以下ORF：12.1K、23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K。在本文中的一些实施方案中，E3区中的缺失包含23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K ORF的缺失。在其他实施方案中，E3区中的缺失仅是24.8K、6.3K和29.7K ORF的缺失。
异源的：来自不同的遗传来源或物种。例如，异源多肽或多核苷酸是指来自不同来源或物种的多肽或多核苷酸。
免疫反应：免疫系统的细胞(如B细胞、T细胞或单核细胞)对刺激的反应。在一些实施方案中，该反应对特定抗原(如SARS-CoV-2刺突蛋白)具有特异性(“抗原特异性反应”)。在一些实施方案中，免疫反应是T细胞反应，如CD4+反应或CD8+反应。在另一些实施方案中，该反应是B细胞反应，并且导致产生特异性抗体。“初免免疫反应”指的是用“初免”免疫原/免疫原性成分处理受试者，以诱导免疫反应，其随后通过加强免疫原/免疫原性成分被“加强”。初免免疫和加强免疫共同在受试者中产生希望的免疫反应。
免疫原性组合物：包含免疫原或编码免疫原(如SARS-CoV-2刺突蛋白)的核酸分子或载体的组合物，当施用给受试者时，其诱发针对该免疫原的可测量的CTL反应，和/或诱发针对该免疫原的可测量的B细胞反应(如产生抗体)。它进一步指编码免疫原的分离的核酸，如可用于表达免疫原的核酸分子(并因此被用于诱发针对该免疫原的免疫反应)。对于体内使用，免疫原性组合物可以包括药学上可接受的载体中的蛋白质或核酸分子，也可能包括其他试剂，如佐剂。
使免疫：使受试者免受特定感染原(如SARS-CoV-2)的感染。免疫并不要求100％保护。在一些实施例中，与没有免疫情况下的感染相比，免疫提供至少50％、至少60％、至少70％、至少80％、至少90％或至少95％的针对感染的保护。
分离的：“分离的”生物组分已从其他生物组分(如天然存在该组分的其他生物组分，如其他染色体和染色体外DNA、RNA和蛋白质)基本分离或纯化。已“分离”的蛋白质、肽、核酸和病毒包括通过标准纯化方法纯化的那些。分离不要求绝对纯度，可以包括至少50％分离的，如至少75％、80％、90％、95％、98％、99％或甚至99.9％分离的蛋白质、肽、核酸或病毒分子。
中和抗体：通过与感染原，如病毒(例如，冠状病毒)上的特定抗原结合来降低感染原的感染滴度的抗体。在一些实施方案中，对SARS-CoV-2刺突蛋白特异性的抗体中和SARS-CoV-2的感染滴度。例如，中和SARS-CoV-2的抗体可以通过直接结合病毒并限制其进入细胞来干扰病毒。另外，中和抗体可以干扰病原体与受体的一种或更多种附着后的相互作用，例如，通过干扰病毒利用受体进入。在一些实施方案中，相比于对照抗体，SARS-CoV-2中和抗体抑制SARS-CoV-2感染细胞，例如，至少50％、至少60％、至少70％、至少80％或至少90％抑制。
药学上可接受的载体：所使用的药学上可接受的载体是常规的。Remington’sPharmaceutical Sciences,by E.W.Martin,Mack Publishing Co.,Easton,PA,19thEdition,1995描述了适于所公开的免疫原(如表达SARS-CoV-2 S蛋白的重组Ad4)和免疫原性组合物的药物递送的组合物和制剂。
通常，载体的性质将取决于所采用的特定施用方式。例如，肠胃外制剂通常包含可注射的流体，其包括药学上和生理学上可接受的流体，如水、生理盐水、平衡盐溶液、葡萄糖水溶液、甘油等作为溶媒。对于固体组合物(例如，粉末、丸剂、片剂或胶囊形式)，常规的无毒固体载体可以包括，例如，药物级甘露醇、乳糖、淀粉或硬脂酸镁。除了生物中性载体之外，待施用的药物组合物可以含有少量的无毒辅助物质，如润湿剂或乳化剂、防腐剂和pH缓冲剂等，例如乙酸钠或脱水山梨糖醇单月桂酸酯。在特定的实施方案中，适于向受试者施用的载体可以是无菌的，和/或悬浮的或以其他方式包含在单位剂型中，该单位剂型含有一个或更多个计量剂量的适于诱发所希望的抗SARS-CoV-2的免疫反应的组合物。它也可以与药物一起使用，用于治疗目的。单位剂型可以是，例如，在含有无菌内容物的密封瓶中或在用于向受试者注射的注射器中，或冻干以用于随后的溶解和施用，或者为固体或控释剂型。
预防、治疗或改善疾病：“预防”疾病是指抑制疾病的全面发展。“治疗”是指在疾病或病理状况开始发展后改善其体征或症状的治疗性干预，如减少病毒载量。“改善”是指减少疾病(如冠状病毒感染)的体征或症状的数量或严重程度。
重组：重组的核酸、载体或病毒是具有非天然存在的序列或具有由两个原本分离的序列片段通过人工组合而成的序列的核酸、载体或病毒。这种人工组合可以，例如，通过对分离的核酸片段进行人工操作来实现，例如，使用基因工程技术。
具有复制能力的病毒：能够进行基因组复制和蛋白质合成以产生子代病毒的病毒。
序列同一性：氨基酸或核苷酸序列之间的相似性以序列之间的相似性来表示，也称为序列同一性。序列同一性经常以同一性百分比来衡量；百分比越高，两个序列越相似。当使用标准方法进行比对时，多肽或多核苷酸的同源物、直向同源物或变体将具有相对高度的序列同一性。
用于比较的序列比对方法是已知的。各种程序和比对算法描述于：Smith&Waterman,Adv.Appl.Math.2:482,1981；Needleman&Wunsch,J.Mol.Biol.48:443,1970；Pearson&Lipman,Proc.Natl.Acad.Sci.USA 85:2444,1988；Higgins&Sharp,Gene,73:237-44,1988；Higgins&Sharp,CABIOS 5:151-3,1989；Corpet et al.,Nuc.Acids Res.16:10881-90,1988；Huang et al.Computer Appls.In the Biosciences 8,155-65,1992；andPearson et al.,Meth.Mol.Bio.24:307-31,1994.Altschul et al.,J.Mol.Biol.215:403-10,1990，详细介绍了序列比对方法和同源性计算。
多肽或核苷酸序列的变体的典型特征在于在与感兴趣的氨基酸或核苷酸序列的全长比对上具有至少约75％，例如，至少约80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的序列同一性。当使用这种方法评估时，与参考序列具有更大相似性的序列将显示出增加的同一性百分比，例如至少80％、至少85％、至少90％、至少95％、至少98％或至少99％的序列同一性。当少于全序列的序列被用来比较序列同一性时，同源物和变体通常在10-20个氨基酸(或30-60个核苷酸)的短窗口内具有至少80％的序列同一性，并且可能具有至少85％或至少90％或95％的序列同一性，取决于它们与参考序列的相似性。在这种短窗口上确定序列同一性的方法可在互联网上的NCBI网站上获得。
如本文所使用的，提及“至少90％同一性”(或类似用语)是指与指定的参考序列具有“至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％或甚至100％同一性”。
SARS-CoV-2：2019年首次在人类中出现的一种beta冠状病毒(betacoronavirus)属的冠状病毒。这种病毒也被称为2019-nCoV或2019新型冠状病毒。术语“SARS-CoV-2”包括其变体，例如，但不限于，alpha(B.1.1.7和Q系)；beta(B.1.351和子系)；delta(B.1.617.2和AY系)；gamma(P.1和子系)；epsilon(B.1.427和B.1.429)；eta(B.1.525)；iota(B.1.526)；kappa(B.1.617.1)；1.617.3；mu(B.1.621、B.1.621.1)，zeta(P.2)和omicron(B.1.1.529和BA系)。SARS-CoV-2感染的症状包括发烧、寒战、干咳、呼吸短促、疲劳、肌肉/身体疼痛、头痛、新的味觉或嗅觉丧失、喉咙痛、恶心或呕吐以及腹泻。病情严重的患者可能发展成肺炎、多器官衰竭和死亡。从接触到出现症状的时间大约为2至14天。SARS-CoV-2病毒包括带有大型刺突糖蛋白的病毒包膜。SARS-CoV-2基因组与大多数冠状病毒一样，具有共同的基因组结构，复制酶基因被包含在基因组的5’-三分之二处，结构基因被包含在基因组的3’-三分之一处。SARS-CoV-2基因组按照5’-刺突(S)-包膜(E)-膜(M)和核壳体(N)-3’的顺序编码一组典型的结构蛋白基因。
SARS刺突(S)蛋白：I类融合糖蛋白，SARS-CoV最初合成为大约1256个氨基酸的前体蛋白，SARS-CoV-2最初合成为1273个氨基酸的前体蛋白。单个前体S多肽形成同源三聚体，在高尔基体内进行糖基化，并通过处理去除信号肽，在SARS-CoV的大约第679/680位和SARS-CoV-2的第685/686位之间被细胞蛋白酶裂解，产生独立的S1和S2多肽链，它们作为S1/S2原体在同源三聚体内保持关联，从而形成异源二聚体的三聚体。S1亚基位于病毒膜的远端，含有受体结合域(RBD)，该结构域被认为介导病毒与其宿主受体的附着。S2亚基被认为含有融合蛋白机制，如融合肽。S2还包括两个七肽重复序列(HR1和HR2)和融合糖蛋白的典型中央螺旋、跨膜结构域和胞质尾部结构域。示例性的野生型(武汉株)SARS-CoV-2刺突蛋白序列在本文中如SEQ ID NO:2所示。示例性的修饰的武汉型SARS-CoV-2刺突蛋白序列在本文中如SEQ ID NO:3-5所示。此外，示例性的SARS-CoV-2变体刺突蛋白序列在本文中如SEQ ID NO:7-12所示。
受试者：活的多细胞脊椎动物有机体，该类别包括人类和非人类的哺乳动物。在一些实施方案中，受试者是人类。在一些实施例中，选择需要抑制或预防SARS-CoV-2感染的受试者。例如，受试者可以是未感染且有SARS-CoV-2感染风险的。
治疗有效量：特定物质的量，如公开的免疫原(例如表达SARS-CoV-2 S蛋白的重组Ad4)或免疫原性组合物，其足以在接受治疗的受试者中达到希望的效果，如保护性免疫反应。“治疗有效量”可以是在已被SARS-CoV 2感染的受试者中抑制SARS-CoV-2复制或治疗COVID-19所需的量。“预防有效量”是指抑制或预防感染(如SARS-CoV-2感染)建立的试剂或组合物的施用。可以理解的是，为获得针对感兴趣的抗原的保护性免疫反应，可能需要多次施用所公开的免疫原/免疫原性组合物，和/或施用所公开的组合物作为初免加强方案中的“初免”，其中加强免疫原可以不同于初免免疫原性组合物。因此，所公开的免疫原/免疫原性组合物的有效量可以是足以在受试者中引发初免的免疫反应的免疫原或免疫原性组合物的量，该免疫反应可以随后被相同的或不同的免疫原加强以引发保护性的免疫反应。
在一个实施例中，希望的反应是引发抑制或预防SARS-CoV-2感染的免疫反应。SARS-CoV-2感染的细胞不需要被完全消除或预防，该组合物就是有效的。例如，施用有效量的免疫原或免疫原性组合物可以引发免疫反应，与未免疫情况下的SARS-CoV-2感染细胞数量相比，该免疫反应使SARS-CoV-2感染细胞数量减少(或预防细胞感染)希望的量，例如减少至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少98％，或甚至至少100％(消除或预防可检测的SARS-CoV-2感染细胞)。
单位剂型：物理上离散的单位，如胶囊、片剂或溶液，适于作为人类患者的单位剂量，每个单位含有预定量的一种或更多种活性成分，其经过计算与至少一种药学上可接受的稀释剂或载体或其组合一起可产生治疗效果。
疫苗：在受试者中诱发预防性或治疗性免疫反应的药物组合物。在一些情况下，该免疫反应是保护性免疫反应。典型地，疫苗诱发针对病原体(例如病毒病原体)抗原或针对与病理状况相关的细胞组分的抗原特异性免疫反应。疫苗可包括多核苷酸(如编码所公开的抗原的核酸)、肽或多肽(如所公开的抗原)、病毒、细胞或一种或更多种细胞组分。在一个特定的非限制性的实例中，与对照相比，疫苗可降低SARS-CoV-2感染相关的症状的严重程度和/或减少病毒载量。在另一个非限制性的实例中，与对照相比，疫苗可减少SARS-CoV-2的感染和/或传播。
载体(vector)：含有DNA或RNA分子的实体，携带(一个或多个)可操作连接至感兴趣的蛋白质(如免疫原性蛋白)的编码序列并且可以表达该编码序列的启动子。非限制性的实例包括裸露或包装的(脂质和/或蛋白质)DNA，裸露或包装的RNA，病毒或细菌或其他可能不具有复制能力的微生物的亚组分，或病毒或细菌或其他可能具有复制能力的微生物。载体有时被称为构建体。重组DNA载体是具有重组DNA的载体。载体可以包括允许其在宿主细胞中复制的核酸序列，如复制起点。载体还可以包括一种或更多种选择标记基因和其他基因元件。病毒载体是具有衍生自一种或更多种病毒的至少一些核酸序列的重组核酸载体。病毒载体的非限制性的实例包括腺病毒载体、腺相关病毒(AAV)载体，和痘病毒载体(例如牛痘、禽痘)。
III.介绍
在用于向免疫系统呈递病毒糖蛋白的可用的疫苗平台中，复制型载体与大多数非复制型载体相比具有几个重要的优势(Robert-Guroff,Curr Opin Biotechnol 18(6):546-556,2007)。具有复制能力的载体可以表达病毒表面蛋白，从而使抗原总剂量远远超过那些非复制型载体。复制型粘膜疫苗诱导粘膜免疫，包括IgA和IgG抗体，和平衡的T细胞反应，其包括驻留记忆T细胞。此外，复制型载体，如具有复制能力的腺病毒(Ad)载体，在很长一段时间内表达病毒糖蛋白，类似于活病毒感染。该特征被认为对淋巴结中树突状细胞的装载和诱导持久的抗体反应很重要(Cirelli et al.,Cell 177(5):1153-1171,2019；Tamet al.,Proc Natl Acad Sci USA 113(43):E6639-E6648,2016；Mueller et al.,MolPharm 12(5):1356-1365,2015)。这些特征中的每一个都有助于复制型病毒疫苗接种后观察到的免疫反应的强度和持久性。
本文公开的疫苗构建物是编码SARS-CoV-2刺突(S)蛋白的具有复制能力的Ad4。在所公开的从Ad4疫苗株衍生的Ad4载体中，编码SARS-CoV-2刺突蛋白的基因被克隆进入具有多个E3 ORF缺失的E3区中。亲本Ad4疫苗载体已经被提供给超过1000万人，并具有优秀的安全记录。Ad4重组体已经被开发用于流感病毒H5和人类免疫缺陷病毒(HIV)包膜(Env)和Gag蛋白。这些基于Ad4的疫苗已经在兔中进行了对于免疫原性的临床前测试，并在临床1期试验中进行了人体测试。
与其他已提出的和被许可的SARS-CoV-2疫苗相比，基于具有复制能力的Ad4的疫苗平台有几个明显优势。例如，Ad4疫苗的功效已经得到证实，因为其已经在美国军队中作为单剂肠溶胶囊被常规性施用，发现其预防呼吸道疾病的功效超过95％。此外，当鼻内施用或在扁桃体上施用时，具有复制能力的基于Ad4的疫苗可在人类受试者中诱导中和抗体反应。上呼吸道施用也可绕过大多数人已经存在的Ad4免疫。通过诱导粘膜免疫，基于Ad4的疫苗平台不仅为接种疫苗的受试者提供保护，还有可能阻断SARS-CoV-2向其他个体的传播。与非复制型病毒疫苗形成对比，具有复制能力的基于Ad4的系统可产生持久的免疫反应。而且，与基于mRNA的SARS-CoV-2疫苗不同，Ad4疫苗可以长期在4-8储存。此外，本文公开的疫苗平台在可扩展性和成本方面是无与伦比的。据估算，所公开的SARS-CoV-2疫苗的生产成本低于1美分/剂。
IV.实施方案概述
本文公开了表达SARS-CoV-2刺突(S)蛋白(在一些实施方案中，被称作“Ad4-SARS-CoV-2-刺突”或“Ad4-刺突”)的重组4型腺病毒(Ad4)、编码该重组Ad4-刺突的重组Ad4核酸载体，及其免疫原性组合物。
在一个方面，本文提供了表达SARS-CoV-2 S蛋白的重组Ad4。该重组Ad4具有复制能力，且该Ad4的基因组包括腺病毒E3区中的缺失和SARS-CoV-2 S蛋白编码序列的插入。在一些实施方案中，该S蛋白的氨基酸序列与天然的S蛋白(如本文中SEQ ID NO:2所示的武汉型SARS-CoV-2毒株的S蛋白)的氨基酸序列至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在特定的实施例中，该S蛋白的氨基酸序列包含SEQ ID NO:2或由其组成。
本文对SARS-CoV-2 S蛋白残基的氨基酸编号参考如SEQ ID NO:2所述的野生型武汉株SARS-CoV-2 S序列。参考如SEQ ID NO:2所述的SARS-CoV-2 S蛋白序列，该SARS-CoV-2S蛋白的胞外域约包括残基16-1208。残基1-15是信号肽，其在细胞加工过程中被去除。S1/S2切割位点位于第685/686位。HR1约位于残基915-983。中央螺旋约位于残基988-1029。HR2约位于1162-1194。S2胞外域的C末端约位于残基1208。S蛋白的位置编号在不同的SARS-CoV-2毒株之间可能会有所不同，但可以对序列进行对比以确定相关的结构域的切割位点(参见例如图4)。
在一些实施方案中，重组Ad4包含SARS-CoV-2 S蛋白的编码序列，其包含一个或更多个(如两个，例如两个连续的)在HR1结构域和中央螺旋结构域之间的分界处或其附近的脯氨酸取代，使S蛋白在融合前构象下稳定。在一些这样的实施方案中，该使S蛋白在融合前构象下稳定的一个或更多个(如两个，例如两个连续的)脯氨酸取代位于HR1 C端残基的N端15位氨基酸和中央螺旋N端残基的C端5位氨基酸之间。在一些实施方案中，该使S蛋白在融合前构象下稳定的一个或更多个(如两个，例如两个连续的)脯氨酸取代位于残基975-995(如981-992)之间。在一些实施方案中，通过K986P和V987P取代(“PP”或“2P”)使SARS-CoV-2S蛋白在融合前构象下稳定。在一些实施方案中，通过三聚体中的S胞外域前体的D985、K986或V987位置的一个或两个脯氨酸取代使SARS-CoV-2 S蛋白在融合前构象下稳定。在一些实施例中，通过一个或更多个脯氨酸取代(如K986P和V987P取代)在融合前构象下稳定的SARS-CoV-2S蛋白包含一个或更多个使其在融合前构象下稳定的额外的修饰。
在一些实施方案中，由重组Ad4基因组编码的SARS-CoV-2 S蛋白包含与SEQ IDNO:3(武汉型-PP)至少90％(如至少95％、至少96％、至少97％、至少98％或至少99％)相同的氨基酸序列，其中SARS-CoV-2 S蛋白通过本文所述的一个或更多个修饰(如K986P和V987P取代)在融合前构象下稳定。在其他实施方案中，该稳定化的、脯氨酸取代的S蛋白衍生自SARS-CoV-2变体。在一些实施例中，衍生自SARS-CoV-2变体的稳定化的S蛋白包含与SEQ ID NO:7(beta-PP)、SEQ ID NO:8(武汉型/RDB-beta-PP)、SEQ ID NO:9(delta-PP)、SEQ ID NO:10(gamma-PP)、SEQ ID NO:11(delta plus-PP)或SEQ ID NO:12(omicron-PP)至少90％(如至少95％、至少96％、至少97％、至少98％或至少99％)相同的氨基酸序列。在特定的实施例中，该稳定化的SARS-CoV-2 S蛋白包含SEQ ID NO:3、SEQ ID NO:7、SEQ IDNO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12，或由其组成。
在其他实施方案中，由重组Ad4基因组编码的SARS-CoV-2 S蛋白包含C端的截短，如胞质尾部的截短或内吞基序的截短。在特定的实施例中，该被截短的SARS-CoV-2 S蛋白包含SEQ ID NO:4或SEQ ID NO:5的氨基酸序列，或由其组成。
如SEQ ID NO:6所示提供了示例性的编码SARS-CoV-2 S蛋白的核酸序列。在一些实施例中，编码SARS-CoV-2 S蛋白的核酸序列与SEQ ID NO:6至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在特定的非限制性的实施例中，编码SARS-CoV-2 S蛋白的核酸序列包含SEQ ID NO:6或由其组成。
上文所述的示例性的SARS-CoV-2 S蛋白的DNA序列可以通过修饰引入本文所公开的氨基酸取代和缺失，以实现融合前稳定。在一些实施方案中，该DNA序列(具有或不具有引入氨基酸取代的修饰)可以作为编码SARS-CoV-2 S蛋白的序列被包括在重组Ad4载体中。在一些实施方案中，S蛋白由密码子优化的核酸序列编码。在一些实施例中，编码S蛋白的核酸序列与SEQ ID NO:13(beta-PP)、SEQ ID NO:14(武汉型/RBD beta-PP)、SEQ ID NO:15(delta-PP)、SEQ ID NO:16(gamma-PP)、SEQ ID NO:17(delta plus-PP)、SEQ ID NO:18(omicron-PP)或SEQ ID NO:19(武汉型-PP)至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在特定的实施例中，编码S蛋白的核酸序列包括SEQ ID NOs:13-19中的任何一个，或由其组成。
在一些实施方案中，E3区中的缺失是至少两个、至少三个、至少四个、至少五个、至少六个或至少七个E3开放阅读框(ORF)的缺失。在一些实施例中，该缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K的ORF中的至少两个、至少三个、至少四个、至少五个、至少六个或至少七个。在特定的非限制性的实施例中，E3区中的缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K的ORF中每一个的缺失。
在一些实施方案中，SARS-CoV-2 S蛋白的编码序列被插入至E3区缺失的位置。
在一些实施方案中，重组Ad4的基因组的核苷酸序列与SEQ ID NO:1至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在一些实施例中，重组Ad4的基因组的核苷酸序列包含SEQ ID NO:1或由其组成。
本文还提供了一种重组的、具有复制能力的Ad4核酸载体。在一些实施方案中，重组Ad4载体包括腺病毒E3区的缺失和SARS-CoV-2 S蛋白编码序列的插入。在一些实施方案中，该S蛋白的氨基酸序列与天然的S蛋白的氨基酸序列至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同，该天然的S蛋白如本文SEQ ID NO:2所示的武汉型SARS-CoV-2毒株的S蛋白。在特定的实施例中，该S蛋白的核酸序列包含SEQID NO:2或由其组成。
在一些实施方案中，通过K986P和V987P取代(“PP”或“2P”)使SARS-CoV-2 S蛋白在融合前构象下稳定。在一些实施方案中，通过三聚体中的S胞外域前体的D985、K986或V987位置的一个或两个脯氨酸取代使SARS-CoV-2 S蛋白在融合前构象下稳定。在一些实施例中，通过一个或更多个脯氨酸取代(如K986P和V987P取代)在融合前构象下稳定的SARS-CoV-2 S蛋白包含一个或更多个额外的使其在融合前构象下稳定的修饰。
在一些实施方案中，由重组Ad4核酸载体编码的SARS-CoV-2 S蛋白包含与SEQ IDNO:3(武汉型-PP)至少90％(如至少95％、至少96％、至少97％、至少98％或至少99％)相同的氨基酸序列，其中SARS-CoV-2 S蛋白通过本文所述的一种或更多种修饰(如K986P和V987P替代)在融合前构象下稳定。在其他实施方案中，该稳定化的、脯氨酸取代的S蛋白衍生自SARS-CoV-2变体。在一些实施方案中，S蛋白由密码子优化的核酸序列编码。在一些实施例中，衍生自SARS-CoV-2变体的稳定化的S蛋白包含与SEQ ID NO:7(beta-PP)、SEQ IDNO:8(武汉型/RDB-beta-PP)、SEQ ID NO:9(delta-PP)、SEQ ID NO:10(gamma-PP)、SEQ IDNO:11(delta plus-PP)或SEQ ID NO:12(omicron-PP)至少90％(如至少95％、至少96％、至少97％、至少98％或至少99％)相同的氨基酸序列。在特定的实施例中，稳定化的SARS-CoV-2 S蛋白的氨基酸序列包含SEQ ID NO:3、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ IDNO:10、SEQ ID NO:11或SEQ ID NO:12，或由其组成。
在其他实施方案中，由重组Ad4核酸载体编码的SARS-CoV-2 S蛋白包含C端的截短，如胞质尾部的截短或内吞基序的截短。在特定的实施例中，该被截短的SARS-CoV-2 S蛋白包含SEQ ID NO:4或SEQ ID NO:5的氨基酸序列，或由其组成。
在所公开的Ad4载体的一些实施方案中，E3区中的缺失是至少两个、至少三个、至少四个、至少五个、至少六个或至少七个E3 ORF的缺失。在一些实施例中，该缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K的ORF中的至少两个、至少三个、至少四个、至少五个、至少六个或至少七个。在特定的非限制性的实施例中，E3区中的缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K的ORF中每一个的缺失。
在所公开的Ad4载体的一些实施方案中，SARS-CoV-2 S蛋白的编码序列被插入至E3区缺失的位置。在一些实施例中，该S蛋白的编码序列与SEQ ID NO:2-5和7-12中的任一个至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在特定的非限制性的实施例中，该S蛋白的编码序列包含SEQ ID NO:2-5和7-12中的任一个或由其组成。
在一些实施方案中，Ad4载体的核苷酸序列与SEQ ID NO:1至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％或至少99％相同。在一些实施例中，Ad4载体的核苷酸序列包含SEQ ID NO:1或由其组成。
本文进一步提供了免疫原性组合物，其包括重组Ad4或重组Ad4载体，和药学上可接受的载体。在一些实施方案中，免疫原性组合物进一步包括佐剂。在其他实施方案中，免疫原性组合物不包括佐剂。
还提供了在受试者中诱发针对SARS-CoV-2的免疫反应的方法。在一些实施方案中，该方法包括向受试者施用治疗有效量的本文公开的重组Ad4、重组Ad4(核酸)载体或免疫原性组合物。还提供了针对SARS-CoV-2感染免疫受试者的方法。在一些实施方案中，该方法包括向受试者施用治疗有效量的本文公开的重组Ad4、重组Ad4载体或免疫原性组合物。
在所公开的方法的一些实施方案中，重组Ad4、重组Ad4载体或免疫原性组合物通过鼻内施用或施用至扁桃体上。在一些实施例中，鼻内施用包括气溶胶的施用。该气溶胶的粒径应允许其被递送至上呼吸道，但不会递送至下呼吸道。在特定的实施例中，该气溶胶含有直径大于10微米，如大于20微米、大于30微米、大于40微米或大于50微米的颗粒。在特定的实施例中，该气溶胶含有约10至约150微米，如约20至约125微米或约30至约100微米的颗粒。本领域技术人员能够选择合适的装置来将所公开的重组Ad4、重组Ad4载体或免疫原性组合物通过鼻内施用至上呼吸道。该装置的非限制性的实例包括AccusprayTM(Becton-Dickinson)和MAD NasalTM 雾化器。
在一些实施方案中，该方法包括施用约104至约106个重组Ad4颗粒，如约5×104至约5×105的病毒颗粒或约1×105的病毒颗粒的剂量。在一些实施例中，该剂量是约1×104、2×104、3×104、4×104、5×104、6×104、7×104、8×104、9×104、1×105、2×105、3×105、4×105、5×105、6×105、7×105、8×105、9×105或1×106个重组Ad4颗粒。
在一些实施方案中，该重组Ad4、该重组Ad4载体，或该免疫原性组合物以单剂施用。
在一些实施方案中，该重组Ad4、该重组Ad4载体，或该免疫原性组合物作为初免-加强免疫方案的部分进行施用。在一些实施例中，该重组Ad4、该重组Ad4载体或该免疫原性组合物是初免剂。在其他实施例中，该重组Ad4、该重组Ad4载体或该免疫原性组合物是加强剂。
V.与COVID-19疫苗开发相关的临床前和临床研究
通过在一系列活口服脊髓灰质炎病毒(OPV)攻击试验中研究疫苗诱导的粘膜中和抗体反应，研究人员已经有力地证明了全身性抗体和粘膜抗体系统的显著分离(Brickleyet al.,Clin Infect Dis.2018；67(suppl_1):S42-S50)。该研究表明，尽管灭活的Salk疫苗诱导了高水平的血清抗体并提供了对麻痹型脊髓灰质炎的个体保护，但却未能诱导肠道IgA反应，而该反应对于抑制肠道脊髓灰质炎病毒复制和预防粪口传播至关重要。相比之下，减毒Sabin OPV的初次接种即可在活OPV攻击时诱导强大的IgA反应和杀毒免疫力。这一观察结果强调了诱导粘膜免疫对预防COVID-19感染和传播的重要性。可以相信的是，观察到的OPV的粘膜免疫原性的缺乏会在亚单位或不具有复制能力的全身性施用的SARS-CoV-2疫苗中再次出现。
在SARS-CoV-2疫苗的临床前试验中，已观察到与黏膜免疫类似的在阻断感染方面的优势。在雪貂中，使用具有复制缺陷的Ad5-刺突重组体进行IM或黏膜免疫，可在血清中诱导类似水平的刺突特异性抗体，但只有黏膜免疫才能诱导对上呼吸道(URT)的杀毒保护(Wuet al.,Nat Commun 11(1):4081,2020)。在可被SARS-CoV-2感染的小鼠模型中使用慢病毒-刺突或黑猩猩腺病毒-刺突重组体时，观察到鼻内施用相比于肌肉内施用，在诱导黏膜免疫和对URT的杀毒保护方面具有类似的优势(Ku et al.,Cell Host Microbe S1931-3128(20)30672-7,2020；Hassan et al.,Cell 183(1):169-184,2020；King et al.,Kinget al.,bioRxiv 2020.10.10.331348,2020)。已经观察到，局部特异性IgA与人类在冠状病毒229E攻击后终止病毒脱落高度相关(Callow et al.,J Hyg 95(1):173-189,1985)。
先前曾尝试使用肠胃外施用的非复制型疫苗以保护未接触过病毒的宿主免受病毒粘膜感染，但以失败告终或导致疾病加重。实例包括呼吸道合胞病毒(RSV)、副流感病毒(PIV)-3、Ad4、轮状病毒和麻疹病毒。这些失败的原因部分在于难以保护顶端表面被病毒受体覆盖的黏膜表面，这些表面的抗体比血清低100-1000倍，以及非复制型载体产生的扭曲的和短暂的免疫反应。所公开的Ad4-SARS-CoV-2-刺突疫苗的临床试验将详细评估针对SARS-CoV-2刺突蛋白和腺病毒载体的体液和粘膜反应。预计所公开的Ad4-SARS-CoV-2-刺突疫苗将在呼吸道产生粘膜抗体，并最大限度地模拟自然感染SARS-CoV-2后观察到的免疫特征。此外，相信所公开的疫苗为在COVID-19大流行期间持久地阻断传播提供了最佳可能性。
在可供人类使用的重组病毒载体中，复制型腺病毒提供了几个重要的优势。复制型Ad4已经作为针对Ad4呼吸系统疾病的疫苗提供给军队中超过1千万人，具有极高的安全性和有效性记录(Gaydos and Gaydos,Mil Med.1995；160(6):300-304)。该重组的Ad4以肠溶包衣片剂的形式向胃肠道施用从而减毒，不会引起呼吸系统疾病(Choudhry etal.,Vaccine 2016:34(38)4558-4564)。使用肠溶胶囊递送，对4000名参加基础军事训练的志愿者进行了3期研究。结果表明，疫苗对Ad4引起的呼吸系统疾病的有效性为99.3％，血清转化率为94.5％(Kuschner et al.,Vaccine 2013:31 2963-2971)。
在一项人体试验中，通过肠道递送的表达H5流感病毒的复制型重组腺病毒载体仅具有适度的免疫原性。这很可能与胃肠道施用使复制减弱(Gurwith et al.,LancetInfect Dis.2013；13(3):238-50)，以及E3区缺失有关。将编码冠状病毒刺突蛋白的大型基因引入腺病毒载体，需要去除大多数早期(在本例中为E3)基因，并在组织培养、黑猩猩和人类中显示出相对于亲本腺病毒至少10倍的衰减(Lubeck et al.,Nat Med.1997；3(6):651-8)。
在另一项临床试验中，与胃肠(GI)道相比，当向URT施用表达5型流感病毒血凝素越南型的具有复制能力的Ad4(Ad4-H5-Vtn)时，观察到高且显著持久水平的流感特异性中和抗体(Matsuda et al.,Sci Immunol.2019；4(34):eaau2710；Matsuda et al.,J ClinInvest 131(5):e140794,2021)。递送至URT的疫苗是非常安全的(25％的参与者出现鼻塞或喉咙不适，均未超过2级)，最高剂量可达108。这种反应原性水平与安慰剂中观察到的水平大致相同，与目前正在测试的一些针对SARS-CoV-2的肠胃外施用的非复制型平台大致相同，低于目前获得许可的水痘-带状疱疹(Shingrix)疫苗的水平。向Ad4血清阳性的人类进行腺病毒URT施用确实会导致再感染。URT施用利用保护上呼吸道树的困难发挥其优势来克服载体特异性免疫。这方面的实例是表达埃博拉糖蛋白的腺病毒有能力在腺免疫灵长类动物中通过鼻内途径诱导针对埃博拉攻击的保护性免疫，而先前在腺免疫动物中IM施用埃博拉构建体后没有观察到保护。
先前关于Ad4-H5-Vtn和Ad4-HIV重组体的结果表明，几乎所有的人类参与者都对该转基因产生了反应。在单次鼻内或扁桃体施用疫苗后，观察到H5特异性B细胞、H5特异性抗体体细胞超突变和效力的增加。疫苗也诱导了非常持久的反应。对获得许可的分离式流感疫苗的反应通常会在免疫后的2-6个月内减弱5-10倍。然而，当Ad4-H5-Vtn参与者在3-5年后被要求返回进行加强免疫时，中和抗体仍然处于用获得许可的疫苗免疫后观察到的峰值反应水平。本文公开的Ad4-SARS-CoV-2-刺突疫苗构建体可用于在全身接种后产生粘膜免疫。或者，可以在用所公开的疫苗免疫后施用亚单位疫苗，以加强粘膜和全身性抗体，已显示在使用H5-Vtn疫苗构建体时会发生此情况。
VI.免疫原性组合物
本文还提供了免疫原性组合物，其包括所公开的免疫原(例如表达SARS-CoV-2 S蛋白的重组的Ad、或包含SARS-CoV-2 S蛋白编码序列的重组Ad4核酸载体)和药学上可接受的载体。这种组合物可以通过多种施用模式向受试者施用，例如，鼻内、扁桃体上、吸入、口服、肌内、皮下、静脉内、动脉内、关节内、腹膜内或肠胃外途径。制备可施用组合物的方法在如Remingtons Pharmaceutical Sciences,19th Ed.,Mack Publishing Company,Easton,Pennsylvania,1995的出版物中有更详细地描述。
因此，本文所述的免疫原可以与药学上可接受的载体一起配制以助于保持生物活性，同时也促进在可接受的温度范围内增加储存期间的稳定性。可能的载体包括但不限于生理平衡培养基、磷酸盐缓冲盐溶液、水、乳液(例如油/水或水/油乳液)、各种类型的润湿剂、防冻添加剂或稳定剂，例如蛋白质、肽或水解产物(例如白蛋白、明胶)、糖(例如蔗糖、乳糖、山梨糖醇)、氨基酸(例如谷氨酸钠)或其他保护剂。得到的水溶液可以按原样包装使用或冻干。冻干制剂在单次或多次给药前与无菌溶液混合。
配制的组合物，尤其是液体制剂，可以含有抑菌剂以防止或尽量减少储存期间的降解，包括但不限于有效浓度(通常≤1％w/v)的苯甲醇、苯酚、间甲酚、氯丁醇、对羟基苯甲酸甲酯和/或对羟基苯甲酸丙酯。一些患者可能禁用抑菌剂；因此，冻干制剂可以在含有或不含有这种组分的溶液中复溶。
本公开的免疫原性组合物可以含有接近生理条件所需的药学上可接受的载体物质，例如pH调节剂和缓冲剂、张力调节剂、润湿剂等，例如，乙酸钠、乳酸钠、氯化钠、氯化钾、氯化钙、脱水山梨糖醇单月桂酸酯和油酸三乙醇胺。
药物组合物可以可选地包括佐剂以增强宿主的免疫反应。合适的佐剂是例如toll样受体激动剂、明矾、AlPO4、铝胶、Lipid-A及其衍生物或变体、油乳剂、皂苷、中性脂质体、含有疫苗和细胞因子的脂质体、非离子嵌段共聚物和趋化因子。含有聚氧乙烯(POE)和聚氧丙烯(POP)的非离子型嵌段聚合物，例如POE-POP-POE嵌段共聚物、MPLTTM(3-O-脱酰基单磷酰脂质A；Corixa,Hamilton,IN)和IL-12(Genetics Institute,Cambridge,MA)可以用作佐剂(Newman et al.,1998,Critical Reviews in Therapeutic Drug Carrier Systems15:89-142)。这些佐剂的优势在于它们有助于以非特异性方式刺激免疫系统，从而增强对药物产品的免疫反应。在一些实施方案中，不需要佐剂，因此不与Ad4-刺突疫苗一起施用佐剂。
在一些实施方案中，组合物可以作为无菌组合物提供。药物组合物通常含有有效量的所公开的免疫原并且可以通过常规技术制备。通常地，每剂免疫原性组合物中的免疫原的量被选择为能诱发免疫反应而没有显著不良副作用的量。在一些实施例中，剂量约为1×104至约106个病毒颗粒，如约5×104至约5×105病毒颗粒或约1×105个病毒颗粒。
在一些实施方案中，该组合物可以以单位剂型提供，用于在受试者中诱发免疫反应，例如，在受试者中预防SARS-CoV-2感染。单位剂型含有用于向受试者施用的合适的单一预选剂量，或两个或更多个预选单位剂量的合适的标记的或计量的倍数，和/或用于施用单位剂量或其倍数的计量机制。在一些实施例中，单位剂量为约1×104至约106个病毒颗粒，如约5×104至约5×105病毒颗粒。在具体的实施例中，单位剂量为约1×105个病毒颗粒。
VII.诱发免疫反应的方法
所公开的免疫原(例如，表达SARS-CoV-2刺突蛋白的重组的具有复制能力腺病毒)、编码所公开的免疫原的多核苷酸和载体，以及包括它们的组合物可在诱导针对SARS-CoV-2的免疫反应的方法中使用，以预防、抑制(包括抑制传播)和/或治疗SARS-CoV-2感染。
本文提供了在受试者中诱发针对SARS-CoV-2的免疫反应的方法。在一些实施方案中，该方法包括向受试者施用有效量的本文公开的重组腺病毒、腺病毒载体或免疫原性组合物。在一些实施例中，该重组腺病毒、载体或免疫原性组合物通过鼻内(如喷雾)或口服(如使用肠溶包衣片剂)施用。
当抑制、治疗或预防SARS-CoV-2感染时，所述方法可用于避免SARS-CoV-2血清阴性受试者中的感染(例如，通过诱导保护免收SARS-CoV-2感染的免疫反应)，或治疗SARS-CoV-2血清阳性受试者中的现有感染。
为了鉴别按照本公开的方法预防或治疗的受试者，采用公认的筛查方法来确定与目标或疑似疾病或病况相关的风险因素，或者确定受试者中现有疾病或病症的状态。这些筛查方法包括，例如，用于确定可能与目标或疑似疾病或病况相关的环境、家族、职业和其他此类风险因素的常规检查，以及用于检测和/或表征SARS-CoV-2感染的诊断方法，例如各种ELISA和其他免疫测定方法。这些方法和其他常规方法允许临床医生选择需要使用本公开的方法和免疫原性组合物进行治疗的患者。根据这些方法和原理，可以根据本文的教导或其他常规方法施用组合物，作为独立的预防或治疗方案，或作为其他治疗的后续、辅助或协调治疗方案。
该公开的免疫原可以用于协同(或初免-加强)免疫方案或联合制剂。在特定的实施方案中，新型联合免疫原性组合物和协同免疫方案采用单独的免疫原或制剂，每一种免疫原或制剂均旨在引发抗SARS-CoV-2的免疫反应，例如针对SARS-CoV-2刺突蛋白的免疫反应。引发抗SARS-CoV-2免疫反应的单独的免疫原性组合物可以被组合成多价免疫原性组合物，在单个免疫步骤中施用于受试者中，或者它们可以在协同免疫方案中单独施用(以单价免疫原性组合物的形式)。
在一个实施方案中，合适的免疫疗程包括至少两次单独的接种，接种一种或更多种包括所公开的Ad4-刺突的免疫原性组合物，其中第二次接种在第一次接种后超过约两周、约三至八周或约四周施用。第三次接种可以在第二次接种后几个月施用，并且在特定的实施方案中，可以在第一次接种后超过约五个月、第一次接种后超过约六个月至约两年，或第一次接种后超过约八个月至约一年施用。在第三次接种以后定期接种以增强受试者“免疫记忆”也是可取的。所选择的疫苗接种参数，例如配方、剂量、疗程等的充分性，可以通过在免疫程序过程中从受试者获取等分试样的血清并测定抗体滴度来确定。或者，可以通过常规方法监测T细胞群。此外，可以监测受试者的临床状况以获得期望的效果，例如预防SARS-CoV-2感染、改善疾病状态(例如降低病毒载量)或降低传播频率。如果这种监测表明疫苗接种没有达到最优效果，则可以用另外剂量的免疫原性组合物给受试者加强，并且可以以预期增强免疫反应的方式修改疫苗接种参数。因此，例如，可以增加所公开的免疫原的剂量或改变施用途径。
可以考虑进行数次加强，每次的加强剂可以是不同的免疫原。在一些实施例中还考虑加强剂可以是与另一加强剂或初免剂相同的免疫原。
初免剂和加强可以作为单剂或多剂施用，例如可以在数天、数周或数月内向受试者施用两剂、三剂、四剂、五剂、六剂或更多剂。也可以给予多次加强剂，如一至五次，或更多次。在一系列连续接种中可以使用不同的剂量。例如，在初次接种中使用相对较大的剂量，然后以相对较小的剂量进行加强。针对所选抗原表面的免疫反应可以通过受试者的一次或更多次接种来引发。
在几个实施方案中，所公开的免疫原向受试者的施用可以与佐剂的施用同时进行。在其他实施方案中，免疫原可以在施用佐剂之后并在足以诱发免疫反应的时间内施用于受试者。在其它实施方案中，不施用佐剂。
该方法的有效不需要完全抑制SARS-CoV-2感染。例如，与没有免疫时的SARS-CoV-2感染相比，引发对SARS-CoV-2的免疫反应可以以期望的量减少或抑制SARS-CoV-2感染，例如至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少98％或甚至至少100％(消除或预防可检测到的SARS-CoV-2感染细胞)。在另外的实施例中，可以通过所公开的方法减少或抑制SARS-CoV-2复制。该方法的有效不需要完全消除SARS-CoV-2复制。例如，与没有免疫反应时的SARS-CoV-2复制相比，使用一种或更多种公开的免疫原引发的免疫反应可以以期望的量减少SARS-CoV-2复制，例如至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少98％或甚至至少100％(消除或预防可检测到的SARS-CoV-2复制)。
在受试者免疫后，可以在适当的时间点从受试者收集血清，冷冻并储存用于中和试验。测定中和活性的方法，包括但不限于空斑减少中和(PRNT)测定、微量中和测定、基于流式细胞术的测定、单周期感染测定和假病毒中和测定。
在一些实施方案中，通过施用重组Ad4载体DNA来实现免疫。通过核酸构建体进行免疫在例如美国专利号5,643,578(其描述了通过引入编码期望抗原的DNA以引发细胞介导的反应或体液反应来使脊椎动物免疫的方法)、美国专利号5,593,972和美国专利号5,817,637(其描述了将编码抗原的核酸序列可操作地连接至能够表达的调节序列)中有所教导，并在Janeway&Travers,Immunobiology:The Immune System In Health and Disease,page 13.25,Garland Publishing,Inc.,New York,1997和McDonnell&Askari,N.Engl.J.Med.334:42-45,1996中进行了广泛的描述。
提供以下实施例以说明某些特定特征和/或实施方案。这些实施例不应被解释为将本公开限制于所描述的特定特征或实施方案。
实施例
实施例1：野生型和修饰型SARS-CoV-2刺突蛋白的表达
以下研究评估了野生型武汉株SARS-CoV-2刺突蛋白(SEQ ID NO:2)和武汉株刺突蛋白的三种被修饰版本的细胞表面表达：稳定型(PP)、尾部截短型(TT)和内吞基序截短型(no-Endo)。PP含有在第986位和第987位氨基酸的双脯氨酸稳定化取代(SEQ ID NO:3)；TT包括胞质尾部末端的24个氨基酸的缺失(SEQ ID NO:4)；no-Endo含有C端内吞信号基序的缺失(SEQ ID NO:5)(见图4)。
在A549细胞中对SARS-CoV-2的WT、PP、TT和no-Endo刺突蛋白的表达进行了评估。细胞用含有WT或修饰的SARS-CoV-2刺突蛋白基因的穿梭载体质粒转染。未转染的细胞用作阴性对照，用表达HIV-1Env蛋白的质粒转染的细胞被用作转染的阳性对照。刺突和Env的表达分别使用SARS-CoV-2刺突蛋白特异性抗体和HIV Env特异性抗体(VRC01)通过流式细胞术测量。如图1所示，相对于野生型刺突蛋白，经转染的A549细胞中的SARS-CoV-2刺突蛋白表达随着尾部的截短和内吞基序的截短而减少。
编码WT、PP或TT SARS-CoV-2刺突蛋白的核酸序列被插入具有复制能力的Ad4载体的E3区，该载体具有E3的23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K ORF的缺失。含有WT刺突蛋白编码序列的重组Ad4的核苷酸序列在本文中以SEQ ID NO:1列出。评估用重组Ad4感染的A549细胞中WT、稳定型和截短型的刺突蛋白的表达。携带WT刺突核酸序列(nCoV-WT)、PP稳定型刺突核酸序列(nCov-PP)或尾部截短型刺突核酸序列(nCov-TT)的复制型Ad4被用于感染A549细胞。表达HIV-1Env蛋白(FDE3)的复制型腺病毒被用作感染的阳性对照，未感染(unIF)细胞被用作阴性对照。刺突蛋白的表达使用SARS-CoV-2刺突蛋白特异性抗体通过流式细胞术测量。抗体VRC01用于检测HIV-1Env的表达。感染2天后Ad4-刺突的刺突蛋白表达如图2A所示。在图2B中，显示了PP稳定型和截短型的刺突蛋白的表达。如图2A-2B所示，nCoV-WT和nCoV-PP构建体的刺突蛋白的表达都很高。
实施例2：Ad4-刺突(WT)在兔中的免疫原性
在新西兰白兔中检测Ad4-刺突(表达SEQ ID NO:2的WT刺突蛋白序列)的免疫原性。兔和其他实验动物不复制Ad4病毒，但是肌肉内施用(IM)通常用于免疫原性筛选。在第0天和第28天，兔子用1.29×109个感染单位(IFU)的纯化的复制型Ad4-刺突进行IM免疫。使用荧光素酶测定法，在4周时(第二次免疫前)检测到针对武汉型SARS-CoV-2假病毒的血清中和，并在12周的研究期间持续增加。
实施例3：仓鼠中的免疫原性研究
人类腺病毒能够感染叙利亚黄金仓鼠(van der Lubbe et al.,NPJ Vaccines 6(1):39,2021)。因此，在这些动物中进行了免疫原性研究。对102-107个感染形成单位(IFU)的鼻内施用的具有PP稳定化的Ad4-SARS-CoV-2武汉型刺突(Ad4-SARS-CoV-2WuPP)进行了剂量滴定。在最高剂量的Ad4-SARS-CoV-2WuPP的慢病毒假型测定中，在第4周(图5A)和第8周(图5B)观察到强血清中和。
这些结果表明，仓鼠对Ad4是半受纳的，但复制的病毒足以诱导血清中和抗体。在第60天的洗鼻液中也观察到刺突特异性IgA和IgG。
然后用鼻内Ad4对仓鼠进行免疫，该Ad4表达来自所关注的变体(VOC)的稳定化的(双脯氨酸取代-PP)刺突蛋白。本研究包括Ad4-CoV2-武汉型、Ad4-CoV2-SA(beta)、Ad4-CoV2-Wu/RBD-SA、Ad4-CoV2-印度型(delta)和Ad4-CoV2-巴西型(gamma)。表达H5流感病毒血凝素的Ad4(Ad4-H5)和假接种作为阴性对照。
鼻内施用后28天和56天测定针对武汉型、delta和omicron假病毒的血清中和作用。结果示于图6A-6E中。表达武汉型-PP(SEQ ID NO:3)或Delta-PP(SEQ ID NO:9)的Ad4是最具免疫原性的。
实施例4：仓鼠中的攻击研究
该实施例描述了在叙利亚黄金仓鼠模型中测试候选疫苗的研究。
在本研究中，叙利亚黄金仓鼠以107个IFU的剂量被鼻内施用实施例3中确认的免疫原性候选物(候选物1或候选物2)，随后通过与SARS-CoV-2Delta感染的或SARS-CoV-2Omicron感染的动物共栖，受到SARS-CoV-2攻击(van Doremalen et al.,Sci Transl Med13(607):eabh0755,2021)。表1显示了所使用的动物的组。A组中的动物在第60天受到攻击，而B组中的动物在免疫后6个月受到攻击。接受Ad4-H5-Vtn鼻内施用的仓鼠作为阴性对照。辉瑞的mRNA或Ad26-刺突作为比较对象进行肌肉内施用。
表1.仓鼠中的攻击研究
| A组 | 候选疫苗 | 剂量 |
| 1a | Ad4-H5-Vtn | 1×107IFU IN |
| 2a | 候选物1 | 1×107IFU IN |
| 3a | 候选物2 | 1×107IFU IN |
| 4a | 辉瑞的mRNA BNT162b2 | 5μg×2IM |
| 5a | Ad26-刺突 | 1×109VPU IM |
| B组 | 候选疫苗 | 剂量 |
| 1b | Ad4-H5-Vtn | 1×107IFU IN |
| 2b | 变体1 | 1×107IFU IN |
| 3b | 变体2 | 1×107IFU IN |
| 4a | 辉瑞的mRNA BNT162b2 | 5μg×2IM |
| 4b | Ad26-刺突 | 1×109VPU IM |
预计鼻内施用Ad4-刺突疫苗将提供与mRNA或Ad26相同量级但更持久的全身性中和抗体。还预计，与非肠道施用的疫苗相比，Ad4-刺突会对攻击的病毒造成更大的限制。
实施例4：人类临床研究
在健康志愿者中进行了单剂鼻内施用Ad4-刺突的第1/2期开放标签研究。入组的志愿者之前可能患有过或未患有过2019冠状病毒疾病(COVID-19)或可能接种过或未接种过疫苗。选择的国际环境是COVID-19疫苗供应有限的地方，可能更容易招募未接触过SARS-CoV-2(SARS-CoV-2-naive)的志愿者。所有未接触过SARS-CoV-2的参与者，如果在研究结束时或6个月后的时间点，其中和滴度低于～40(这是Moderna mRNA 1272疫苗的四分位数范围的下限)，会为其提供紧急使用授权(EUA)疫苗。每个研究参与者接受单剂鼻内Ad4-SARS-CoV-2疫苗或使用被授权或许可的加强剂进行肌肉内(IM)免疫。在整个研究期间，对研究参与者进行不良事件(AE)监测，并周期性地收集血液和呼吸分泌物进行免疫原性和安全性测试。收集鼻拭子以监测腺病毒脱落，收集洗鼻液以监测粘膜免疫反应。愿意参与的家人和密切接触者也被征集，并通过血清学监测疫苗病毒的传播。
主要终点是安全性，通过接种疫苗后前28天内被引发的和非被引发的不良事件的频率和级别来衡量。通过在随访期间分别评价试验候选疫苗组中不良事件的发生率、严重程度和类型来评估安全性。预计21％(N＝10/48)的疫苗接种者可能会经历与疫苗相关的体征和症状(例如，头痛、疲劳、肌痛、流鼻涕、恶心、腹泻)。通过描述连续收集的洗鼻液样本中脱落病毒的存在、数量和持续时间来评估疫苗病毒的脱落。
次要终点是免疫原性。在连续收集的血清、鼻和粪便样本中评估免疫原性。免疫原性通过基于慢病毒的假病毒中和测定来确定。该测定包括通过B细胞克隆、补体增强和抗体依赖性增强、粘膜和T细胞免疫的表征测量的功能性抗体。在COVID-19感染后可以看到呼吸道粘膜反应，因此预计这将是Ad4-刺突疫苗的显著标志。如果Ad4载体的SARS-CoV-2疫苗在95％的受种者中“生效”，并且在这些受种者的90％中对腺病毒4和SARS-CoV-2刺突蛋白具有免疫原性，则预计85％(N＝44/52)的疫苗受种者将被诱导全身性免疫反应，在90-100％的志愿者中将会诱导粘膜反应。
在30天时没有证据表明疫苗生效的少见情况下，在60天施用第二剂。然而，主要分析是在1剂后进行的，因为该疫苗预计是单剂疗程。在先前的基于Ad4的疫苗试验中，大多数参与者在第二次免疫后没有产生更高的反应，第二剂只在参与者第一次接种时未被感染的不常见情况下才诱导反应。
由于志愿者没有经过血清抗体的预筛选，一部分志愿者在基线时对Ad4呈血清阳性(约30％，N＝20/60)，这是由于其暴露于流通的野生型腺病毒导致的。在先前的载体疫苗试验中，已有Ad4免疫者的反应表明，Ad4免疫可能调节对载体的反应并限制病毒脱落，但载体特异性免疫仍会被诱导。
对参与者进行一年的安全性和免疫原性监测。1期试验可选地包括设计在临床试验中的平行探索组，以允许将Ad4-刺突与其他SARS-CoV-2刺突免疫原如DNA、mRNA或蛋白质疫苗结合使用。与非复制型、非肠道施用的蛋白质或核酸疫苗相比，预计Ad4-刺突将提供更高的持久性和粘膜T和B细胞反应。
目标研究人群仅排除那些可能受到呼吸道毒感染负面影响的人群，如孕妇或严重免疫缺陷的那些人。重组的Ad4疫苗接种的症状，一旦出现，往往是轻微的和自限性的。那些在处理上呼吸道感染方面没有困难的人接种Ad4-刺突疫苗后应该不会出现严重症状。尽管对Ad4已有的免疫并不罕见(30％)，但它在很大程度上可以通过鼻内接种克服。将对克服载体特异性免疫的程度进行评估，并预计其会是疫苗病毒复制和刺突蛋白免疫原性的函数。Ad4抗体在16岁以下人群中的出现率极低，这使得这种疫苗成为在学龄儿童中诱导持久免疫的非常有吸引力的模式。主要终点是安全性和免疫原性。如果达到主要终点，安全性将在2期试验得到明确解决。
当先前的Ad4重组病毒疫苗通过鼻内提供时，病毒以低水平复制2-4周。然而，通过病毒培养检测到的病毒脱落水平较低，中位数为一天。参与者被建议在接种疫苗后的14天内避免密切接触。由于这些原因，尚未观察到疫苗病毒向家人或密切接触者传播。大多数接种疫苗者是无症状的。然而，最常见的不良事件(AE)是25％的参与者出现喉咙不适和鼻塞，都没有超过2级。预计包含SARS-CoV-2刺突蛋白的重组的Ad4将产生类似于先前基于Ad4的鼻内施用疫苗的结果。
2期之后进行3期研究和/或攻击研究。
鉴于所公开的主题的原理可以应用于许多可能的实施方案，应该认识到所示的实施方案仅仅是本公开的优选实施例，并且不应该被认为限制了本公开的范围。相反，本公开的范围由以下权利要求限定。因此，我们主张在这些权利要求的范围和精神内的所有内容。
序列表
<110> 美国政府，由卫生和人类服务部的部长所代表
<120> 具有复制能力的4型腺病毒SARS-COV-2疫苗及其用途
<130> 4239-105641-02
<150> US 63/138,221
<151> 2021-01-15
<160> 19
<170> PatentIn version 3.5
<210> 1
<211> 40459
<212> DNA
<213> 人工序列
<220>
<223> 重组载体
<400> 1
taaatttaaa tgaattccgt caagggcgac acaaaaggta ttctaaatgc ataataaata 60
ctgataacat cttatagttt gtattatatt ttgtattatc gttgacatgt ataattttga 120
tatcaaaaac tgattttccc tttattattt tcgagattta ttttcttaat tctctttaac 180
aaactagaaa tattgtatat acaaaaaatc ataaataata gatgaatagt ttaattatag 240
gtgttcatca atcgaaaaag caacgtatct tatttaaagt gcgttgcttt tttctcattt 300
ataaggttaa ataattctca tatatcaagc aaagtgacag gcgcccttaa atattctgac 360
aaatgctctt tccctaaact ccccccataa aaaaacccgc cgaagcgggt ttttacgtta 420
tttgcggatt aacgattact cgttatcaga accgcccagg atgcctggca gttccctact 480
ctcgccgctg cgctcggtcg ttcggctgcg ggacctcagc gctagcggag tgtatactgg 540
cttactatgt tggcactgat gagggtgtca gtgaagtgct tcatgtggca ggagaaaaaa 600
ggctgcaccg gtgcgtcagc agaatatgtg atacaggata tattccgctt cctcgctcac 660
tgactcgcta cgctcggtcg ttcgactgcg gcgagcggaa atggcttacg aacggggcgg 720
agatttcctg gaagatgcca ggaagatact taacagggaa gtgagagggc cgcggcaaag 780
ccgtttttcc ataggctccg cccccctgac aagcatcacg aaatctgacg ctcaaatcag 840
tggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg cggctccctc 900
gtgcgctctc ctgttcctgc ctttcggttt accggtgtca ttccgctgtt atggccgcgt 960
ttgtctcatt ccacgcctga cactcagttc cgggtaggca gttcgctcca agctggactg 1020
tatgcacgaa ccccccgttc agtccgaccg ctgcgcctta tccggtaact atcgtcttga 1080
gtccaacccg gaaagacatg caaaagcacc actggcagca gccactggta attgatttag 1140
aggagttagt cttgaagtca tgcgccggtt aaggctaaac tgaaaggaca agttttggtg 1200
actgcgctcc tccaagccag ttacctcggt tcaaagagtt ggtagctcag agaaccttcg 1260
aaaaaccgcc ctgcaaggcg gttttttcgt tttcagagca agagattacg cgcagaccaa 1320
aacgatctca agaagatcat cttattaagc ttagaaaaac tcatcgagca tcaaatgaaa 1380
ttgcaattta ttcatatcag gattatcaat accatatttt tgaaaaagcc gtttctgtaa 1440
tgaaggagaa aactcaccga ggcagttcca taggatggca agatcctggt atcggtctgc 1500
gattccgact cgtccaacat caatacaacc tattaatttc ccctcgtcaa aaataaggtt 1560
atcaagtgag aaatcaccat gagtgacgac tgaatccggt gagaatggca aaagtttatg 1620
catttctttc cagacttgtt caacaggcca gccattacgc tcgtcatcaa aatcactcgc 1680
atcaaccaaa ccgttattca ttcgtgattg cgcctgagcg aggcgaaata cgcgatcgct 1740
gttaaaagga caattacaaa caggaatcga gtgcaaccgg cgcaggaaca ctgccagcgc 1800
atcaacaata ttttcacctg aatcaggata ttcttctaat acctggaacg ctgtttttcc 1860
ggggatcgca gtggtgagta accatgcatc atcaggagta cggataaaat gcttgatggt 1920
cggaagtggc ataaattccg tcagccagtt tagtctgacc atctcatctg taacatcatt 1980
ggcaacgcta cctttgccat gtttcagaaa caactctggc gcatcgggct tcccatacaa 2040
gcgatagatt gtcgcacctg attgcccgac attatcgcga gcccatttat acccatataa 2100
atcagcatcc atgttggaat ttaatcgcgg cctcgacgtt tcccgttgaa tatggctcat 2160
attcttcctt tttcaatatt attgaagcat ttatcagggt tattgtctca tgagcggata 2220
catatttgaa tgtatttaga aaaataaaca aataggggtc agtgttacaa ccaattaacc 2280
aattctgaac attatcgcga gcccatttat acctgaatat ggctcataac accccttgtt 2340
tgcctggcgg cagtagcgcg gtggtcccac ctgaccccat gccgaactca gaagtgaaac 2400
gccgtagcgc cgatggtagt gtggggactc cccatgcgag agtagggaac tgccaggcat 2460
caaataaaac gaaaggctca gtcgaaagac tgggcctttc gcccgggcta attagggggt 2520
gtcgccctta tcgctgagga tccatttaaa tttaattaac atcatcaata atatacctta 2580
ttttttttgt gtgagttaat atgcaaataa ggcgtgaaaa tttggggatg gggcgcgctg 2640
attggctgtg acagcggcgt tcgttagggg cggggcaggt gacgttttga tgacgcgact 2700
atgaggagga gttagtttgc aagttctggt ggggaaaagt gacgtcaaac gaggtgtggt 2760
ttaaacacgg aaatactcaa ttttcccacg ctgtctaaca ggaaatgagg tgtttttggg 2820
cggatgcaag tgaaaacgga ccattttcgc gcgaaaactg aatgaggaag tgaaatctga 2880
gtaatttagt gtttatgaca gggaggagta tttgccgagg gccgagtaga ctttgaccgt 2940
ttacgtgggg gtttcgatta ccgtgttttt cacctaaagt tccgcgtacg gtgtcaaagt 3000
ccggtgtttt tacgtaggtg tcagctgatc gtcagggtat ttaaacctgc gctctgcagt 3060
caagaggcca ctcttgagtg ccagcgagaa gagttttctc ctccgcgccg cgagtcagat 3120
ctacactttg aaatatgagg cacctaagag acctgcccga tgaggaaatt atcatcgctt 3180
ccgggagcga gattctggaa ctggtggtaa atgctatgat gggcgacgac catccggaac 3240
cccccacccc atttgagaca ccttcgctgc acgatttgta tgatctggag gtggatgtgc 3300
ccgaggacga ccccaacgag aaggcggtaa atgatttatt tagcgatgcc gcgctgctag 3360
ctgccgagga ggcttcaagc cctagctcag acagcgactc ttcactgcat acccctagac 3420
acgacagagg tgagaaagag atccccgggc ttaaatggga aaagatggac ttgcgttgct 3480
atgaggaatg cctgccccca agcgatgatg aggacgagca ggcgattcag aacgcagcga 3540
gccatggagt gcaagccgtc agcgagagct ttgcactgga ctgcccgcct ttgcccggac 3600
acggctgtaa gtcttgtgaa tttcatcgca tcaatactgg agataaagct gtgttatgtg 3660
cactttgcta tatgagagcg tacaaccatt gtgtttacag taagtgtgat taagtgaact 3720
ttaaagggag gcaaagagta gggtgactgg gtgatgactg gtttatttat gtatatctgt 3780
tttttatata ggtcccgttt ctgacgcaga tgatgagacc cccactacag agtccacttt 3840
gtcaccccct gaaattggca cgtctccatc tgacaatatt gttagaccag ttcctgtaag 3900
agccactggg aggagagcag ctgtagaatg tttggatgat ttgcttcagg gtggagatga 3960
acctttggac ttgtgtaccc ggaaacgccc caggcattaa gtgccacaca tgtgtgttta 4020
cttgaggtga tgtcagtatt tatagggtgt ggagtgcaat aaaatatgtg ttgactttaa 4080
gtgcgtggtt tatgactcag gggaggggac tttgggtata taagcaggtg cagacctgtg 4140
tggttagctc agagcggtat ggagatttgg acggttttgg aagactttca caagactagg 4200
cagctgctag agaacgcctc gaacggagtc tcttacctgt ggagattctg cttcggcggt 4260
gacctagcta agctagtcta tagggccaaa caggattata gggaacaatt tgaggatatt 4320
ttgagagagt gtcctggtct ttttgacgct cttaacttgg gccatcagtc tcactttaac 4380
cagagaattt caagagccct tgactttact actcctggca gaaccactgc agcagtagcc 4440
ttttttgctt ttatttttga caaatggagt caagaaaccc atttcagcag ggattaccag 4500
ctggatttct tagcagtagc tttgtggaga acatggaagt gccagcgcct gaatgcaatc 4560
tccggctact tgccggtaca gccgctagac actctgagga tcctgagtct ccagcagcag 4620
gaggatcaag aagagaatcc gagagccggc ctggaccctc cggcggagga gtagctgacc 4680
tgtttcctga actgcaccgg gtgctgacta ggtcttcgag tggtcgggag aggggtatta 4740
agcgggagag gcatgatgag actaatcaca gaattgaact gactgtgggt ctgatgagcc 4800
gcaagcgtcc agaaacagtg tggtggtatg aggtgcagtc aactggcaca gatgaggtgt 4860
cagtcatgca tgagagattt tccctagaac aagtcaagac ttgttggttg gagcctgagg 4920
atgattggga ggtagccatc aggaattatg ccaagctggc tctgaggcca gatagaaagt 4980
acaagattac taagctgata aatatcagaa atgcctgcta catctcaggg aatggggctg 5040
aagtggagat ctgtctccag gatagagtgg ctttcagatg ctgcatgatg aatatgtacc 5100
cgggagtggt ggacatggat ggggtcacct ttatgaacat gaggttcagg ggagatgggt 5160
ataatgggac ggtctttatg gccaatacca agctgacagt gcatggatgc tccttctttg 5220
ggtttaataa cacctgcatc gaggcttggg gtcaggtcgg tgttaagggg tgcagttttt 5280
cagccaactg gatgggggta gtgggcagga ccaagagtat gctgtctgtg aagaaatgct 5340
tgtttgagag gtgccacctg ggggtgatga gcgagggcga agccagaatc cgccactgtg 5400
cctctaccga gacgggctgt tttgtgctgt gcaagggcaa tgccaagatc aagcataata 5460
tgatctgtgg agcctcggac gagcgcggct accagatgct gacctgcgcc ggtgggaaca 5520
gtcatatgct ggccgccgtg catgtggctt cccattcccg caagccctgg cctgagttcg 5580
agcacaatgt catgaccagg tgcaatatgc atctgggggc tcgccgaggc atgtttatgc 5640
cctaccagtg caacctgaat tatgtaaagg tgctcctgga gcccgatgtc atgtccagag 5700
tgagcctgac gggggtgttt gacatgaatg tggaagtgtg gaagattcta agatatgatg 5760
aatacaagac caggtgtcga gcctgcgagt gcggagggaa gcatgccagg ttccagcccg 5820
tgtgtgtgga tgtgacggag gacctgcgac ccgatcattt ggtgttgtcc tgcaccggga 5880
cggagttcgg ctccagtggg gaagaatctg actagagtga gtagtgtttt ggggagggag 5940
aggacctgca taaggggcag aatgattaaa atctgtgctt ttctgtgtgt tgcagcagca 6000
tgagcggaaa cggctccttt gagggagggg tattcagccc ttatctgacg gggcgtctcc 6060
cctcctgggc gggagtgcgt caaaatgtga tgggatccac ggtggacggc cggcccgtac 6120
agcccgcgaa ctcttcaacc ctgacctatg caaccctgag ctcctcgtcg gtggacgcag 6180
ctgccgccgc agctgctgct tctgccgcca gcgccgtgcg cggaatggcc atgggcgccg 6240
gctattacgg cactctggtg gccaactcga gttccactaa taatcccgcc agcctgaacg 6300
aggagaagct gctgctgttg atggcccagc tcgaggcctt gacccagcgc ctgggcgagc 6360
tgacccagca ggtggctcag ctgcaggagc agacgcgggc cgcggttgcc acggtgaaat 6420
ccaaataaaa aatgaatcaa taaataaacg gagacggttg ttgattttaa aaatcagagt 6480
ctgaatcttt atttgatttt tcgcgcacgg taggccctgg accaccggcc tcgatcattg 6540
agcacccggt ggatcttttc caagacccgg tagaggtggg attggatatt gaggtacatg 6600
ggcatgagcc cgtcccgggg gtgaaggtag ctccattgca gggcctcgtg ctcgggggtg 6660
gtgttgtaaa tcacccagtc atagcaggga cgcagggcgt ggtgttgcac aatatctttg 6720
aggaggagac tgatggccac gggcagccct ttggtgtagg tgtttacaaa cctgttgagc 6780
tgggagggat gcatgcgggg ggagatgagg tgcatcttag cctggatctt cagattggcg 6840
atgttaccgc ccagatcccg cctgggattc atgttgtgca ggaccaccag cacggtgtat 6900
ccggtgcact tggggaattt gtcatgcaac ttggaaggga aggcatgaaa gaatttggag 6960
acgcccttgt ggccgcccag gttttccatg cactcatcca tgataatggc tatgggcccg 7020
tgggcggcgg cttgggcaaa gacgtttcgg gggtcggaca catcgtagtt gtggtcctgg 7080
gtgagatctt cataggccat tttaatgaat ttggggcgga gggtgcccga ttgggggacg 7140
aaggtaccct caatcccggg ggcgtagttt ccctcacaga tctgcatctc ccaggcctta 7200
agctccgagg gggggatcat gtccacctgc ggggcgataa agaaaacggt ttccggggcg 7260
ggggagatga gctgggcgga aagcaggttg cggagtagct gggacttacc gcagccggtg 7320
gggccgtaga taaccccaat gaccggctgc aggtggtagt tgagggagac acagctgccg 7380
tcctccctaa gaaggggggc cacctcgttc atcatttggc gcacgtgcat gttctcgcgc 7440
accagttccg ccaggagtcg ctctccgccc agcgagagga gctcctggag cgaggcgaag 7500
tttttcagcg gcttgagccc gtcggccatg ggcattttgg aaagggtctg ttgcaggagt 7560
tccaagcggt cccagagctc ggtgatgtgc tctacggcat ctcgatccag cagacctcct 7620
cgtttcgcgg gttggggcga ctgcgggagt agggcgccag acgatgggcg tccagcgcgg 7680
ccagggtccg gtccttccag ggtcgcagcg tccgcgtcag ggtggtctcc gtcacggtaa 7740
aggggtgcgc gccgggctgg gcgcttgcga gggtgcgctt caggctcatc cggctggtcg 7800
agaaccgctc ccgatcggcg ccctgtgcgt cggccaggta gcaattgacc atgagttcgt 7860
agttgagcgc ctcggccgcg tggcctttgg cgcggagctt acctttggaa gtctgcccac 7920
aggcgggaca gaggagggac ttgagggcgt agagcttggg ggcgaggaag acggactcgg 7980
gggcgtaggc gtccgcgccg cagtgggcgc agacggtctc gcactccacg agccaggtga 8040
ggtcgggctg attgggatca aaaaccagtt ttccgccgtt ctttttgatg cgtttcttac 8100
ctctggtctc catgagctcg tgtccccgct gggtgacaaa gaggctgtcc gtgtccccgt 8160
aaaccgactt tatgggtcgg tcctcgagtg ggacgccgcg gtcctcgtcg tagaggaaac 8220
ccgaccactc tgagacgaag gcccgggtcc aagccagcac gaaggaggcc acgtgggagg 8280
gatagcggtc gttatccacc agcgggtcca ccttctccag tgtatgcaaa cacatgtccc 8340
cctcgtccac atccaggaag gtgattggct tgtaagtgta ggccacgtga ccgggggtcc 8400
cggccggggg ggtataaaag ggggcgggcc gctgctcgtc ttcactgtct tccggatcgc 8460
tgtccaggag cgccagctgt tggggtaggt attccctctc aaaggcgggc atgacctccg 8520
cactcaggtt gtcagtttct agaaacgagg aggatttgat attgacggtg ccggcggaga 8580
tgcctttcaa gagcccctcg tccatctggt cagaaaagac aatctttttg ttgtcgagtt 8640
tggtggcgaa ggagccgtag agggcgttgg agaggagctt ggcgatggag cgcatggtct 8700
ggttcttttc cttgtcggcg cgctccttgg cggcgatgtt gagctgcacg tactcgcgcg 8760
ccacgcactt ccattcgggg aagacggtgg ttagctcgtc tggcacgatt ctgacctgcc 8820
agccccggtt atgcagggtg atgaggtcaa cgctggtggc cacctcgccg cgcaggggct 8880
cgttggtcca gcagaggcgg ccgcccttgc gcgagcagaa ggggggcagg gggtccagca 8940
taagctcgtc gggggggtca gcatcgatgg tgaagatgcc tggcaggagg tcggggtcga 9000
agtagcttat gcaggtgccc agatcgtcca gagaagcttg ccattcgcgc acggccagcg 9060
cgcgctcgta gggactaagg ggcgtgcccc agggcatggg gtgggtgagc gcggaggcgt 9120
acatgccgca gatgtcgtag acgtagaggg gctcatcaag gatgccaatg taggtggggt 9180
agcagcggcc cccgcggatg ctggcgcgca cgtagtcata caactcgtgc gagggggcga 9240
ggagcccggc tccgagattg gcgcggctgg gtttttcggc gcggtagacg atctgacgga 9300
agatggcgtg ggagttggag gagatggtgg gtctttggaa gatgttgaag tgggcgtggg 9360
gcaggccgac cgagtcgcgg atgaagtggg cgtaggagtc ttgcagcttg gcgacaagct 9420
cggcggtgac gaggacgtcc agggcgcagt agtcaagggt ctcttggatg atgtcatact 9480
tgagctggcc cttttgtttc cacagctcgc ggttgagaag gaactcttcg cggtccttcc 9540
agtactcttc aagggggaac ccgtcctggt cggcacggta agagcctagc atgtagaact 9600
ggttaacggc cttgtaggcg cagcagccct tctccacggg gagggcatag gcctgggcgg 9660
ccttgcgcag ggaggtgtgc gtgagggcga aggtgtccct gaccatgacc tttaggaact 9720
ggtgcttgaa gtcgatatcg tcgcagcccc cctgctccca gagctggaag tccgtgcgct 9780
tcttgtaggc ggggttgggc aaagcgaaag taacatcgtt gaagaggatc ttgcccgcgc 9840
ggggcataaa gttgcgagtg atgcggaaag gctggggcac ctcggcccgg ttgttgatga 9900
cctgggcggc gagcacgatc tcgtcgaagc cgttaatgtt gtggcccaca atgtatagtt 9960
ccacgaaccg cgggcggccc ttgacgtggg gcagtttctt gagctcctcg taggtgagct 10020
cgtcggggtc gctgagcccg tgctgctcga gggcccagtc ggcgagatgg gggttggcgc 10080
ggaggaagga agtccagaga tccacggcca gggcggtttg cagacgatcc cggtactggc 10140
ggaactgctg acccacggcc attttttcgg gggtgacgca gtagaaggtg cgggggtcgc 10200
cgtgccaacg gtcccatttt agctggaggg cgagatcaag ggcgagctca acgagccggt 10260
cgtccccgga gagtttcatg accagcatga aggggacgag ctgcttgccg aaggacccca 10320
tccaggtgta ggtttccaca tcgtaggtga ggaagagcct ttcggtgcga ggatgcgagc 10380
cgatggggaa gaactggatc tcctgccacc agttggagga atggctgttg atgtgatgga 10440
agtagaaatg ccgacggcgc gccgaacatt cgtgcttgtg tttatacaag cggccacagt 10500
gctcgcaacg ctgcacggga tgcacgtgct gcacgagctg tacctgggtt cctttgacga 10560
ggaatttcag tgggaagtgg agtcgtggcg cctgcatctg gtgctgtact acgtcgtggt 10620
ggtcggcctg gccctcttct gcctcgatgg tggtcatgct gacgagcccg cgcgggaggc 10680
aggtccagac ctcggcgcga acgggtcgga gagcgaggac gagggcgcgc aggccggagc 10740
tgtccagggt cctgagacgc tgcggagtca ggtcagtggg cagcggcggc gcgcggttga 10800
cttgcaggag tttttcaagg gcgcgcggga ggtccagatg gtacttgatc tccaccgcgc 10860
cgttggtggc gacgtcgatg gcttgcagtg tcccgtgccc ctggggagtg accaccgtcc 10920
cccgtttctt cttggcgggc ggaagcggtt tggcttccat ggttaaaagc ggcggcgagg 10980
acgcgcgccg ggcggtaggg gcggctcggg acccggaggc agtggtggca ggggcacgtc 11040
ggcgccgcgc gcgggcaggt tctggtactg cgcccggaga agactggcgt gagcgacgac 11100
gcgacggttg acgtcctgga tctgacgcct ctgggtgaag gccacgggac ccgtgagttt 11160
gaacctgaaa gacagttcga cagaatcaat ctcggtatca ttgacggcgg cctgccgcag 11220
aatctcttgc acgtcgcccg agttgtcctg gtaggcaatc tcggtcatga actgctcgat 11280
ctcctcctcc tgaaggtctc cgcggccggc gcgctccacg gtggccgcga ggtcgttgga 11340
gatgcggccc atgagctgcg agaaggcgtt catgcccgcc tcgttccaga cgcggctgta 11400
aaccacggcg ccctcgggat cgcgggcgcg catgaccacc tgggcgaggt tgagctccac 11460
gtggcgcgca aaaaccgcgt agttgcagag gcgctggtag aggtagttga gcgtggtggc 11520
aatgtgctca gtgacaaaga agtacataat ccagcggcgg agcggcattt cgctgacgtc 11580
gcccagggct tccaagcgct ccatggcctc gtaaaagtcc acggcgaagt tgaaaaactg 11640
ggagttgcgt gcagatacgg tcaagtcctc ctccagaaga cggatgagct cggcgatggt 11700
ggcgcgcacc tcgcgctcga aggctcccgt gagttcctcc acttcctcct cttcatccac 11760
taacatctct tctacttcct cctcaggcgg tggtggcggg ggagggggcc tgcgtcgccg 11820
gcggcgcacg ggcagacggt cgatgaaacg ctcgatggtc tcgccgcgcc ggcgtcgcat 11880
ggtctcggtg acggcgcgcc cgtcctcgcg gggtcgcagc gtaaagacgc cgccgcgcat 11940
ctccaggtgg cccggggggt ccccgttggg cagggagagt gcgctgacga tgcatcttat 12000
caattgcccc gtagggactc cgcgcaagga cctaagcgtc tctagatcca cgggatctga 12060
aaaccgttga acgaaggctt cgagccagtc gcagtcgcaa ggtaggctga gcacggtttc 12120
ttctggcggc ggtggggtgt gggcgggggc gatgctgctg gtgatgaagt tgaaataggc 12180
ggttctgaga cggcggatgg tggcgaggag caccaggtct ttgggcccgg cttgctggat 12240
gcgcagacgg tcggccatgc cccaggcgtg gtcctgacac ctggccaggt ccttgtagta 12300
gtcctgcatg agccgctcca cgggcacctc ctcctcgccc gcgcggccgt gcatacgcgt 12360
gagcccaaac ccgcgctgcg gctggacgag cgccaggtca gcgacgacgc gctcggcgag 12420
gatggcctgc tggatctggg tgagggtggt ctggaagtcg tcaaagtcga cgaagcggtg 12480
gtaggctccg gtgttaatgg tgtaggagca gttggccatg acggaccagt tgacagtctg 12540
gtgaccgggc cgcgcgagct cgtggtactt gaggcgcgag taggcgcgcg agtcgaagat 12600
gtagtcgttg caggtgcgca ccaggtactg gtagccgatg aggaagtgcg gcggcggctg 12660
gcggtagagc ggccatcgct cggtggcggg ggcgccgggc gctaggtcct cgagcatggt 12720
gcggtggtag ccgtagatgt accttgacat ccaggtgatg ccggcggcgg tggtggaggc 12780
gcgagggaac tcgcggacgc ggttccagat gttgcgcagc ggcaggaagt agttcatggt 12840
gggcacggtc tggcccgtga ggcgcgcgca gtcgttgatg ctctagacat acgggcaaaa 12900
acgaaagcgg tcagcggctc gactccgtgg cctggaggct aagcgaacgg gttgggctgc 12960
gcgtgtaccc cggttcgaat ctcgaatcag gctggagccg cagctaacgt ggtactggca 13020
ctcccgtctc gacccaggcc tgcacaaaac ctccaggata cggaggcggg tcgttttgca 13080
aatttttggc ggtcgaaaaa agctagtaag cgcggaaagc ggccgaccgc aatggctcac 13140
tgccgtagat tggagaagaa tcgccagggt tgcgttgcgg tgtgccccgg ttcgagaccg 13200
ctcgggtcgg ccgaattccg cggctaacga gggcgtggct gccccgtcgt ttccaagacc 13260
ccataagcca gccgacttct ccagttacgg agcgagcccc tcttttgttt tgttttttgc 13320
cagatgcatc ccgtactgcg gcagatgcgc ccccaccctc caccgcaaca gcagccccct 13380
cctacgcaac agccggcgct tctgcctccg ccccagcagc agcaacttcc agccactacc 13440
gccgcggccg ccgtgagcgg ggccgggcag agtcagtatg acctggcttt ggaagagggc 13500
gaggggctgg cgcgcctggg ggcgtcgtcg ccggagcggc acccgcgcgt gcagatgaaa 13560
agggacgctc gcgaggccta cgtgcccaag cagaacctgt tcagagacag gagcggcgag 13620
gagcccgagg agatgcgcgc agcccgtttc cacgcggggc gggagctgcg gcgcggcctg 13680
gacagaaaga gggtgctgag ggacgaggat ttcgaggcgg acgagctgac ggggatcagc 13740
cctgcgcgcg cgcacgtggc cgcggccaac ctggtcacgg cgtacgagca gaccgtgaag 13800
gaggagagca acttccaaaa atccttcaac aaccacgtgc gcaccctgat cgcgcgcgag 13860
gaggtgaccc tgggcctgat gcacctgtgg gacctgctgg aggccattgt gcagaacccc 13920
accagcaaac cgctgacggc gcagctgttc ctggtggtgc agcacagtcg ggacaacgag 13980
acttttaggg aggcgctgct gaatatcacc gagcccgagg gccgctggct tctggacctg 14040
gtgaatattc tgcagagcat cgtggtgcag gagcgcgggc tgccgctgtc cgagaagctg 14100
gcggccatca acttttcggt gctgagtttg ggcaagtact acgctaggaa gatctacaag 14160
accccgtacg tgcccataga caaggaggtg aagatcgacg ggttttacat gcgcatgacc 14220
ctgaaagtgc tgaccctgag cgacgatctg ggggtgtacc gcaacgacag gatgcgccgc 14280
gcggtaagcg ccagcaggcg gcgcgagctg agcgatcagg agctgatgca cagcctgcag 14340
cgggccctga ccggggccgg gaccgagggg gagagctact ttgacatggg cgcggacctg 14400
cactggcagc ccagccgccg ggtcttggaa gccgcggcgg tcccttacgt agaagaggtg 14460
gacgatgagg atgagggcga gtacctggaa gactgatggc gcgaccgtat ttttgctaga 14520
tgcagcaaca gccacctcct gatcccgcaa tgcgggcggc gctgcagagc cagccgtccg 14580
gcattaactc ctcggacgat tggacccagg ccatgcaacg catcatggcg ctgacgaccc 14640
gcaaccccga agcctttaga cagcagcccc aggccaaccg gctctcggcc atcctggagg 14700
ccgtggtgcc ctcgcgctcc aaccccacgc acgagaaggt gctggccatc gtgaacgcgc 14760
tggttgagaa caaggccatt cgcggcgacg aggccgggct ggtgtacaac gcactgctgg 14820
agcgcgtggc ccgctacaac agcaccaacg tgcagaccaa cctggaccgc atggtgaccg 14880
acgtgcgcga agccgtggcc cagcgcgaac ggttccaccg cgagtccaac ctgggatcca 14940
tggtggcact gaacgccttc ctcagcacgc agcccgccaa cgtgccccgg ggccaggagg 15000
actacaccaa cttcattagc gccctgcggc taatggtgac cgaggtgccc cagagcgagg 15060
tgtaccagtc gggcccggac tacttcttcc agaccagtcg ccagggcttg cagaccgtga 15120
acctgagtca ggctttcaag aacttgcagg gactgtgggg cgtgcaggct ccggtcgggg 15180
accgcgcgac ggtgtcgagc ctgctgacgc cgaactcgcg cctgctgctg ctgctggtgg 15240
cgcccttcac ggacagcggt agtatcaacc gcaactcgta cctgggctac ctgattaacc 15300
tgtaccgcga ggccattggc caggcgcacg tggacgagca gacctaccag gagattaccc 15360
acgtgagccg cgcccttggc caggacgacc cgggcaatct ggaagccacc ctgaacttct 15420
tgctgaccaa ccggtcgcag aagatcccgc cccagtacgc gctgagcgcc gaggaggagc 15480
gtatattgag atacgtgcag caaagtgtgg gactgttcct gatgcaggag ggggccaccc 15540
ccagcgccgc gctcgacatg accgcgcgca acatggagcc cagcatgtac gccagtaatc 15600
gcccgtttat taataagctg atggactacc tgcatcgggc ggccgccatg aactctgact 15660
atttcaccaa cgccatcctg aacccccact ggctcccgcc gccggggttc tacacgggcg 15720
agtacgacat gcccgacccc aatgacgggt ttctgtggga cgacgtggac agcagcgtgt 15780
tctccccccg accgggtgct aacgagcgcc ccttgtggaa gaaagagggc agcgaccggc 15840
gcccgtcctc ggcgctgtcc ggccgcacgg gtgctgccgc agcggtgccc gaggccgcca 15900
gtccctttcc gagcttgtca ctgaacagcg tccgcagtag cgagctgggc aggatcacgc 15960
gcccgcgctt gctgggcgag gaggagtact taaataactc gctgttgagg cccgagcggg 16020
agaagaactt ccccaataac gggatagaga gtctggtgga taagatgagc cgctggaaga 16080
cgtacgcgca tgagcacagg gacgatcccc gggcaacgca gggggccacc agccggggca 16140
gtgccgcccg taaacgccgc tggcacgaca ggcagcgggg actgatgtgg gacgatgagg 16200
attccgccga cgacagcagc gtgttggact tgggcgggag tggtggtggt aacccgttcg 16260
ctcacctgcg cccccgcgtc gggcgcctga tgtaaaaaga aaccaaaaat aaatggtact 16320
caccaaggcc atggcgacca gcgtgcgttc gtttcttctc tgttgtatct agtatgatga 16380
ggcgtgcgta cccggagggt cctcctccct cgtacgagag cgtgatgcag caggcaatgg 16440
cggcggcggc ggcgatgcag cccccgctgg aggctcctta cgtgccaccg cggtacctgg 16500
cgcctacgga ggggcgaaac agcattcgtt actcggagct ggcacccttg tacgatacca 16560
cccggttgta cctggtggac aacaagtcgg cggacatcgc ctcgctgaac taccagaacg 16620
accacagcaa ctttctgacc accgtggtgc agaacaacga tttcaccccc acggaggcca 16680
gcacccagac catcaacttt gacgagcgct cgcggtgggg cggtcagctg aaaaccatca 16740
tgcataccaa catgcccaac gtgaacgagt tcatgtacag caacaagttc aaggcgcggg 16800
tcatggtctc ccgcaagacc cccaacgggg tgacagtagg ggatgattat gatggtagtc 16860
aggatgagct gaaatacgag tgggtggagt ttgagctgcc cgaaggcaac ttctcggtga 16920
ccatgaccat tgacctgatg aacaacgcca tcatcgacaa ttacttggca gtggggcggc 16980
agaacggggt gctggagagc gacatcggcg tgaagttcga cacccggaac ttcaggctgg 17040
gttgggaccc cgtgaccgag ctggtcatgc ccggggtgta caccaacgag gccttccacc 17100
ccgacatcgt gctgttgccc ggctgcgggg tggactttac cgagagccgc ctcagtaata 17160
tgctgggcat ccgcaagagg cagcccttcc aggagggttt ccagatcatg tacgaggacc 17220
tggatggagg taacatcccc gcgctcttgg atgtcgaggc ctatgagaaa agcaaggagg 17280
agagcgtcgc cgcgtcaacc gcagccgtag ccaccgcctc taccgaggtc cggggcgata 17340
attttgctag cgccgcagca gtggcggcgg ccaaggctga tgaaaccgaa agtaagatag 17400
ttattcagcc ggtggagaag gatagcaagg ataggagcta caacgtgctc tcggacaaga 17460
aaaacaccgc ctaccgcagc tggtacctgg cctacaacta tggcgaccac gagaagggcg 17520
tgcgctcctg gacgctgctc accacctcgg acgtcacctg cggcgtggag caagtctact 17580
ggtcgctgcc cgacatgatg caagacccgg tcaccttccg ctccacgcgt caagttagca 17640
actacccggt ggtgggcgcc gagctcatgc ccgtctactc caagagcttc ttcaacgagc 17700
aggccgtcta ctcgcagcag ctgcgcgcct tcacctcgct cacgcacgtc ttcaaccgct 17760
tccctgagaa ccagatcctc gtccgcccgc ccgcgcccac cattaccacc gtcagtgaaa 17820
acgttcctgc tctcacagat cacgggaccc tgccgctgcg cagcagtatc cggggagtcc 17880
agcgcgtgac cgttactgac gccagacgcc gcacctgccc ctacgtctac aaggccctgg 17940
gcatagtcgc gccgcgcgtc ctctcgagcc gcaccttcta aaaaatgtcc attctcatct 18000
cgcccagtaa taacaccggt tggggtctgc gcgcgcccag caagatgtac ggaggcgctc 18060
gccaacgctc cacgcaacac cccgtgcgcg tgcgcgggca cttccgcgct ccctggggcg 18120
ccctcaaggg ccgcgtgcgg tcgcgcacca ccgtcgacga cgtgatcgac caggtggtgg 18180
ccgacgctcg caactacacc cccgccgccg cgcccgtctc caccgtggac gccgtcattg 18240
acagcgtggt gtccgacgcg cgccggtacg cccgcgccaa gagccggcgg cggcgcatcg 18300
cccggcggca ccgtagcacc accgccatgc gtgcggcgcg agccttgctg cgcagggcca 18360
ggcgcacggg acgcagggcc atgctcaggg cggccagacg cgcggcttca ggcgccagcg 18420
ccggcaggac tcggagacgc gcggccacgg cggcggcagc ggccatagcc agcatgtccc 18480
gcccgcggcg agggaacgtg tactgggtgc gcgacgccgc caccggtgtg cgcgtgcccg 18540
tgcgcacccg cccccctcgc acttgaagat gttcacttcg cgatgttgat gtgtcccagc 18600
ggcgaggaga aggatgtcca agcgcaaatt caaggaagag atgctccagg tcatcgcgcc 18660
tgagatctac ggccccgcgg cggcggtgaa ggatgaaaga aatccccgca aaatcaagcg 18720
ggtcaaaaag gacaaaaagg aagaagatga tgtggacgat atggtagagt ttgtgcgcga 18780
gtttgccccc cggaggcgcg tgcagtggcg cgggcggaaa gtgcgtccgg tgctgagacc 18840
cggcaccacg gtggttttcg cgcctggcga gcggtccggc acgacatcca agcgctccta 18900
cgatgaggtg tacggggacg aggatattct cgagcaggcg gccgagcgcc tgggcgagtt 18960
tgcttacggc aagcgcaacc gccttgcgcc cctgaaggaa gaggtggtgt ccatcccgct 19020
ggaccacggc aaccccacgc cgagtcttaa gcccgtgacc ctgcagcagg tgctgccgag 19080
cgcggcgccg cgtcggggct tgaagcgcga gggcgaggat gtgtacccca ccatgcagct 19140
gatggtgccc aagcgccaga agctggaaga cgtgctggag accatgaagg tggacccgga 19200
cgtgcagccc gaggtcaagg tgaggcccat caagcaggtg gccccgggcc ttggcgtgca 19260
gaccgtggac atcaagatcc ccacggagcc catggaaacg cagaccgagg tcgtgaagcc 19320
catcaccagc accatggagg tgcagacgga tccttggatg ccggcggcgc cccgaaaacc 19380
ccggcgcaag tacggcgcgg ccagcctgct gatgcccaac tacgcgctgc atccttccat 19440
catccccacg ccgggctacc gcggcacgcg cttctaccac ggctataccg gctcccgccg 19500
ccgcaagacc accacccgcc gccgtcgtcg ccgcacagct gcaactcccg ctgccgccct 19560
ggtgcggaga gtgtaccgcc gcggccgcgc gcctctgacc ctgccgcggg cgcgctacca 19620
cccgagcatt accatttaac tttgccgtcg cctttgcaga tatggctctc acatgccgca 19680
ttcgcgtccc cattacgggc taccgaggaa gaaaaccgcg ccgtagaagg ctggcgggaa 19740
gcgggatgcg ccgccacccc caccggcggc ggcgcgccat cagcaagcgg ttggggggag 19800
gcttcctgcc cgcgctgatc cccatcatcg ccgcggcgat cggggcgatc cccggcattg 19860
cttccgtggc ggtgcaggcc tctcagcgcc actgagacac acacttggaa attgtaataa 19920
acccgaatgg actctgacgc tcctggtcct gtgatgtgtt tttgtagaca gatggaagac 19980
atcaattttt cgtccctggc tccgcgacac ggcacgcggc cgtttatggg cacctggagc 20040
gacatcggca ccagccaact gaacgggggc gccttcaatt ggagcagtct ctggagcggg 20100
cttaagaatt ttgggtccac gcttaaaacc tatggcagca aggcgtggaa cagcaccaca 20160
gggcaggcgc tgagagataa gctgaaagag cagaacttcc agcagaaggt agtcgatggc 20220
ctcgcctcag gcatcaacgg ggtggtggac ctggccaatc aggccgtgca gcggcagatc 20280
aacagccgcc tggacccggt tccccccgcc ggctccgtgg agatgccgca ggtggaggag 20340
gagctgcctc ccctggacaa gcggggcgac aagcgtcccc gtcccgacgc ggaggagacg 20400
ctgctgacgc acacggacga accgcccccg tacgaggagg cggtgaaact gggcctgccc 20460
accacgcgtc ccattgcgcc tctagctacc ggggtgctga aacccgagag tagtaagccc 20520
gcgaccttgg acttgcctcc tccgcccact ccccgcccct ccacagtggc taagcccctg 20580
ccgccggtgg ccgtggcccg cgcgcgaccg ggggctcgcc ctcaggcgaa ctggcagagc 20640
actctgaaca gcatcgtggg tctgggagtg cagagtgtga agcgccgccg ctgttattaa 20700
aaaacactgt agcgcttaac ttgcttgtct gtgtatatgt gtatgtccgc cgccgctgct 20760
gtccagaagg aggagtgaag agaaaggcgc gtcgtcgagt tgcaagatgg ccaccccatc 20820
gatgctgccc cagtgggcgt acatgcacat cgccggacag gacgcttcgg agtacctgag 20880
tccgggtctg gtgcagttcg cccgcgccac agacacctac ttcagtctgg ggaacaagtt 20940
taggaacccc acggtggcgc ctacccacga tgtgaccacc gaccgcagcc agcggctgac 21000
gctgcgcttt gtgcccgtgg accgggagga caacacctac tcgtacaaag tgcgctacac 21060
gctggccgtg ggcgacaacc gcgtgctgga catggccagc acctactttg acatccgcgg 21120
cgtgctggat cggggcccta gcttcaaacc ctactccggc actgcctaca acagcctggc 21180
tcccaaggga gcgcccaaca cctgccagtg gaaggattct gacagcaaaa tgcatacctt 21240
tggggcagct gccatgcccg gtgttactgg gaaaaagata gaagctgatg ggctgcctat 21300
tagaatagat tcaacttctg gaactgacac agtaatttat gctgataaaa ctttccaacc 21360
agaaccacaa gttggaaatg acagttgggt tgacaccaat ggtgcagagg aaaaatatgg 21420
aggcagagct ctaaaggaca ctacaaaaat gaaaccctgt tatggttcat tcgccaagcc 21480
taccaacaaa gaaggtggtc aggctaactt aaaagattca gaacccgccg ccaccactcc 21540
taactatgat atagacctgg ctttctttga cagcaaaact attgttgcta actacgatcc 21600
agatattgta atgtacacag aaaatgttga cttgcagact ccagatactc atattgtata 21660
caaacctgga acagaggaca ccagctctga atccaatttg ggtcagcagg ccatgcctaa 21720
cagacccaac tacattggct tcagagacaa ttttatcggg ctcatgtact acaacagcac 21780
tggcaatatg ggggtgctgg ccggtcaggc ctctcagctg aatgctgtgg ttgacttgca 21840
agacagaaac actgaactgt cctaccagct cttgcttgac tctctgggtg acagaacccg 21900
gtatttcagt atgtggaatc aggcggtgga cagctatgat cctgatgtgc gcattattga 21960
aaaccatggt gtggaggatg aattgccaaa ctattgcttt ccgttgaatg gtgtgggatt 22020
gacagacact taccagggtg ttaaagttaa aacagatgca ggttctgaaa agtgggacaa 22080
agatgacacc acagttagta atgctaatga aatccatgta ggcaatcctt ttgccatgga 22140
aatcaacatc caagccaacc tgtggaggaa cttcctctat gccaatgttg ccctctattt 22200
gcctgataaa tacaaataca caccggccaa catcaccctg cccaccaaca ccaacaccta 22260
cgagtacatg aacggccggg tggtggcgcc ctcgctggtg gacgcctaca ttaacattgg 22320
ggcgcgctgg tcgctggacc ccatggacaa cgtaaatccc ttcaaccacc accgcaatgc 22380
gggcttgcgc taccgctcca tgctcctggg caacgggcgc tacgtgccat tccacatcca 22440
ggtgccccag aaattttttg ccattaagag cctcctgctc ctgcccgggt cctacaccta 22500
cgagtggaac ttccgcaagg acgtcaacat gatcctgcag agttcccttg gcaacgacct 22560
gcgcacagac ggggcctcca tcaccttcac cagcattaac ctctacgcca ccttcttccc 22620
catggcgcac aacaccgcct ccacgcttga ggccatgctg cgcaacgaca ccaatgacca 22680
atccttcaac gactacctct cggcggccaa catgctctat cccatcccgg ccaacgccac 22740
caacgtgccc atctccatcc cctcgcgcaa ctgggccgcc tttcgcggct ggtccttcac 22800
gcgtctcaag accaaagaga cgccctcgct gggctccggg ttcgacccct acttcgtcta 22860
ctcgggctcc atcccctacc tcgacggcac cttctacctc aaccacacct tcaagaaggt 22920
ctccatcacc ttcgactctt ccgtcagctg gcccggcaac gaccggctcc tgacgcccaa 22980
cgagttcgaa atcaagcgca ccgtcgacgg cgagggatac aacgtggccc agtgcaacat 23040
gaccaaggac tggttcctgg tccagatgct ggcccactac aacatcggct accagggctt 23100
ctacgtgccc gagggctaca aggaccgcat gtactccttc ttccgcaact tccagcccat 23160
gagccgccag gtggtggacg aggttaacta caaggactac caggccgtca ccctggccta 23220
ccaacacaac aactcgggct tcgttggata cctcgcgccc actatgcgcc agggccagcc 23280
ctaccccgcc aactacccct acccgctcat cggcaagagc gccgttacca gcgtcaccca 23340
gaaaaagttc atctgcgaca gggtcatgtg gcgcatcccc ttctccagca acttcatgtc 23400
catgggcgcg ctcaccgacc tcggccagaa catgctctat gctaactccg cccacgcgct 23460
agacatgaat ttcgaagtcg accccatgga tgagtccacc cttctctatg ttgtcttcga 23520
agtcttcgac gtcgtccgag tgcaccagcc ccaccgcggc gtcattgagg ccgtctacct 23580
gcgcaccccc ttctcagccg gtaacgccac cacataaatt cttgcttctt gcaagaagcc 23640
atggccgcgg gctccggcga gcaggagctc agggccatca tccgcgacct ggggtgcggg 23700
ccctacttcc tgggcacctt cgataagcga ttcccgggat tcatggcccc gcacaaggtg 23760
gcctgcgcca tcgtcaacac ggccggccgc gagaccgggg gcgagcattg gctggccttc 23820
gcctggaacc cgcgctcgaa cacctgctac ctcttcgacc ccttcgggtt ctcggaccag 23880
cgcctcaagc aaatctacca gttcgagtac gagggactgc tgcgccgcag cgccctggcc 23940
accaaggacc gctgcgttac cctggaaaag tccacccaga ccgtgcaggg tccgcgttcg 24000
gccgcctgcg ggcttttctg ctgcatgttc ctacacgcct tcgtgcactg gcccaaccgc 24060
cccatggaca aaaatcccac catgaacttg ctgacggggg tgcccaacgg catgctccag 24120
tcgccccagg tggaacctac cctgcgccgc aaccaggagg cactctaccg cttcctcaac 24180
tcccactctg catactttcg ctctcaccgc gcgcgcattg agaaggccac cgccttcgac 24240
cgcatgaatc aagacatgta acagtgtgtt ttaaaatatg tttaataaac agcacttttt 24300
atgtgacaca tgcatttgag ataattttat tcttaaaaat cgaaggggtt ctgccgggag 24360
gtttcggcat ggcccgcggg cagggacacg ttgcggaact ggtacttggc cagccacttg 24420
aactcgggga tcagcagttt cggcagcagg gtgtcgggga acgagtcggt ccacagcttc 24480
cgcgtcagtt gcagggcgcc cagcaggtcg ggcgcggaga tcttgaaatc gcagttggga 24540
cccgcgtttt gcgcgcgaga gttgcggtac acagggttgc agcactggaa caccatcagg 24600
gccggatgct tcacgctcgc cagcaccgta gcgtcggtga tcccgtccac gtcgaggtct 24660
tcggcgttgg ccatcccgaa gggggtcatc ttgcaggtct gccggcccat ggtgggcacg 24720
cagccgggct tgtggttgca atcgcagtgc agggggatca gcatcatctg ggcctggtcg 24780
gcgttcatcc ccgggtacat ggccttcatg aaagcctcca gctgcttaaa cgcctgctgg 24840
gccttggctc cctcggtgaa gaagaccccg caggacttgc tagaaaactg gttggtagcg 24900
cacccggcgt cgtgcacgca gcagcgcgcg tcgttgttgg ccagctgcac cacgctgcgc 24960
ccccagcggt tctgggtaat cttggcccgg tcggggttct cctttagcgc gcgttgcccg 25020
ttctcgcttg ccacatccat ctcgatcatg tgctccttct ggatcatggt ggtcccgtgc 25080
aggcaccgca gcttgccctc gacttcggta cagccgtgca gccacagcgc gcaccccgtg 25140
ctctcccagt tcttgtgggc gatctgggaa tgcgcatgca cgaacccctg caggaagcgg 25200
cccatcatgg tcgtcagggt cttgttactg gtaaaggtca gcggaatgcc gcggtgctcc 25260
tcgttgatgt acaggtggca gatgcggcga tacacctcgc cctgctcggg catcagttgg 25320
aagttggatt ttaggtcgct ttccacacgg tagcgctcca tcagcatatt catgatttcc 25380
atgcccttct cccaggccga tacaatgggc aggctcaggg ggttcgtcac cgccatctta 25440
gcgctagcag ccttcgtcag cgggtcgttc tcattgagag tctcaaagct ccgcttgccg 25500
tccttctcgg tgatccgcac gggggggtag ctgaagccca cggccgccag ctcctcctcg 25560
gcctctcttt cgtcctcgct gtcctggctg acgtcctgca ggggcacatg cttcgttttg 25620
cggggtttct ttttgggcgg ctgctgcggc ggcggtggtt gttcctgagg cgagggggag 25680
cgcgagttct cgctcaccac tactatctct tcttcttggt ccgaggccac gcggcggtag 25740
gtatgtctct tcaggggcag aggcggaggc gacgggctct cgcggcccgg cgggtggctg 25800
gcagagcccc ttccgcgatc gggggtgcgc tcccggcggc gctctaactg acttcctccg 25860
cggccggcca ttgtgttctc ctagggaaca acaacaagca tggagactca gccatcgtcg 25920
ccaacctcgc catctgcccc caccgccgac aagaagcagc agcagaatga gagcttaacc 25980
gccccgccgc ccagccccgc cacctttgtc gcggccccag acatgcaaga gatggaggaa 26040
tccattcaga ttgacctggg ctatgtgacg cccgcggagc acgaggagga gcttgcagtg 26100
cgcttttcaa cccaggaaga gatacaccaa gaacagccag agcaggaagc aaagagcgag 26160
catgactacc tccaccagag cgggggggag gacgccctca tcaagcatct ggcccggcag 26220
gccatcatcg tcaaggacgc gctgcttgac cgcaccgagg tgcccctcag cgtggaggag 26280
ctcagccgcg cctacgagct caacctcttc tcgccgcgcg tgccccccaa gcgccagccc 26340
aacggcacct gcgagcccaa cccacgcctc aacttctacc cggtcttcgc ggtgcccgag 26400
gccctggcca cctaccacat ctttttcaag aaccaaagga tccctgtctc ctgtcgcgcc 26460
aaccgcaccc gcgccgactc ccttttcaac ctgggccccg gtgcccgcct acctgatatc 26520
gcctccttgg aagaggttcc caagatcttc gagggtctgg gcagcgacga gactcgggcc 26580
gcaaacgctc tgcaaggaga aggaggagat catgagcacc acagcgccct ggtggagttg 26640
gaaggcgaca acgcgcgtct ggcggtgctc aagcgcacga tcgagctgac ccatttcgcc 26700
tacccggcgc ttaacctgcc ccccaaagtc atgagcacgg ttatggatca ggtgctcatc 26760
aagcgcgcgt cgcccatctc caaggagatg caagaccccg agagctccga ggagggcaag 26820
cccgtggtca gcgacgagca gctggcgcgg tggctgggac cccaagctag tccccagagc 26880
ttggaagagc ggcgcaagct cataatggcc gtggtcctgg tgaccgcgga gctggagtgt 26940
ctgcgccgct tcttcgccga cgcagaaatt ctgcgcaagg tcgaggagaa cctgcactac 27000
atcttcaggc acgggttcgt acgccaggcc tgcaagatct ccaacgtgga gctgaccaac 27060
ctggtctcct acatgggcat cttgcacgag aaccgcctgg ggcagaacgt gctgcacacc 27120
accctgcgcg gggaggcccg ccgcgactac atccgcgact gcgtttacct ctacctctgc 27180
cacacctggc agacagccat gggcgtgtgg cagcagtgtc tggaggagca gaacctaaaa 27240
gagctctgca agctcctgca gaagaacctc aaggccctgt ggaccgggtt cgacgagcgc 27300
accaccgcct cggacctggc agacctcatt ttccccgagc gtctcaggct gacgctgcgc 27360
aacggtttgc ccgactttat gagtcaaagc atgttgcaaa actttcgctc tttcatcctc 27420
gaacgctccg ggatcctgcc ggccacctgc tccgcgctgc cctcggactt cgtgccgctg 27480
accttccgcg agtgcccccc gccgctgtgg agccactgct acctgctgcg cttggccaac 27540
tacctggcct accactcgga cgtgatcgag gacgtcagca gcgagggcct gctcgagtgc 27600
cactgccgct gcaacctctg cacgccgcac cgctccctgg cctgcaaccc ccagctgctg 27660
agcgagaccc agatcatcgg caccttcgag ttgcaagggc ccggcgatga gggttctgcc 27720
gccaaggggg gtctgaaact caccccgggg ctgtggacct cggcctactt gcgcaagttc 27780
gtgcccgagg actaccatcc cttcgagatc aggttctacg aggaccaatc ccagccgccc 27840
aaggccgagc tgtcggcctg cgtcatcacc cagggggcga tcctggccca attgcaagct 27900
atccagaaat cccgccaaga attcttgctg aaaaagggcc gcggggtcta ccttgatccc 27960
cagaccggtg aggagcttaa ccccggcttc ccccaggatg ccccgaggaa gcagcaagaa 28020
gctgaaagtg gagctgccgc ccgtggagga tttggaggaa gactgggaga gcagtcaggc 28080
agaggaggag gagatggaag actgggacag cactcaggca gaggacagcc tgcaagacag 28140
tctggaagac gaggaggagg cagaggaggt ggaagaagta gccgccgccg ccagaccgtc 28200
gtcctcggcg gagaaagcaa gcagcacgga taccatctcc gctccgggtc ggggtcccgc 28260
tcgaccccac agtagatggg acgagaccgg gcgattcccg aaccccacca cccagaccgg 28320
taagaaggag cggcagggat acaagtcctg gcgggggcac aaaaacgcca tcgtctcctg 28380
cttgcaagct tgcgggggca acatctcatt cacccggcgc tacctgctct ttcaccgcgg 28440
ggtgaacttc ccccgcaaca tcttgcatta ctaccgtcac ctccacagcc cctactactt 28500
ccaagaagag gcagaaaaag acaaaaccag cagctagaaa atccacagcg gcggcggcgg 28560
caggtggact gaggatcgcg gcgaacgagc cggcgcagac ccgggaactg aggaaccgga 28620
tctttcccac cctctatgcc atcttccagc agagtcgggg gcaggagcag gaactgaaag 28680
tcaagaaccg ttctctgcgc tcgctcaccc gcagttgtct gtatcacaag agcgaagacc 28740
aacttcagcg cacgcttgag gacgccgagg ctctcttcaa caagtactgc gcactcactc 28800
ttaaagagta gcccgcgccc gcccacacac ggaaaaaggc gggaattacg tcacctgtgc 28860
acccccaccc agcaccgcta tgagcaaaga aattcccacg ccttacatgt ggagctacca 28920
gccccagatg ggcctggccg ccggcgccgc ccaggactac tccacccgca tgaattggct 28980
cagcgccggg cccgggatga tctcacgggt gaatgacatc cgcgcccacc gaaaccagat 29040
actcctagaa cagtcagcgc tcaccgccac gccccgcaat cacctcaatc cgcgtaattg 29100
gcccgccgcc ctagtgtacc aggaaattcc ccagcccacg accgtactac ttccgcgaga 29160
cgcccaggcc gaagtccagc tgactaactc aggtgtccag ctggcgggcg gcgccaccct 29220
gtgtcgtcac caccccgctc agggtataaa gcggctggtg atccggggca gaggcacaca 29280
gctcaacgac gaggtggtga gctcttcact gggtttgcga cctgacggag tcttccaact 29340
cgccggatcg ggaagatctt ttcggggcaa catctcattc acccggcgct acctgctctt 29400
tcaccgcggg gtgaacttcc cccgcaacat cttgcattac taccgtcacc tccacagccc 29460
ctactacttc caagaagagg cagaaaaaga caaaaccagc agctagaaaa tccacagcgg 29520
cggcggcggc aggtggactg aggatcgcgg cgaacgagcc ggcgcagacc cgggaactga 29580
ggaaccggat ctttcccacc ctctatgcca tcttccagca gagtcggggg caggagcagg 29640
aactgaaagt caagaaccgt tctctgcgct cgctcacccg cagttgtctg tatcacaaga 29700
gcgaagacca acttcagcgc acgcttgagg acgccgaggc tctcttcaac aagtactgcg 29760
cactcactct taaagagtag cccgcgcccg cccacacacg gaaaaaggcg ggaattacgt 29820
cacctgtgca cccccaccca gcaccgctat gagcaaagaa attcccacgc cttacatgtg 29880
gagctaccag ccccagatgg gcctggccgc cggcgccgcc caggactact ccacccgcat 29940
gaattggctc agcgccgggc ccgggatgat ctcacgggtg aatgacatcc gcgcccaccg 30000
aaaccagata ctcctagaac agtcagcgct caccgccacg ccccgcaatc acctcaatcc 30060
gcgtaattgg cccgccgccc tagtgtacca ggaaattccc cagcccacga ccgtactact 30120
tccgcgagac gcccaggccg aagtccagct gactaactca ggtgtccagc tggcgggcgg 30180
cgccaccctg tgtcgtcacc accccgctca gggtataaag cggctggtga tccggggcag 30240
aggcacacag ctcaacgacg aggtggtgag ctcttcactg ggtttgcgac ctgacggagt 30300
cttccaactc gccggatcgg gaagatcttc cttcacgcct cgtcaggccg tgctgacttt 30360
ggagagttct tcctcgcaac ctcgctcggg cggcatcggc actctccagt ttgtggagga 30420
gttcactccc tcggtctact tcaacccctt ctccggctcc cccggccact atccggacga 30480
gttcatcccg aacttcgatg ccatcagcga atcggtagac ggctacgatt gaatgtccca 30540
tggtggcgcg gctgacctag ctcggcttcg acacctggac cactgccgcc gctttcgctg 30600
cttcgctcgg gacctcgccg agtttaccta ctttgagctg tccgaggagc accctcaggg 30660
cccggcccac ggagtgcgga tcgtcgtcga agggggccta gactcccacc tgcttcgtat 30720
cttcagccag cgcccgatcc tggtccagcg ccaacagggc aacaccctcc tgacccttta 30780
ctgcatctgc aaccaccccg gcctgcacga aagtctttgt tgtctgctgt gtactgagta 30840
taataaaagc tgagatcagc gactactccg gactcgattg tgttccagca gtctggcgat 30900
accaagggtt gcatccactg ctcctgcgac tcccccgagt gcgttcacac cctcatcaag 30960
accctatgcg gcctccgcga cctcctcccc atgaactaat caactaaccc cttaccccat 31020
tacccatcca gtaaaaaaaa taaagattaa agagacgatg attttgaatt actagttatt 31080
aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc cgcgttacat 31140
aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa 31200
taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg 31260
agtatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc 31320
cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct 31380
tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt accatggtga 31440
tgcggttttg gcagtacatc aatgggcgtg gatagcggtt tgactcacgg ggatttccaa 31500
gtctccaccc cattgacgtc aatgggagtt tgttttggca ccaaaatcaa cgggactttc 31560
caaaatgtcg taacaactcc gccccattga cgcaaatggg cggtaggcgt gtacggtggg 31620
aggtctatat aagcagagct cactgtcttc cggatcgctg tccaggagcg ccagctgttg 31680
ggctcgcggt tgagaaggaa ctcttcgcgg tccttccagt actcttcaag ggggaacccg 31740
tcctggtcgg cacgggactc cgcgcaagga cctaagcgtc tccagatcca cgggatctga 31800
aaaccgttga acgaaggctt cgagccagtc gcagtcgcaa gtctagagcc accatgttcg 31860
tcttcctggt cctgctgccc ctggtctcat ctcagtgcgt gaatctgact acaagaactc 31920
agctgcctcc cgcctacacc aattccttca cccggggcgt gtactatcct gacaaggtgt 31980
ttagaagctc cgtgctgcac tctacacagg atctgtttct gccattcttt agcaacgtga 32040
cctggttcca cgccatccac gtgagcggca ccaatggcac aaagcggttc gacaatcccg 32100
tgctgccttt taacgatggc gtgtacttcg cctctaccga gaagagcaac atcatcagag 32160
gctggatctt tggcaccaca ctggactcca agacacagtc tctgctgatc gtgaacaatg 32220
ccaccaacgt ggtcatcaag gtgtgcgagt tccagttttg taatgatccc ttcctgggcg 32280
tgtactatca caagaacaat aagagctgga tggagtccga gtttagagtg tattctagcg 32340
ccaacaattg cacatttgag tacgtgtccc agcctttcct gatggacctg gagggcaagc 32400
agggcaattt caagaacctg agggagttcg tgtttaagaa tatcgatggc tacttcaaga 32460
tctactctaa gcacaccccc atcaacctgg tgcgcgacct gcctcagggc ttcagcgccc 32520
tggagccact ggtggatctg cctatcggca tcaacatcac ccggtttcag acactgctgg 32580
ccctgcacag aagctacctg acacccggcg actcctctag cggatggacc gcaggagcag 32640
cagcctacta tgtgggctat ctgcagccta ggaccttcct gctgaagtac aacgagaatg 32700
gcaccatcac agacgcagtg gattgcgccc tggaccccct gagcgagaca aagtgtacac 32760
tgaagtcctt taccgtggag aagggcatct atcagacatc caatttcagg gtgcagccaa 32820
ccgagtctat cgtgcgcttt cctaatatca caaacctgtg cccatttggc gaggtgttca 32880
acgcaaccag gttcgcaagc gtgtacgcat ggaataggaa gcgcatctct aactgcgtgg 32940
ccgactatag cgtgctgtac aactccgcct ctttcagcac ctttaagtgc tatggcgtgt 33000
cccccacaaa gctgaatgac ctgtgcttta ccaacgtgta cgccgattct ttcgtgatca 33060
ggggcgacga ggtgcgccag atcgcacctg gacagacagg caagatcgcc gactacaatt 33120
ataagctgcc agacgatttc accggctgcg tgatcgcctg gaacagcaac aatctggatt 33180
ccaaagtggg cggcaactac aattatctgt accggctgtt tagaaagagc aatctgaagc 33240
ccttcgagag ggacatctct acagagatct accaggccgg cagcacccct tgcaatggcg 33300
tggagggctt taactgttat ttcccactgc agtcctacgg cttccagccc acaaacggcg 33360
tgggctatca gccttaccgc gtggtggtgc tgagctttga gctgctgcac gcaccagcaa 33420
cagtgtgcgg acccaagaag tccaccaatc tggtgaagaa caagtgcgtg aacttcaact 33480
tcaacggcct gaccggaaca ggcgtgctga ccgagtccaa caagaagttc ctgccatttc 33540
agcagttcgg cagggacatc gcagatacca cagacgccgt gcgcgaccca cagaccctgg 33600
agatcctgga tatcacaccc tgctctttcg gcggcgtgag cgtgatcaca ccaggaacca 33660
atacaagcaa ccaggtggcc gtgctgtatc aggacgtgaa ttgtaccgag gtgcctgtgg 33720
ccatccacgc cgatcagctg accccaacat ggcgggtgta cagcaccggc tccaacgtgt 33780
tccagacaag agcaggatgc ctgatcggag cagagcacgt gaacaattcc tatgagtgcg 33840
acatcccaat cggcgccggc atctgtgcct cttaccagac ccagacaaac tctccaagga 33900
gagcacggag cgtggcatcc cagtctatca tcgcctatac catgtccctg ggcgccgaga 33960
attctgtggc ctactctaac aatagcatcg ccatcccaac caacttcaca atctctgtga 34020
ccacagagat cctgcccgtg tccatgacca agacatctgt ggactgcaca atgtatatct 34080
gtggcgattc taccgagtgc agcaacctgc tgctgcagta cggcagcttt tgtacccagc 34140
tgaatagagc cctgacaggc atcgccgtgg agcaggataa gaacacacag gaggtgttcg 34200
cccaggtgaa gcagatctac aagacccccc ctatcaagga ctttggcggc ttcaattttt 34260
cccagatcct gcctgatcca tccaagcctt ctaagcggag ctttatcgag gacctgctgt 34320
tcaacaaggt gaccctggcc gatgccggct tcatcaagca gtatggcgat tgcctgggcg 34380
acatcgcagc acgggacctg atctgtgccc agaagtttaa tggcctgacc gtgctgccac 34440
ccctgctgac agatgagatg atcgcacagt acacaagcgc cctgctggca ggaaccatca 34500
catccggatg gaccttcggc gcaggagccg ccctgcagat cccctttgcc atgcagatgg 34560
cctataggtt caacggcatc ggcgtgaccc agaatgtgct gtacgagaac cagaagctga 34620
tcgccaatca gtttaactcc gccatcggca agatccagga cagcctgtcc tctacagcct 34680
ccgccctggg caagctgcag gatgtggtga atcagaacgc ccaggccctg aataccctgg 34740
tgaagcagct gagctccaac ttcggcgcca tctctagcgt gctgaatgat atcctgagcc 34800
ggctggacaa ggtggaggca gaggtgcaga tcgaccggct gatcacaggc agactgcagt 34860
ctctgcagac ctatgtgaca cagcagctga tcagggcagc agagatcagg gcaagcgcca 34920
atctggcagc aaccaagatg tccgagtgcg tgctgggcca gtctaagaga gtggactttt 34980
gtggcaaggg ctatcacctg atgtccttcc ctcagtctgc cccacacggc gtggtgtttc 35040
tgcacgtgac ctacgtgccc gcccaggaga agaacttcac cacagcccct gccatctgcc 35100
acgatggcaa ggcccacttt ccaagggagg gcgtgttcgt gtccaacggc acccactggt 35160
ttgtgacaca gcgcaatttc tacgagcccc agatcatcac cacagacaat accttcgtga 35220
gcggcaactg tgacgtggtc atcggcatcg tgaacaatac cgtgtatgat ccactgcagc 35280
ccgagctgga cagctttaag gaggagctgg ataagtactt caagaatcac acctcccctg 35340
acgtggatct gggcgacatc agcggcatca atgcctccgt ggtgaacatc cagaaggaga 35400
tcgaccgcct gaacgaggtg gccaagaatc tgaacgagag cctgatcgat ctgcaggagc 35460
tgggcaagta tgagcagtac atcaagtggc catggtacat ctggctgggc ttcatcgccg 35520
gcctgatcgc catcgtgatg gtgaccatca tgctgtgctg tatgacatcc tgctgttctt 35580
gcctgaaggg ctgctgtagc tgtggctcct gctgtaagtt tgatgaggac gattccgaac 35640
ccgtgctgaa gggagtgaag ctgcattaca cctgaggatc cctcgagctg tgccttctag 35700
ttgccagcca tctgttgttt gcccctcccc cgtgccttcc ttgaccctgg aaggtgccac 35760
tcccactgtc ctttcctaat aaaatgagga aattgcatcg cattgtctga gtaggtgtca 35820
ttctattctg gggggtgggg tggggcagga cagcaagggg gaggattggg aagacaatag 35880
caggcatgct ggggatgcgg tgggctctat ggtgatcaat aaagaatcac ttacttgaaa 35940
tctgaaacca ggtctctgtc catgttttct gtcagcagca cttcgctccc ctcttcccag 36000
ctctggtact gcaggccccg gcgggctgca aacttcctcc acactctgaa ggggatgtca 36060
aattcctcct gtccctcaat cttcattttt tatttctatt agatgtccaa aaagcgcgcg 36120
cgggtggatg atggcttcga ccccgtgtat ccctacgatg cagacaacgc accgaccgtg 36180
cccttcatca accctccctt cgtctcttca gatggattcc aagaaaagcc cctgggggtg 36240
ttgtccctta ggctggccga ccctgtcacc accaagaatg gggaaattac cctcaagctg 36300
ggggaggggg tggaccttga cgactcggga aaactcattg caaacacagt aaacaaggcc 36360
attgcccctc tcagtttttc caacaacacc atttccctta acatggatac ccctttatac 36420
accaaagatg gaaaactatc cttacaagtt tctccaccat taagtatatt aaaatcaaca 36480
attttgaata cattagctct agcttttggc tcaggtttag gactcagtgg cagcgccctg 36540
gcagtacagt tagcctctcc acttacattt gatgataaag ggaatataaa gattacccta 36600
aacaggggat tgcatgttac aacaggagat gcaattgaaa gcaacatcag ttgggctaaa 36660
ggtataaaat ttgaagatgg tgccatagct acaaacattg gtaaggggct agagttcgga 36720
accagtagta cagaaacagg agttaataat gcttatccaa tccaagttaa acttggctct 36780
ggtctcagct ttgacagcac aggagccata atggctggca ataaagacta tgataaatta 36840
actttgtgga caacgcctga cccatcacca aactgtcaaa tacttgcaga aaatgatgca 36900
aaactaacac tttgcttaac taagtgtgac agtcaaatac tggccactgt atcagttttg 36960
gttgttagaa gtggaaactt aaacccaatt actggcacag taagcagtgc tcaagttttt 37020
ctacgttttg atgcaaatgg tgttctttta acagaacact ctacactaaa aaaatactgg 37080
ggctacaagc aaggagatag catagatggc actccataca ccaatgctgt tggttttatg 37140
ccaaattcaa cagcttatcc aaagacccaa agttctacta ctaaaaataa tatagtgggt 37200
caagtataca tgaatggaga tgtttcaaaa cccatgcttc ttactataac tcttaatggt 37260
actgatgaca ccaccagtgc atactcaatg tcattttcat acacctggac taacggaagc 37320
tatatcggag caacatttgg agctaactca tacaccttct cctacatagc ccaacaataa 37380
tcccaccctg catgccaacc caccttttcc ctctatttat aaatggaaac tgaaacaaaa 37440
ataaagttca agtgttttat tgattcaaca gtttttcaca ggattcgagt agttattttc 37500
cctccaccct cccatctcat ggaatacact atcctctccc cacgcacagc cttaaacatc 37560
tgaatgctat tggtaatgga catggttttg atctccacat tccacacagt ttcagagcga 37620
gacagtctcg ggtcggtcaa ggagatgaaa ccctccgggc actcctgcat ctgcacctca 37680
cagttcaaca gctgagggct gtcctcggtg attggaatca cagttatctg gaataagagc 37740
gatgagaatc ataatccgca aacgggatcg ggcggttgtg gcgcatcagg ccccgcagca 37800
gtcgctgtct gcgccgctcc gtcaagctgc tactcaaggg gtccgggtcc agggactccc 37860
tgcgcatgat gccaatggcc ctgagcatca gtcgcctggt acggcgggcg cagcagcgga 37920
tgcggatctc actcaggtcg gagcagtacg tgcagcacag caccaccaag ttgttcaaca 37980
gtccatagtt caacgtgctc cagccaaaac tcatttgtgg aactatgctg cccacatgtc 38040
catcgtacca gatcctgatg taaatcaggt ggcgtcccct ccagaacaca ctgcccatgt 38100
acatgatctc cttgggcatg tgcaggttca ccacctcccg gtaccacatc acccgctggt 38160
tgaacatgca gccctggata attctgcgga accagatggc aagtaccgtc ccgcccgcca 38220
tgcagcgcag ggaccccggg ttctggcaat ggcagtggat cacccaccgc tcgcgaccgt 38280
ggatcaactg ggaactaaac aagtctatgt tggcacagca caggcacacg ctcatgcatg 38340
tcttcagcac tctcaattcc tcgggggtca ggaccatatc ccagggcaca gggaactctt 38400
gcaggacagt gaacccggcc gaacagggca atcctcgcac ggaacttaca ttgtgcatgg 38460
acagggtatc gcaatcaggc agcaccggat gatcctccac cagagaagcg cggctctcgg 38520
tctcctcaca gcgaggtaag gtggccggcg gttggtacgg atgatggcga gataacgcta 38580
atcgtgttct ggatcgtgtc atgatggagc tgtttccgga cattttcgta tttcacaaag 38640
cagaacctgg tccgggcact gcacaccgct cgtcggcgac ggtctcggcg cttcgagcgc 38700
tcaatgttga agttatagaa cagccactcc ctcagaacgt gcagtatctc ctgagcctct 38760
tgggtgatga aaatcccatc cgccctgatg gctctgatta catcaaccac ggtggaatgg 38820
gccaaaccca gccagatgat gcaattttgt tgggtttcgg tgacggcggg ggagggaaga 38880
acaggaagaa ccatgattaa ctttattcca aacggtctcg gaacacttca aaatgcaggt 38940
cccggaggtg gcacctctcg cccccactgt gttggtggaa aataacagcc aggtcaaagg 39000
taacacggtt ctcgagatgt tccacggtgg cttccagcaa agcctccacg cgcacatcca 39060
gaaacaagag gacagcgaaa gcgggagcgt tttctaattc ctcaatcatc atattacact 39120
cctgcaccat gcctagataa ttttcatttt tccagccttg aatgattcgt attagttcct 39180
gaggtaaatc caagccagcc atgataaaaa gctcgcgcag agcgccctcc accggcattc 39240
ttaagcacac cctcataatt ccaacagatt ctgctcctgg ttcacctgta gtagattaac 39300
aagtggaata tcaattgctc tgccgcaatc cctaagctcc tcccttagca gtaactgtat 39360
gtactcattc atatcttctc cgaaattttt agccatagga ccaccaggaa caagagaagg 39420
gcaagccaca ttacagataa agcgaagtcc tccccagtga gcattgccaa atgtaagatt 39480
gaaataagca tgctggctag acccggtgat atcttccaga taactggaca gaaaatcagg 39540
caagcaattt ttaagaaaat taacaaaaga aaagtcgtct aggtgcacgt ttagagcctc 39600
aggaacaacg atggaataag tgcaaggagt acgttccagc atggttagtg tttttggtga 39660
tctgtagaac aaaaaataaa catgcaatat taaaccatgc tagcctggcg aacaggtgga 39720
taaatcactc tttccaacac caggcaggct acagggtctc cggcgcgacc attgtagaag 39780
ctgacattat gattaaaaag catcaccgac agaccttccc ggtggccggc atggatgatt 39840
cgagaagaag catacactcc gggaacattg gcgtccgtga gtgaaaaaaa gcgacctata 39900
aagccttgag gcactacaat gcttaatctt aattccagca aagcgacccc atgcggatga 39960
agcacaaaat tggcaggtgc gtaaaaaatg taattactcc ccttctgcac aggcagcaaa 40020
gcccccgctc cctccagaaa cacatacaaa acctgagcgt ccatagctta ccgagcacgg 40080
caggcgcaag agtcagagaa aaagctgagc tctaacctaa ctgcccgctt ctgtactcaa 40140
tatatagccc taacctcact gacgtaaagg ccaaggtcta aaaatacccg ccaacacgcc 40200
cagaaaccgg tgacacacta aaaaaatacg tgcacttcct caaacgccca aactggcgtc 40260
atttccggtt tcccacgcta cgtcacctct caacgacttt caaattccgt cgaccgttaa 40320
acacatcagt taccccgccc ctaacgaacg ccgctgtcac agccaatcag cgcgccccat 40380
ccccaaattt tcacgcctta tttgcatatt aactcacaca aaaaaaataa ggtatattat 40440
tgatgatgaa gcttttaat 40459
<210> 2
<211> 1273
<212> PRT
<213> SARS-CoV-2
<400> 2
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 3
<211> 1273
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 3
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 4
<211> 1249
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 4
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser
<210> 5
<211> 1268
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 5
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val
1265
<210> 6
<211> 3822
<212> DNA
<213> SARS-CoV-2
<400> 6
atgtttgttt ttcttgtttt attgccacta gtctctagtc agtgtgttaa tcttacaacc 60
agaactcaat taccccctgc atacactaat tctttcacac gtggtgttta ttaccctgac 120
aaagttttca gatcctcagt tttacattca actcaggact tgttcttacc tttcttttcc 180
aatgttactt ggttccatgc tatacatgtc tctgggacca atggtactaa gaggtttgat 240
aaccctgtcc taccatttaa tgatggtgtt tattttgctt ccactgagaa gtctaacata 300
ataagaggct ggatttttgg tactacttta gattcgaaga cccagtccct acttattgtt 360
aataacgcta ctaatgttgt tattaaagtc tgtgaatttc aattttgtaa tgatccattt 420
ttgggtgttt attaccacaa aaacaacaaa agttggatgg aaagtgagtt cagagtttat 480
tctagtgcga ataattgcac ttttgaatat gtctctcagc cttttcttat ggaccttgaa 540
ggaaaacagg gtaatttcaa aaatcttagg gaatttgtgt ttaagaatat tgatggttat 600
tttaaaatat attctaagca cacgcctatt aatttagtgc gtgatctccc tcagggtttt 660
tcggctttag aaccattggt agatttgcca ataggtatta acatcactag gtttcaaact 720
ttacttgctt tacatagaag ttatttgact cctggtgatt cttcttcagg ttggacagct 780
ggtgctgcag cttattatgt gggttatctt caacctagga cttttctatt aaaatataat 840
gaaaatggaa ccattacaga tgctgtagac tgtgcacttg accctctctc agaaacaaag 900
tgtacgttga aatccttcac tgtagaaaaa ggaatctatc aaacttctaa ctttagagtc 960
caaccaacag aatctattgt tagatttcct aatattacaa acttgtgccc ttttggtgaa 1020
gtttttaacg ccaccagatt tgcatctgtt tatgcttgga acaggaagag aatcagcaac 1080
tgtgttgctg attattctgt cctatataat tccgcatcat tttccacttt taagtgttat 1140
ggagtgtctc ctactaaatt aaatgatctc tgctttacta atgtctatgc agattcattt 1200
gtaattagag gtgatgaagt cagacaaatc gctccagggc aaactggaaa gattgctgat 1260
tataattata aattaccaga tgattttaca ggctgcgtta tagcttggaa ttctaacaat 1320
cttgattcta aggttggtgg taattataat tacctgtata gattgtttag gaagtctaat 1380
ctcaaacctt ttgagagaga tatttcaact gaaatctatc aggccggtag cacaccttgt 1440
aatggtgttg aaggttttaa ttgttacttt cctttacaat catatggttt ccaacccact 1500
aatggtgttg gttaccaacc atacagagta gtagtacttt cttttgaact tctacatgca 1560
ccagcaactg tttgtggacc taaaaagtct actaatttgg ttaaaaacaa atgtgtcaat 1620
ttcaacttca atggtttaac aggcacaggt gttcttactg agtctaacaa aaagtttctg 1680
cctttccaac aatttggcag agacattgct gacactactg atgctgtccg tgatccacag 1740
acacttgaga ttcttgacat tacaccatgt tcttttggtg gtgtcagtgt tataacacca 1800
ggaacaaata cttctaacca ggttgctgtt ctttatcagg atgttaactg cacagaagtc 1860
cctgttgcta ttcatgcaga tcaacttact cctacttggc gtgtttattc tacaggttct 1920
aatgtttttc aaacacgtgc aggctgttta ataggggctg aacatgtcaa caactcatat 1980
gagtgtgaca tacccattgg tgcaggtata tgcgctagtt atcagactca gactaattct 2040
cctcggcggg cacgtagtgt agctagtcaa tccatcattg cctacactat gtcacttggt 2100
gcagaaaatt cagttgctta ctctaataac tctattgcca tacccacaaa ttttactatt 2160
agtgttacca cagaaattct accagtgtct atgaccaaga catcagtaga ttgtacaatg 2220
tacatttgtg gtgattcaac tgaatgcagc aatcttttgt tgcaatatgg cagtttttgt 2280
acacaattaa accgtgcttt aactggaata gctgttgaac aagacaaaaa cacccaagaa 2340
gtttttgcac aagtcaaaca aatttacaaa acaccaccaa ttaaagattt tggtggtttt 2400
aatttttcac aaatattacc agatccatca aaaccaagca agaggtcatt tattgaagat 2460
ctacttttca acaaagtgac acttgcagat gctggcttca tcaaacaata tggtgattgc 2520
cttggtgata ttgctgctag agacctcatt tgtgcacaaa agtttaacgg ccttactgtt 2580
ttgccacctt tgctcacaga tgaaatgatt gctcaataca cttctgcact gttagcgggt 2640
acaatcactt ctggttggac ctttggtgca ggtgctgcat tacaaatacc atttgctatg 2700
caaatggctt ataggtttaa tggtattgga gttacacaga atgttctcta tgagaaccaa 2760
aaattgattg ccaaccaatt taatagtgct attggcaaaa ttcaagactc actttcttcc 2820
acagcaagtg cacttggaaa acttcaagat gtggtcaacc aaaatgcaca agctttaaac 2880
acgcttgtta aacaacttag ctccaatttt ggtgcaattt caagtgtttt aaatgatatc 2940
ctttcacgtc ttgacaaagt tgaggctgaa gtgcaaattg ataggttgat cacaggcaga 3000
cttcaaagtt tgcagacata tgtgactcaa caattaatta gagctgcaga aatcagagct 3060
tctgctaatc ttgctgctac taaaatgtca gagtgtgtac ttggacaatc aaaaagagtt 3120
gatttttgtg gaaagggcta tcatcttatg tccttccctc agtcagcacc tcatggtgta 3180
gtcttcttgc atgtgactta tgtccctgca caagaaaaga acttcacaac tgctcctgcc 3240
atttgtcatg atggaaaagc acactttcct cgtgaaggtg tctttgtttc aaatggcaca 3300
cactggtttg taacacaaag gaatttttat gaaccacaaa tcattactac agacaacaca 3360
tttgtgtctg gtaactgtga tgttgtaata ggaattgtca acaacacagt ttatgatcct 3420
ttgcaacctg aattagactc attcaaggag gagttagata aatattttaa gaatcataca 3480
tcaccagatg ttgatttagg tgacatctct ggcattaatg cttcagttgt aaacattcaa 3540
aaagaaattg accgcctcaa tgaggttgcc aagaatttaa atgaatctct catcgatctc 3600
caagaacttg gaaagtatga gcagtatata aaatggccat ggtacatttg gctaggtttt 3660
atagctggct tgattgccat agtaatggtg acaattatgc tttgctgtat gaccagttgc 3720
tgtagttgtc tcaagggctg ttgttcttgt ggatcctgct gcaaatttga tgaagacgac 3780
tctgagccag tgctcaaagg agtcaaatta cattacacat aa 3822
<210> 7
<211> 1270
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 7
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Phe Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Ala
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Gly Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu His Ile Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr
245 250 255
Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe
260 265 270
Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys
275 280 285
Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr
290 295 300
Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr
305 310 315 320
Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly
325 330 335
Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg
340 345 350
Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser
355 360 365
Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu
370 375 380
Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg
385 390 395 400
Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile Ala
405 410 415
Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala
420 425 430
Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr
435 440 445
Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp
450 455 460
Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val
465 470 475 480
Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro
485 490 495
Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe
500 505 510
Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr
515 520 525
Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr
530 535 540
Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln
545 550 555 560
Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro
565 570 575
Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val
580 585 590
Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu
595 600 605
Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp
610 615 620
Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe
625 630 635 640
Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser
645 650 655
Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln
660 665 670
Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala Ser Gln Ser
675 680 685
Ile Ile Ala Tyr Thr Met Ser Leu Gly Val Glu Asn Ser Val Ala Tyr
690 695 700
Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr
705 710 715 720
Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr
725 730 735
Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln
740 745 750
Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala
755 760 765
Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln
770 775 780
Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser
785 790 795 800
Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu
805 810 815
Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys
820 825 830
Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys
835 840 845
Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp
850 855 860
Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr
865 870 875 880
Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala
885 890 895
Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val
900 905 910
Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile
915 920 925
Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys
930 935 940
Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val
945 950 955 960
Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp
965 970 975
Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg
980 985 990
Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln
995 1000 1005
Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala
1010 1015 1020
Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp
1025 1030 1035
Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1040 1045 1050
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1055 1060 1065
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys
1070 1075 1080
Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His
1085 1090 1095
Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr
1100 1105 1110
Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly
1115 1120 1125
Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp
1130 1135 1140
Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser
1145 1150 1155
Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val
1160 1165 1170
Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys
1175 1180 1185
Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
1190 1195 1200
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile
1205 1210 1215
Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys
1220 1225 1230
Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly
1235 1240 1245
Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys
1250 1255 1260
Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 8
<211> 1273
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 8
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 9
<211> 1273
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 9
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Thr Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Lys Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro His Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Gln Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr Asp Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 10
<211> 1273
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 10
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Phe Thr Asn Arg Thr Gln Leu Pro Ser Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Tyr Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Ser Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu Tyr Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
1010 1015 1020
Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys
1025 1030 1035
Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
1040 1045 1050
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val
1055 1060 1065
Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His
1070 1075 1080
Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095
Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
1100 1105 1110
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val
1115 1120 1125
Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro
1130 1135 1140
Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
1145 1150 1155
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn
1160 1165 1170
Ala Ser Phe Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu
1175 1180 1185
Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu
1190 1195 1200
Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215
Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met
1220 1225 1230
Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro
1250 1255 1260
Val Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 11
<211> 1271
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 11
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val Tyr Ser Ser
145 150 155 160
Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp
165 170 175
Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe
180 185 190
Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile
195 200 205
Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu
210 215 220
Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu
225 230 235 240
Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp
245 250 255
Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr
260 265 270
Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp
275 280 285
Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe
290 295 300
Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro
305 310 315 320
Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe
325 330 335
Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn
340 345 350
Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn
355 360 365
Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys
370 375 380
Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile
385 390 395 400
Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile
405 410 415
Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile
420 425 430
Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn
435 440 445
Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg
450 455 460
Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys Asn Gly
465 470 475 480
Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln
485 490 495
Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser
500 505 510
Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser
515 520 525
Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu
530 535 540
Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe
545 550 555 560
Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp
565 570 575
Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly
580 585 590
Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val
595 600 605
Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala
610 615 620
Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val
625 630 635 640
Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn
645 650 655
Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr
660 665 670
Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val Ala Ser Gln
675 680 685
Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala
690 695 700
Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val
705 710 715 720
Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys
725 730 735
Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu
740 745 750
Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile
755 760 765
Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys
770 775 780
Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe
785 790 795 800
Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile
805 810 815
Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile
820 825 830
Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile
835 840 845
Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr
850 855 860
Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile
865 870 875 880
Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe
885 890 895
Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn
900 905 910
Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala
915 920 925
Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly
930 935 940
Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu
945 950 955 960
Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn
965 970 975
Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp
980 985 990
Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln
995 1000 1005
Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala
1010 1015 1020
Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser
1040 1045 1050
Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala
1055 1060 1065
Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly
1070 1075 1080
Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr
1085 1090 1095
His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile
1100 1105 1110
Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile
1115 1120 1125
Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu
1130 1135 1140
Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr
1145 1150 1155
Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser
1160 1165 1170
Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
1175 1180 1185
Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys
1190 1195 1200
Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe
1205 1210 1215
Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys
1220 1225 1230
Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys
1235 1240 1245
Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu
1250 1255 1260
Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 12
<211> 1270
<212> PRT
<213> 人工序列
<220>
<223> 合成蛋白
<400> 12
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Val Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp Asn Pro
65 70 75 80
Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Ile Glu Lys Ser
85 90 95
Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser Lys Thr
100 105 110
Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile Lys Val
115 120 125
Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp His Lys Asn Asn
130 135 140
Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn
145 150 155 160
Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp Leu Glu Gly
165 170 175
Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe Lys Asn Ile
180 185 190
Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile Ile Val Glu
195 200 205
Pro Glu Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu Val
210 215 220
Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu Ala
225 230 235 240
Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp Thr
245 250 255
Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr Phe
260 265 270
Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp Cys
275 280 285
Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe Thr
290 295 300
Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro Thr
305 310 315 320
Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Asp
325 330 335
Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg
340 345 350
Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Leu
355 360 365
Ala Pro Phe Phe Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu
370 375 380
Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg
385 390 395 400
Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Asn Ile Ala
405 410 415
Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala
420 425 430
Trp Asn Ser Asn Lys Leu Asp Ser Lys Val Ser Gly Asn Tyr Asn Tyr
435 440 445
Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp
450 455 460
Ile Ser Thr Glu Ile Tyr Gln Ala Gly Asn Lys Pro Cys Asn Gly Val
465 470 475 480
Ala Gly Phe Asn Cys Tyr Phe Pro Leu Arg Ser Tyr Ser Phe Arg Pro
485 490 495
Thr Tyr Gly Val Gly His Gln Pro Tyr Arg Val Val Val Leu Ser Phe
500 505 510
Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr
515 520 525
Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Lys
530 535 540
Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln
545 550 555 560
Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro
565 570 575
Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val
580 585 590
Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu
595 600 605
Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp
610 615 620
Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe
625 630 635 640
Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu Tyr Val Asn Asn Ser
645 650 655
Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln
660 665 670
Thr Gln Thr Lys Ser His Arg Arg Ala Arg Ser Val Ala Ser Gln Ser
675 680 685
Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr
690 695 700
Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr
705 710 715 720
Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr
725 730 735
Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln
740 745 750
Tyr Gly Ser Phe Cys Thr Gln Leu Lys Arg Ala Leu Thr Gly Ile Ala
755 760 765
Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln
770 775 780
Ile Tyr Lys Thr Pro Pro Ile Lys Tyr Phe Gly Gly Phe Asn Phe Ser
785 790 795 800
Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu
805 810 815
Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys
820 825 830
Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys
835 840 845
Ala Gln Lys Phe Lys Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp
850 855 860
Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr
865 870 875 880
Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala
885 890 895
Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val
900 905 910
Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile
915 920 925
Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys
930 935 940
Leu Gln Asp Val Val Asn His Asn Ala Gln Ala Leu Asn Thr Leu Val
945 950 955 960
Lys Gln Leu Ser Ser Lys Phe Gly Ala Ile Ser Ser Val Leu Asn Asp
965 970 975
Ile Phe Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp Arg
980 985 990
Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln
995 1000 1005
Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala
1010 1015 1020
Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp
1025 1030 1035
Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1040 1045 1050
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
1055 1060 1065
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys
1070 1075 1080
Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His
1085 1090 1095
Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr
1100 1105 1110
Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly
1115 1120 1125
Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp
1130 1135 1140
Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser
1145 1150 1155
Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val
1160 1165 1170
Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys
1175 1180 1185
Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
1190 1195 1200
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile
1205 1210 1215
Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met Leu Cys Cys
1220 1225 1230
Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys Ser Cys Gly
1235 1240 1245
Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val Leu Lys
1250 1255 1260
Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 13
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 13
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa cttcaccaca 60
agaacccagc tgccccctgc ctacaccaat tccttcacaa ggggcgtgta ctatcccgac 120
aaggtgtttc gctctagcgt gctgcactcc acacaggatc tgtttctgcc tttcttttct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gcggttcgcc 240
aatccagtgc tgccctttaa cgacggcgtg tacttcgcct ccaccgagaa gtctaacatc 300
atcagaggct ggatctttgg caccacactg gatagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa tgacccattc 420
ctgggcgtgt actatcacaa gaacaataag tcttggatgg agagcgagtt tagggtgtac 480
tcctctgcca acaattgcac atttgagtac gtgagccagc ccttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgcgc gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actccaagca caccccaatc aacctggtga ggggactgcc acagggcttc 660
tctgccctgg agccactggt ggacctgccc atcggcatca acatcacccg ctttcagaca 720
ctgcacatca gctacctgac accaggcgat agctcctctg gatggaccgc aggagcagca 780
gcctactatg tgggctacct gcagcccagg accttcctgc tgaagtataa cgagaatggc 840
accatcacag acgcagtgga ttgcgccctg gaccccctgt ctgagaccaa gtgtacactg 900
aagagcttta ccgtggagaa gggcatctac cagacaagca atttccgggt gcagcctacc 960
gagtccatcg tgagatttcc caatatcaca aacctgtgcc cttttggcga ggtgttcaac 1020
gccacccgct tcgccagcgt gtatgcctgg aataggaagc gcatctccaa ctgcgtggcc 1080
gactattctg tgctgtacaa cagcgcctcc ttctctacct ttaagtgcta cggcgtgagc 1140
cccacaaagc tgaatgacct gtgctttacc aacgtgtatg ccgattcctt cgtgatcagg 1200
ggcgacgagg tgcgccagat cgcaccaggc cagacaggca atatcgccga ctacaactat 1260
aagctgcctg acgatttcac cggctgcgtg atcgcctgga acagcaacaa tctggatagc 1320
aaagtgggcg gcaactacaa ttatctgtac cggctgttta gaaagtctaa cctgaagcca 1380
ttcgagaggg acatctccac agagatctac caggccggct ctaccccctg caatggcgtg 1440
aagggcttta actgttattt ccctctgcag agctacggct tccagccaac ctacggcgtg 1500
ggctatcagc cctaccgcgt ggtggtgctg tcttttgagc tgctgcacgc acctgcaaca 1560
gtgtgcggcc caaagaagag caccaatctg gtgaagaaca agtgcgtgaa cttcaacttc 1620
aacggactga ccggcacagg cgtgctgacc gagtccaaca agaagttcct gccttttcag 1680
cagttcggcc gggacatcgc cgataccaca gacgccgtga gagaccctca gaccctggag 1740
atcctggata tcacaccatg ctccttcggc ggcgtgtctg tgatcacacc aggcaccaat 1800
acaagcaacc aggtggccgt gctgtaccag ggcgtgaatt gtaccgaggt gcccgtggca 1860
atccacgcag accagctgac ccctacatgg agggtgtatt ctaccggcag caacgtgttc 1920
cagacacgcg ccggatgcct gatcggagca gagcacgtga acaatagcta cgagtgcgat 1980
atccctatcg gcgccggcat ctgtgcctcc tatcagaccc agacaaactc cccacggaga 2040
gcccggtctg tggcaagcca gtccatcatc gcctacacca tgagcctggg cgtggagaac 2100
agcgtggcct attccaacaa ttctatcgcc atccctacca acttcacaat ctccgtgacc 2160
acagagatcc tgccagtgag catgaccaag acatccgtgg actgcacaat gtacatctgt 2220
ggcgattcca ccgagtgctc taacctgctg ctgcagtatg gctctttttg tacccagctg 2280
aatagagccc tgacaggcat cgccgtggag caggacaaga acacacagga ggtgttcgcc 2340
caggtgaagc agatctacaa gaccccaccc atcaaggact ttggcggctt caacttcagc 2400
cagatcctgc ccgatcctag caagccatcc aagcggtctt ttatcgagga cctgctgttc 2460
aacaaggtga ccctggccga tgccggcttc atcaagcagt acggcgattg cctgggcgac 2520
atcgcagcca gagacctgat ctgtgcccag aagtttaatg gcctgaccgt gctgcctcca 2580
ctgctgacag atgagatgat cgcccagtat acatctgccc tgctggcagg aaccatcaca 2640
agcggatgga ccttcggcgc aggagccgcc ctgcagatcc cctttgccat gcagatggcc 2700
tacaggttca acggcatcgg cgtgacccag aatgtgctgt atgagaacca gaagctgatc 2760
gccaatcagt ttaactccgc catcggcaag atccaggact ctctgagctc cacagcaagc 2820
gccctgggca agctgcagga tgtggtgaat cagaacgccc aggccctgaa taccctggtg 2880
aagcagctgt ctagcaactt cggcgccatc tcctctgtgc tgaatgatat cctgagccgg 2940
ctggaccctc ctgaggcaga ggtgcagatc gaccggctga tcacaggcag actgcagtcc 3000
ctgcagacct acgtgacaca gcagctgatc agggcagcag agatcagggc atctgccaat 3060
ctggccgcca ccaagatgag cgagtgcgtg ctgggccagt ccaagagagt ggacttttgt 3120
ggcaagggct accacctgat gagcttccca cagtccgccc ctcacggcgt ggtgtttctg 3180
cacgtgacct atgtgccagc ccaggagaag aacttcacca cagcaccagc catctgccac 3240
gatggcaagg cacactttcc tcgggagggc gtgttcgtga gcaacggcac ccactggttt 3300
gtgacacaga gaaatttcta cgagccacag atcatcacca cagacaatac cttcgtgagc 3360
ggcaactgtg acgtggtcat cggaatcgtg aacaataccg tgtacgatcc tctgcagcca 3420
gagctggact cttttaagga ggagctggat aagtatttca agaatcacac cagccccgac 3480
gtggatctgg gcgacatctc tggcatcaat gccagcgtgg tgaacatcca gaaggagatc 3540
gaccgcctga acgaggtggc caagaatctg aacgagtccc tgatcgatct gcaggagctg 3600
ggcaagtatg agcagtacat caagtggccc tggtacatct ggctgggctt catcgccggc 3660
ctgatcgcca tcgtgatggt gaccatcatg ctgtgctgta tgacaagctg ctgttcctgc 3720
ctgaagggct gctgttcttg tggcagctgc tgtaagtttg atgaggacga tagcgagcct 3780
gtgctgaagg gcgtgaagct gcactatacc tga 3813
<210> 14
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 14
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa cctgaccaca 60
aggacccagc tgccccctgc ctacaccaat tccttcacac ggggcgtgta ctatcccgac 120
aaggtgttta gatctagcgt gctgcactcc acacaggatc tgtttctgcc tttcttttct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gcggttcgac 240
aatccagtgc tgccctttaa cgatggcgtg tacttcgcct ccaccgagaa gtctaacatc 300
atcagaggct ggatctttgg caccacactg gacagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa tgatccattc 420
ctgggcgtgt actatcacaa gaacaataag tcttggatgg agagcgagtt tcgcgtgtac 480
tcctctgcca acaattgcac atttgagtac gtgagccagc ccttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgagg gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actccaagca caccccaatc aacctggtgc gcgacctgcc acagggcttc 660
tctgccctgg agccactggt ggatctgccc atcggcatca acatcacccg gtttcagaca 720
ctgctggccc tgcacagaag ctacctgaca ccaggcgaca gctcctctgg atggaccgca 780
ggagcagcag cctactatgt gggctacctg cagcccagga ccttcctgct gaagtataac 840
gagaatggca ccatcacaga cgcagtggat tgcgccctgg accccctgtc tgagaccaag 900
tgtacactga agagctttac cgtggagaag ggcatctacc agacaagcaa tttcagggtg 960
cagcctaccg agtccatcgt gcgctttccc aatatcacaa acctgtgccc ttttggcgag 1020
gtgttcaacg ccacccgctt cgccagcgtg tatgcctgga ataggaagcg catctccaac 1080
tgcgtggccg actattctgt gctgtacaac agcgcctcct tctctacctt taagtgctac 1140
ggcgtgagcc ccacaaagct gaatgacctg tgctttacca acgtgtatgc cgattccttc 1200
gtgatcaggg gcgacgaggt gcgccagatc gcaccaggcc agacaggcaa tatcgccgac 1260
tacaactata agctgcctga cgatttcacc ggctgcgtga tcgcctggaa cagcaacaat 1320
ctggatagca aagtgggcgg caactacaat tatctgtacc ggctgtttag aaagtctaac 1380
ctgaagccat tcgagaggga catctccaca gagatctacc aggccggctc taccccctgc 1440
aatggcgtga agggctttaa ctgttatttc cctctgcaga gctacggctt ccagccaacc 1500
tacggcgtgg gctatcagcc ctaccgcgtg gtggtgctgt cttttgagct gctgcacgca 1560
cctgcaacag tgtgcggccc aaagaagagc accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggactgac cggcacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccttttcagc agttcggcag ggacatcgca gataccacag acgccgtgcg cgaccctcag 1740
accctggaga tcctggatat cacaccatgc tccttcggcg gcgtgtctgt gatcacacca 1800
ggcaccaata caagcaacca ggtggccgtg ctgtaccagg gcgtgaattg taccgaggtg 1860
cccgtggcaa tccacgcaga ccagctgacc cctacatggc gggtgtattc taccggcagc 1920
aacgtgttcc agacaagagc cggatgcctg atcggagcag agcacgtgaa caatagctac 1980
gagtgcgata tccctatcgg cgccggcatc tgtgcctcct atcagaccca gacaaactcc 2040
ccacggagag cccggtctgt ggcaagccag tccatcatcg cctacaccat gagcctgggc 2100
gccgagaaca gcgtggccta ttccaacaat tctatcgcca tccctaccaa cttcacaatc 2160
tccgtgacca cagagatcct gccagtgagc atgaccaaga catccgtgga ctgcacaatg 2220
tacatctgtg gcgattccac cgagtgctct aacctgctgc tgcagtatgg ctctttttgt 2280
acccagctga atagagccct gacaggcatc gccgtggagc aggacaagaa cacacaggag 2340
gtgttcgccc aggtgaagca gatctacaag accccaccca tcaaggactt tggcggcttc 2400
aacttcagcc agatcctgcc cgatcctagc aagccatcca agcggtcttt tatcgaggac 2460
ctgctgttca acaaggtgac cctggccgat gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca tcgcagccag agacctgatc tgtgcccaga agtttaatgg cctgaccgtg 2580
ctgcctccac tgctgacaga tgagatgatc gcccagtata catctgccct gctggcagga 2640
accatcacaa gcggatggac cttcggcgca ggagccgccc tgcagatccc ctttgccatg 2700
cagatggcct acagattcaa cggcatcggc gtgacccaga atgtgctgta tgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggactc tctgagctcc 2820
acagcaagcg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaat 2880
accctggtga agcagctgtc tagcaacttc ggcgccatct cctctgtgct gaatgatatc 2940
ctgagccggc tggacccacc agaggcagag gtgcagatcg accggctgat cacaggcaga 3000
ctgcagtccc tgcagaccta cgtgacacag cagctgatca gggcagcaga gatcagggca 3060
tctgccaatc tggccgccac caagatgagc gagtgcgtgc tgggccagtc caagagagtg 3120
gacttttgtg gcaagggcta ccacctgatg agcttcccac agtccgcccc tcacggcgtg 3180
gtgtttctgc acgtgaccta tgtgccagcc caggagaaga acttcaccac agcaccagcc 3240
atctgccacg atggcaaggc acactttccc cgggagggcg tgttcgtgag caacggaacc 3300
cactggtttg tgacacagcg caatttctac gagccacaga tcatcaccac agacaataca 3360
ttcgtgtccg gcaactgtga cgtggtcatc ggaatcgtga acaataccgt gtacgatcct 3420
ctgcagccag agctggactc ttttaaggag gagctggata agtatttcaa gaatcacacc 3480
agccccgacg tggatctggg cgacatctct ggcatcaatg ccagcgtggt gaacatccag 3540
aaggagatcg acaggctgaa cgaggtggcc aagaatctga acgagtccct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggccct ggtacatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacaagctgc 3720
tgttcctgcc tgaagggctg ctgttcttgt ggcagctgct gtaagtttga tgaggacgat 3780
agcgagcctg tgctgaaggg cgtgaagctg cactatacct ga 3822
<210> 15
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 15
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa cctgaccaca 60
accacacagc tgccccctgc ctataccaat tccttcacac gcggcgtgta ctatcctgac 120
aaggtgtttc ggtctagcgt gctgcactcc acacaggatc tgtttctgcc attcttttct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gcggttcgac 240
aatccagtgc tgccctttaa cgatggcgtg tacttcgcct ccaccgagaa gtctaacatc 300
atccggggct ggatctttgg caccacactg gacagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa tgatcccttc 420
ctggacgtgt actatcacaa gaacaataag tcttggatga agagcgagtt tagagtgtat 480
tcctctgcca acaattgcac atttgagtac gtgtcccagc ctttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgaga gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actccaagca caccccaatc aacctggtga gggacctgcc acacggcttc 660
tctgccctgg agccactggt ggatctgccc atcggcatca acatcaccag atttcagaca 720
ctgctggccc tgcacaggag ctacctgaca cccggcgaca gctcctctgg atggaccgcc 780
ggcgctgccg cctactatgt gggctatctg cagcctcgca ccttcctgct gaagtacaac 840
gagaatggca ccatcacaga cgcagtggat tgcgccctgg accccctgtc tgagaccaag 900
tgtacactga agagctttac cgtggagaag ggcatctatc agacaagcaa tttccgcgtg 960
cagccaaccg agtccatcgt gcggtttccc aatatcacaa acctgtgccc ttttggcgag 1020
gtgttcaacg caaccaggtt cgcaagcgtg tacgcatgga atcgcaagcg gatctccaac 1080
tgcgtggccg actattctgt gctgtacaac agcgcctcct tctctacctt taagtgctat 1140
ggcgtgagcc caacaaagct gaatgacctg tgctttacca acgtgtacgc cgattccttc 1200
gtgatccggg gcgacgaggt gcggcagatc gcaccaggac agacaggcaa gatcgcagac 1260
tacaattata agctgcctga cgatttcacc ggctgcgtga tcgcctggaa ctctaacaat 1320
ctggatagca aagtgggcgg caactacaat tatagataca ggctgtttag aaagtctaat 1380
ctgaagccat tcgagaggga catctccaca gagatctacc aggccggctc taccccctgc 1440
aatggcgtgc agggctttaa ctgttatttc cctctgcaga gctacggctt ccagccaacc 1500
aacggcgtgg gctatcagcc ctaccgggtg gtggtgctgt cttttgagct gctgcacgca 1560
cctgcaacag tgtgcggacc aaagaagagc accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggactgac cggaacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccatttcagc agttcggcag agacatcgcc gataccacag acgccgtgag ggaccctcag 1740
accctggaga tcctggatat cacaccatgc tccttcggcg gcgtgtctgt gatcacaccc 1800
ggcaccaata caagcaacca ggtggccgtg ctgtatcagg gcgtgaattg taccgaggtg 1860
ccagtggcaa tccacgcaga ccagctgacc cctacatggc gcgtgtactc taccggcagc 1920
aacgtgttcc agacaagggc aggatgcctg atcggagcag agcacgtgaa caatagctat 1980
gagtgcgata tccccatcgg cgccggcatc tgtgcctcct accagaccca gacaaactcc 2040
cggagaaggg ccagatctgt ggccagccag tccatcatcg cctataccat gagcctgggc 2100
gccgagaaca gcgtggccta ctccaacaat tctatcgcca tccctaccaa cttcacaatc 2160
tccgtgacca cagagatcct gccagtgagc atgaccaaga catccgtgga ctgcacaatg 2220
tatatctgtg gcgattccac cgagtgctct aacctgctgc tgcagtacgg ctctttttgt 2280
acccagctga atagggccct gacaggaatc gcagtggagc aggacaagaa cacacaggag 2340
gtgttcgccc aggtgaagca gatctacaag accccaccca tcaaggactt tggcggcttc 2400
aacttcagcc agatcctgcc cgatcctagc aagccctcca agcggagctt catcgaggac 2460
ctgctgttca acaaggtgac cctggccgat gccggcttca tcaagcagta tggcgattgc 2520
ctgggcgaca tcgcagcaag ggacctgatc tgtgcccaga agtttaatgg cctgaccgtg 2580
ctgcctccac tgctgacaga tgagatgatc gcccagtaca catctgccct gctggcagga 2640
accatcacaa gcggatggac cttcggcgca ggagccgccc tgcagatccc ttttgccatg 2700
cagatggcct atcgcttcaa cggcatcggc gtgacccaga atgtgctgta cgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggactc tctgagctcc 2820
acagcaagcg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaat 2880
accctggtga agcagctgtc tagcaacttc ggcgccatct cctctgtgct gaatgatatc 2940
ctgagcagac tggacccccc cgaggccgag gtgcagatcg acagactgat cacaggcagg 3000
ctgcagtccc tgcagaccta cgtgacacag cagctgatca gggccgccga gatcagggcc 3060
tctgccaatc tggccgccac caagatgagc gagtgcgtgc tgggccagtc caagagggtg 3120
gatttttgtg gcaagggcta tcacctgatg agcttcccac agtccgcccc tcacggagtg 3180
gtgtttctgc acgtgaccta cgtgccagcc caggagaaga acttcaccac agcaccagca 3240
atctgccacg acggcaaggc acactttcca agagagggcg tgttcgtgag caacggcacc 3300
gattggtttg tgacacagag gaatttctac gagccccaga tcatcaccac agacaataca 3360
ttcgtgtccg gcaactgtga cgtggtcatc ggcatcgtga acaataccgt gtatgatcct 3420
ctgcagccag agctggactc ttttaaggag gagctggata agtacttcaa gaatcacacc 3480
agccccgacg tggatctggg cgacatctct ggcatcaatg ccagcgtggt gaacatccag 3540
aaggagatcg accggctgaa cgaggtggcc aagaatctga acgagtccct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggcctt ggtatatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacaagctgc 3720
tgttcctgcc tgaagggctg ctgttcttgt ggcagctgct gtaagtttga tgaggacgat 3780
agcgagccag tgctgaaggg cgtgaagctg cactacacct ga 3822
<210> 16
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 16
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa tttcaccaac 60
agaacacagc tgccttctgc ctacaccaat agcttcacac ggggcgtgta ctatccagac 120
aaggtgttta gatctagcgt gctgcacagc acacaggatc tgtttctgcc attcttttcc 180
aacgtgacct ggttccacgc catccacgtg tccggcacca atggcacaaa gcggttcgac 240
aatcccgtgc tgccttttaa cgatggcgtg tacttcgcct ccaccgagaa gtctaacatc 300
atcagaggct ggatctttgg caccacactg gacagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa ttatcccttc 420
ctgggcgtgt actatcacaa gaacaataag tcttggatgg agagcgagtt tagggtgtac 480
tcctctgcca acaattgcac atttgagtat gtgagccagc ctttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgagc gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actccaagca cacccccatc aacctggtgc gcgacctgcc tcagggcttc 660
tctgccctgg agcccctggt ggatctgcct atcggcatca acatcacccg gtttcagaca 720
ctgctggccc tgcacagaag ctacctgaca cccggcgaca gctcctctgg atggaccgcc 780
ggcgctgccg cctactatgt gggctacctg cagcctagga ccttcctgct gaagtataac 840
gagaatggca ccatcacaga cgcagtggat tgcgccctgg accccctgtc cgagaccaag 900
tgtacactga agtcttttac cgtggagaag ggcatctacc agacatctaa tttcagggtg 960
cagccaaccg agagcatcgt gcgctttcct aatatcacaa acctgtgccc atttggcgag 1020
gtgttcaacg ccacccgctt cgccagcgtg tatgcctgga ataggaagcg catcagcaac 1080
tgcgtggccg actattccgt gctgtacaac agcgcctcct tctctacctt taagtgttac 1140
ggcgtgtctc ctacaaagct gaatgacctg tgctttacca acgtgtatgc cgatagcttc 1200
gtgatcaggg gcgacgaggt gcgccagatc gcaccaggac agaccggaac aatcgcagac 1260
tacaattata agctgcctga cgatttcacc ggctgcgtga tcgcctggaa ctccaacaat 1320
ctggattcta aagtgggcgg caactacaat tatctgtacc ggctgtttag aaagtccaac 1380
ctgaagccat tcgagcggga catcagcaca gagatctacc aggcaggctc caccccatgc 1440
aatggagtga agggctttaa ctgttatttc ccactgcaga gctacggctt ccagcccaca 1500
tatggcgtgg gctatcagcc ttacagagtg gtggtgctgt cctttgagct gctgcacgca 1560
ccagcaacag tgtgcggacc caagaagtct accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggactgac cggaacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccatttcagc agttcggcag ggacatcgca gataccacag acgccgtgcg cgacccacag 1740
accctggaga tcctggatat cacaccctgc agcttcggcg gcgtgtccgt gatcacacca 1800
ggaaccaata caagcaacca ggtggccgtg ctgtaccagg gcgtgaattg taccgaggtg 1860
cctgtggcaa tccacgcaga ccagctgacc ccaacatggc gggtgtattc taccggcagc 1920
aacgtgttcc agacaagagc cggctgcctg atcggcgccg agtatgtgaa caattcttac 1980
gagtgcgata tccctatcgg cgccggcatc tgtgccagct accagaccca gacaaacagc 2040
ccacggagag cacggtccgt ggcaagccag tccatcatcg cctacaccat gtctctgggc 2100
gccgagaata gcgtggccta ttccaacaat tctatcgcca tcccaaccaa cttcacaatc 2160
tccgtgacca cagagatcct gcccgtgtct atgaccaaga caagcgtgga ctgcacaatg 2220
tacatctgtg gcgattccac cgagtgctct aacctgctgc tgcagtatgg cagcttttgt 2280
acccagctga atagagccct gacaggcatc gccgtggagc aggacaagaa cacacaggag 2340
gtgttcgccc aggtgaagca gatctacaag acccccccta tcaaggactt tggcggcttc 2400
aacttcagcc agatcctgcc tgatccaagc aagccatcca agaggtcttt tatcgaggac 2460
ctgctgttca acaaggtgac cctggccgat gccggcttca tcaagcagta cggcgattgc 2520
ctgggcgaca tcgcagcaag ggacctgatc tgtgcccaga agtttaatgg cctgaccgtg 2580
ctgccacccc tgctgacaga tgagatgatc gcccagtata catccgccct gctggccggc 2640
accatcacat ctggatggac cttcggcgca ggagccgccc tgcagatccc ctttgccatg 2700
cagatggcct acaggttcaa cggcatcggc gtgacccaga atgtgctgta tgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggactc cctgagctcc 2820
acagcctctg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaat 2880
accctggtga agcagctgtc tagcaacttc ggcgccatct cctctgtgct gaatgatatc 2940
ctgagccggc tggacccccc cgaggcagag gtgcagatcg accggctgat caccggcaga 3000
ctgcagagcc tgcagaccta cgtgacacag cagctgatca gggccgccga gatcagggca 3060
tccgccaatc tggccgccat caagatgtct gagtgcgtgc tgggccagag caagagagtg 3120
gacttttgtg gcaagggcta ccacctgatg agcttccctc agtccgcccc acacggagtg 3180
gtgtttctgc acgtgaccta tgtgcccgcc caggagaaga acttcaccac agcccctgcc 3240
atctgccacg atggcaaggc ccactttcca agggagggcg tgttcgtgtc caacggcacc 3300
cactggtttg tgacacagcg caatttctac gagccccaga tcatcaccac agacaatacc 3360
ttcgtgagcg gcaactgtga cgtggtcatc ggcatcgtga acaataccgt gtacgatcca 3420
ctgcagcccg agctggactc ctttaaggag gagctggata agtatttcaa gaatcacacc 3480
tctcccgacg tggatctggg cgacatctcc ggcatcaatg cctctttcgt gaacatccag 3540
aaggagatcg accgcctgaa cgaggtggcc aagaatctga acgagtccct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggccct ggtacatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacaagctgc 3720
tgttcctgcc tgaagggctg ctgttcttgt ggcagctgct gtaagtttga tgaggacgat 3780
agcgagcctg tgctgaaggg cgtgaagctg cactatacct ga 3822
<210> 17
<211> 3816
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 17
atgtttgtgt ttctggtgct gctgccactg gtgagtagcc agtgtgtgaa cctgagaacc 60
cgaacacagc tgcctcctgc ctataccaac agcttcacca gaggcgtgta ctaccctgac 120
aaggtgttcc gatctagcgt gctccatagc acccaggacc tgttcttgcc ttttttctct 180
aacgtgacat ggttccacgc cattcacgtg tctggcacca acggaacaaa aagattcgac 240
aaccctgtgc tgcccttcaa cgacggtgtc tattttgcca gcaccgagaa gagcaacatc 300
atcagaggct ggatcttcgg aaccaccctg gacagcaaga cccagagcct gctgatcgtc 360
aataacgcaa caaatgtggt gatcaaggtg tgcgagttcc aattttgcaa cgatcctttc 420
ctggatgtgt actaccacaa gaacaacaaa agctggatgg aaagtggagt ttatagcagc 480
gccaacaact gcaccttcga gtacgtgagc caacctttcc tgatggacct cgaagggaaa 540
cagggcaact tcaagaacct tagagagttc gtctttaaga acatcgacgg ctactttaaa 600
atctactcca agcacacccc catcaacctg gtgcgggacc tgcctcaggg ctttagcgcg 660
ctggaaccct tggttgacct gcccatcggc atcaacatca ctagattcca gacccttctg 720
gccctccacc ggtcttacct gacacctggc gacagtagtt ctggctggac agccggcgcc 780
gctgcctact acgtgggcta tctgcagcct agaaccttcc tgctgaagta caacgagaac 840
ggcaccatca ccgacgctgt ggattgcgcc ctggaccctc tgtccgaaac caagtgcaca 900
ctgaagtcct tcaccgtgga aaagggcatc taccagacct ctaacttccg ggtgcagcct 960
actgaaagca tcgtgcggtt cccaaacatt acaaacctgt gccctttcgg agaagttttc 1020
aacgccactc gcttcgcctc tgtctatgcc tggaacagaa agcggatcag caattgtgtg 1080
gccgattaca gcgtgctgta caacagcgcc agcttttcta cattcaagtg ctacggcgtg 1140
tctcccacca agctgaatga tctgtgcttc accaacgtgt acgccgactc gtttgtgatc 1200
cggggagacg aagtgcgcca gatcgcccct gggcagacag gaaacatcgc cgattacaat 1260
tacaaactgc ctgacgattt tacaggatgt gtgatagctt ggaactccaa caacctcgac 1320
agcaaagtgg gcggcaacta caattaccgg tacagactgt ttagaaagag caacctaaaa 1380
cccttcgaga gagatatctc taccgagatc taccaggccg gcagcaagcc ttgtaatggc 1440
gttgagggct tcaactgtta cttccctctg cagagctacg gcttccagcc caccaacggc 1500
gtcgggtacc agccttacag agttgtggtt ctgagcttcg agctgctcca cgctcctgcc 1560
accgtgtgtg gtcctaagaa aagcaccaac ctggtgaaga acaagtgcgt gaatttcaat 1620
ttcaacggcc tgacaggcac aggcgtgctg accgagagca acaaaaagtt cctgcccttc 1680
cagcagttcg gcagagatat tgccgatacc acagacgccg tgcgggaccc tcaaaccctg 1740
gaaatcttgg acatcacacc ttgcagcttc ggcggagtgt ctgtgatcac tcccgggacc 1800
aacaccagca accaggttgc cgtgctgtac cagggcgtca actgcaccga agtgccagtg 1860
gctatacacg ccgaccagct gacccctaca tggcgggtgt acagcaccgg cagcaacgtg 1920
ttccagacca gagccggctg cctgatcggc gcagagcacg tgaacaactc ttatgaatgc 1980
gacatcccca tcggagccgg catttgcgcc agctaccaga cacagaccaa tagcagaaga 2040
cgggctagaa gcgtggcctc gcagagcata atcgcataca caatgagcct gggagccgag 2100
aacagcgtgg cctacagcaa caatagtatc gccatcccca caaattttac catcagcgtg 2160
acaaccgaaa tcctgccagt gagcatgaca aagaccagcg tcgactgcac aatgtacata 2220
tgtggcgata gcacggagtg cagcaatctg ctgctccaat acggcagctt ctgcacccag 2280
ctgaatcggg cactgaccgg catcgccgtg gaacaggata aaaataccca ggaggtgttt 2340
gcccaggtga agcagatata taagacccct ccgatcaagg acttcggagg cttcaatttc 2400
agccagatcc tgcccgatcc aagcaagcct agcaagcggt ccttcatcga ggatctgctg 2460
ttcaataagg tgaccctggc cgacgccgga ttcatcaaac agtacggcga ctgcctgggc 2520
gacatcgccg ccagagatct gatctgtgct caaaagttca acggactgac agtcctgcca 2580
cctctgttga cagatgaaat gatcgctcag tacacctccg ccctcctggc cgggacgatc 2640
acctctggat ggaccttcgg cgccggcgct gcactgcaga tccctttcgc catgcagatg 2700
gcctacagat tcaacggcat cggagtgacc caaaacgtcc tgtacgagaa ccagaagctg 2760
atcgccaacc agttcaactc tgctatcggc aagatccagg acagcctcag cagcaccgcc 2820
agcgccctgg gcaaactcca gaacgtggtg aaccagaacg cacaggccct gaataccctg 2880
gtgaagcagc tgagcagcaa cttcggcgct atcagctctg tgctgaacga catcctgagc 2940
agactggacc ctcccgaggc cgaggtgcag attgacaggc tgatcacagg cagactgcag 3000
tcgctgcaaa cttacgtgac ccagcaactg atccgggccg ccgaaatcag ggccagcgcc 3060
aacctggctg ctacaaagat gtccgaatgc gtgttgggcc agtccaagag agtggacttc 3120
tgcggcaagg gataccacct gatgagcttc cctcagtccg ctccccacgg cgtcgtgttc 3180
ctgcatgtga catacgtgcc cgcccaggag aagaatttca ccaccgcccc tgccatctgc 3240
cacgacggca aggcccactt ccccagagag ggcgtgttcg tgtccaacgg cacccactgg 3300
ttcgtgaccc agcggaactt ctacgagcct cagatcatca ccaccgataa cacattcgtg 3360
tccggcaact gcgacgtggt tatcggcatc gtgaacaata ccgtgtacga ccctctgcag 3420
ccagaactgg attcttttaa ggaagagctg gacaaatact ttaagaacca cacatctcct 3480
gatgtggacc tgggcgacat cagcggcatc aacgcctccg tggtcaacat ccaaaaggag 3540
atcgatagac tgaacgaggt ggccaagaac ctcaacgagt ctctgattga cctgcaggag 3600
ctgggcaagt acgagcagta catcaagtgg ccttggtaca tctggctggg cttcatcgcc 3660
ggcctgatcg ctatcgtcat ggtgaccatc atgctgtgct gtatgacctc ctgctgcagc 3720
tgtctgaaag gctgctgttc ttgcggcagc tgttgcaagt ttgacgagga cgactccgag 3780
cccgtgctga agggggtgaa gctgcactac acgtga 3816
<210> 18
<211> 3813
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 18
atgttcgtgt tcctggtgct gctgcccctg gtgtctagcc aatgtgtgaa cctgacaaca 60
aggacccagc ttcccccagc ttacaccaat tcatttacaa gaggcgtgta ttaccccgat 120
aaggtgttcc gaagcagcgt gctgcacagc acccaggatc tcttcctgcc ttttttcagc 180
aatgtgactt ggttccacgt gatcagcgga accaacggca ccaagcggtt tgacaatcct 240
gtgctgccct tcaacgacgg cgtgtacttc gccagcatcg agaagagcaa cattatccgg 300
ggctggatct tcggcaccac cctcgatagc aagacccaga gcttactgat cgtaaacaac 360
gccaccaatg tcgtaatcaa ggtctgtgaa tttcagttct gcaacgaccc ctttctggac 420
cacaagaaca acaagtcgtg gatggaaagc gagttcagag tgtacagctc cgctaacaat 480
tgtacattcg agtacgtgtc tcagcctttc ctgatggacc tggaaggcaa gcagggaaac 540
ttcaagaatc tgagggagtt cgtgttcaaa aacatcgacg gctacttcaa gatctacagc 600
aagcataccc ccatcatcgt tgaacctgag agagacctgc cacagggttt cagcgctctg 660
gagcctctgg ttgacctgcc catcggcatc aacatcaccc ggtttcagac actgttagcc 720
ctgcatagat cttacctgac cccaggcgat tcttcctctg gctggaccgc cggagccgca 780
gcctactacg tgggatatct gcagcccaga accttcctgc tgaaatacaa cgagaacgga 840
accatcaccg atgccgtgga ctgcgccctg gaccctctgt ctgaaaccaa gtgcaccctg 900
aagagcttca ccgtggaaaa gggcatctac cagaccagca actttcgggt gcagcccacc 960
gagagcatcg tgagatttcc aaacatcacc aacctgtgtc ctttcgacga ggtgtttaat 1020
gccacaagat tcgccagcgt gtacgcctgg aatagaaaaa gaatctccaa ctgcgtggct 1080
gattactcag tgctttacaa cctggcccca ttcttcacct tcaagtgcta cggcgttagc 1140
cctaccaagc tcaatgatct gtgcttcacg aacgtgtacg ccgacagctt cgtgatccgg 1200
ggcgacgaag tcagacagat cgcccctgga cagaccggta atatcgccga ctacaattac 1260
aagctgcctg atgatttcac aggttgcgtg atcgcctgga actccaacaa gctggacagc 1320
aaggtgtccg gcaactacaa ctacctgtat agacttttca gaaagtccaa cctgaagcca 1380
ttcgagcggg acatcagcac tgagatctac caggccggca acaaaccctg caacggagtt 1440
gccggattca actgctattt ccctctgaga tcttactcct tcagacctac atacggcgtg 1500
ggacaccagc cttacagagt agtggtgctc agcttcgagc ttctgcacgc tcctgccacc 1560
gtgtgcggcc ctaagaagag cacgaacctg gtgaagaaca aatgtgttaa ttttaacttc 1620
aacggcctga agggcacagg agtcctgacc gagagcaata aaaaattctt gcccttccag 1680
cagttcggaa gagacatcgc cgacaccaca gatgctgtga gagaccctca gaccctggaa 1740
atcctcgaca tcaccccttg cagcttcggc ggcgtcagcg tgatcacccc gggcaccaac 1800
acctctaacc aggtggccgt gctgtaccag ggcgtgaatt gcaccgaggt tcctgtggcc 1860
atccacgcgg accagctgac accaacatgg cgggtgtaca gcaccggctc caacgtgttt 1920
cagaccagag ccggctgtct gatcggcgcc gaatatgtga acaacagcta cgaatgcgac 1980
atcccaatcg gcgccggcat ttgcgccagc taccagacac agaccaaaag tcaccggaga 2040
gctcggagcg tggcctctca gagcattatc gcctatacca tgagcctggg ggccgagaac 2100
agcgtggcct attccaacaa cagcatcgcc atccctacca atttcaccat ctctgtgacc 2160
accgagatcc tgccagtgtc catgacaaag acaagcgtgg actgcaccat gtacatctgc 2220
ggcgactcta ccgagtgcag caacctgctg ctgcagtacg gcagcttttg cacacagctg 2280
aaacgggcgc tgacaggaat tgccgttgag caggacaaga acactcagga ggtgtttgcc 2340
caagtgaagc agatatataa gacccctcct atcaaatact tcggcggctt taacttcagc 2400
cagatcctcc ctgatccttc taagcctagc aagcgcagct tcatcgagga cctgctgttc 2460
aacaaggtaa ccctggctga cgccggcttc atcaagcagt acggtgattg cctgggcgac 2520
atcgcagccc gggacctgat ctgtgcccaa aaattcaagg gcctgactgt tctgcctcct 2580
ctgctgacag atgaaatgat cgcccagtac acctccgccc tgctggctgg cacaatcacc 2640
agcggctgga cattcggcgc cggcgccgcg ctgcagatcc ctttcgccat gcagatggcc 2700
tacagattca acggcatcgg agtgactcag aacgtgctgt acgaaaacca gaaactgatt 2760
gcaaatcagt ttaacagcgc aatcggcaag atccaggata gcctgtccag caccgcctcc 2820
gctctgggca agctgcaaga cgtggtgaac cacaatgccc aggctctgaa caccttggtg 2880
aagcagctga gcagcaagtt cggcgccatt tcttccgtgc tgaacgacat cttcagcaga 2940
ctcgatcctc ccgaggccga ggtgcagatc gacagactga tcacgggcag actgcagtct 3000
ctgcagacat acgtgacaca gcaactgatc agagccgctg aaatcagggc ctctgccaac 3060
ctggccgcca ccaagatgtc tgagtgcgtg ctcggccagt ctaaaagagt ggacttctgc 3120
ggcaaaggct accacctgat gagcttcccc cagagcgccc cccacggcgt ggtgttccta 3180
cacgttacct acgtgccggc tcaagaaaag aactttacca ccgcccctgc catctgccac 3240
gacggaaagg cccacttccc tcgggagggt gtgtttgtca gcaacggcac acactggttc 3300
gtgacacagc ggaacttcta cgagccccaa atcatcacaa cagataacac cttcgtcagc 3360
ggcaactgtg acgtggtgat cggcatcgtg aacaacaccg tgtatgaccc tctgcagcct 3420
gagctggaca gctttaagga agagctggac aagtacttca agaatcacac aagtcctgac 3480
gtggatctgg gcgatatcag tggcatcaac gcctctgtgg tgaacataca aaaggagatc 3540
gacagactga acgaggtggc aaagaacctg aatgaaagcc tgatcgacct gcaagaactg 3600
ggcaagtacg agcagtacat caagtggcct tggtacattt ggctgggatt tatcgcaggc 3660
ctcatcgcca tcgtgatggt gacaatcatg ctgtgttgca tgaccagctg ttgcagctgc 3720
ctgaaaggct gttgtagctg cggcagctgc tgcaagttcg atgaggacga cagcgagcct 3780
gtcctgaagg gggtgaagct gcactacaca tga 3813
<210> 19
<211> 3822
<212> DNA
<213> 人工序列
<220>
<223> 合成核酸
<400> 19
atgttcgtct tcctggtcct gctgcccctg gtctcatctc agtgcgtgaa tctgactaca 60
agaactcagc tgcctcccgc ctacaccaat tccttcaccc ggggcgtgta ctatcctgac 120
aaggtgttta gaagctccgt gctgcactct acacaggatc tgtttctgcc attctttagc 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gcggttcgac 240
aatcccgtgc tgccttttaa cgatggcgtg tacttcgcct ctaccgagaa gagcaacatc 300
atcagaggct ggatctttgg caccacactg gactccaaga cacagtctct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa tgatcccttc 420
ctgggcgtgt actatcacaa gaacaataag agctggatgg agtccgagtt tagagtgtat 480
tctagcgcca acaattgcac atttgagtac gtgtcccagc ctttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgagg gagttcgtgt ttaagaatat cgatggctac 600
ttcaagatct actctaagca cacccccatc aacctggtgc gcgacctgcc tcagggcttc 660
agcgccctgg agccactggt ggatctgcct atcggcatca acatcacccg gtttcagaca 720
ctgctggccc tgcacagaag ctacctgaca cccggcgact cctctagcgg atggaccgca 780
ggagcagcag cctactatgt gggctatctg cagcctagga ccttcctgct gaagtacaac 840
gagaatggca ccatcacaga cgcagtggat tgcgccctgg accccctgag cgagacaaag 900
tgtacactga agtcctttac cgtggagaag ggcatctatc agacatccaa tttcagggtg 960
cagccaaccg agtctatcgt gcgctttcct aatatcacaa acctgtgccc atttggcgag 1020
gtgttcaacg caaccaggtt cgcaagcgtg tacgcatgga ataggaagcg catctctaac 1080
tgcgtggccg actatagcgt gctgtacaac tccgcctctt tcagcacctt taagtgctat 1140
ggcgtgtccc ccacaaagct gaatgacctg tgctttacca acgtgtacgc cgattctttc 1200
gtgatcaggg gcgacgaggt gcgccagatc gcacctggac agacaggcaa gatcgccgac 1260
tacaattata agctgccaga cgatttcacc ggctgcgtga tcgcctggaa cagcaacaat 1320
ctggattcca aagtgggcgg caactacaat tatctgtacc ggctgtttag aaagagcaat 1380
ctgaagccct tcgagaggga catctctaca gagatctacc aggccggcag caccccttgc 1440
aatggcgtgg agggctttaa ctgttatttc ccactgcagt cctacggctt ccagcccaca 1500
aacggcgtgg gctatcagcc ttaccgcgtg gtggtgctga gctttgagct gctgcacgca 1560
ccagcaacag tgtgcggacc caagaagtcc accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggcctgac cggaacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccatttcagc agttcggcag ggacatcgca gataccacag acgccgtgcg cgacccacag 1740
accctggaga tcctggatat cacaccctgc tctttcggcg gcgtgagcgt gatcacacca 1800
ggaaccaata caagcaacca ggtggccgtg ctgtatcagg acgtgaattg taccgaggtg 1860
cctgtggcca tccacgccga tcagctgacc ccaacatggc gggtgtacag caccggctcc 1920
aacgtgttcc agacaagagc aggatgcctg atcggagcag agcacgtgaa caattcctat 1980
gagtgcgaca tcccaatcgg cgccggcatc tgtgcctctt accagaccca gacaaactct 2040
ccaaggagag cacggagcgt ggcatcccag tctatcatcg cctataccat gtccctgggc 2100
gccgagaatt ctgtggccta ctctaacaat agcatcgcca tcccaaccaa cttcacaatc 2160
tctgtgacca cagagatcct gcccgtgtcc atgaccaaga catctgtgga ctgcacaatg 2220
tatatctgtg gcgattctac cgagtgcagc aacctgctgc tgcagtacgg cagcttttgt 2280
acccagctga atagagccct gacaggcatc gccgtggagc aggataagaa cacacaggag 2340
gtgttcgccc aggtgaagca gatctacaag acccccccta tcaaggactt tggcggcttc 2400
aatttttccc agatcctgcc tgatccatcc aagccttcta agcggagctt tatcgaggac 2460
ctgctgttca acaaggtgac cctggccgat gccggcttca tcaagcagta tggcgattgc 2520
ctgggcgaca tcgcagcacg ggacctgatc tgtgcccaga agtttaatgg cctgaccgtg 2580
ctgccacccc tgctgacaga tgagatgatc gcacagtaca caagcgccct gctggcagga 2640
accatcacat ccggatggac cttcggcgca ggagccgccc tgcagatccc ctttgccatg 2700
cagatggcct ataggttcaa cggcatcggc gtgacccaga atgtgctgta cgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggacag cctgtcctct 2820
acagcctccg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaat 2880
accctggtga agcagctgag ctccaacttc ggcgccatct ctagcgtgct gaatgatatc 2940
ctgagccggc tggacccccc cgaggcagag gtgcagatcg accggctgat cacaggcaga 3000
ctgcagtctc tgcagaccta tgtgacacag cagctgatca gggcagcaga gatcagggca 3060
agcgccaatc tggcagcaac caagatgtcc gagtgcgtgc tgggccagtc taagagagtg 3120
gacttttgtg gcaagggcta tcacctgatg tccttccctc agtctgcccc acacggcgtg 3180
gtgtttctgc acgtgaccta cgtgcccgcc caggagaaga acttcaccac agcccctgcc 3240
atctgccacg atggcaaggc ccactttcca agggagggcg tgttcgtgtc caacggcacc 3300
cactggtttg tgacacagcg caatttctac gagccccaga tcatcaccac agacaatacc 3360
ttcgtgagcg gcaactgtga cgtggtcatc ggcatcgtga acaataccgt gtatgatcca 3420
ctgcagcccg agctggacag ctttaaggag gagctggata agtacttcaa gaatcacacc 3480
tcccctgacg tggatctggg cgacatcagc ggcatcaatg cctccgtggt gaacatccag 3540
aaggagatcg accgcctgaa cgaggtggcc aagaatctga acgagagcct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggccat ggtacatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacatcctgc 3720
tgttcttgcc tgaagggctg ctgtagctgt ggctcctgct gtaagtttga tgaggacgat 3780
tccgaacccg tgctgaaggg agtgaagctg cattacacct ga 3822
Claims (34)
1.表达SARS-CoV-2刺突(S)蛋白的重组4型腺病毒(Ad4)，其中：
所述S蛋白的氨基酸序列与SEQ ID NO:2至少95％相同；
所述重组Ad4是具有复制能力的；并且
所述重组Ad4的基因组含有腺病毒E3区中的缺失和SARS-CoV-2S蛋白编码序列的插入。
2.根据权利要求1所述的重组Ad4，其中所述S蛋白的氨基酸序列与SEQ ID NO:2至少99％相同。
3.根据权利要求1或2所述的重组Ad4，其中所述S蛋白的氨基酸序列包含SEQ ID NO:2或由其组成。
4.根据权利要求1所述的重组Ad4，其中所述S蛋白的氨基酸序列包含至少一个使该蛋白在融合前构象下稳定的修饰。
5.根据权利要求4所述的重组Ad4，其中所述至少一个修饰包含K986P和V987P取代。
6.根据权利要求4或5所述的重组Ad4，其中所述S蛋白的氨基酸序列包含SEQ ID NO:3、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12，或由其组成。
7.根据权利要求1-6中的任一项所述的重组Ad4，其中所述E3区中的缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K开放阅读框(ORF)的缺失。
8.根据权利要求1-7中的任一项所述的重组Ad4，其中所述SARS-CoV-2S蛋白的编码序列被插入至E3区缺失的位置。
9.根据权利要求1-8中的任一项所述的重组Ad4，其中所述S蛋白由密码子优化的核酸序列编码。
10.根据权利要求9所述的重组Ad4，其中所述密码子优化的核酸序列包含SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18或SEQ IDNO:19，或由其组成。
11.根据权利要求1-3中的任一项所述的重组Ad4，其中所述基因组的核苷酸序列与SEQID NO:1至少95％相同。
12.根据权利要求1-3中的任一项所述的重组Ad4，其中所述基因组的核苷酸序列与SEQID NO:1至少99％相同。
13.根据权利要求1-3中的任一项所述的重组Ad4，其中所述基因组的核苷酸序列包含SEQ ID NO:1或由其组成。
14.重组4型腺病毒(Ad4)载体，包含腺病毒E3区中的缺失和SARS-CoV-2S编码序列的插入，其中所述S蛋白的氨基酸序列与SEQ ID NO:2至少95％相同。
15.根据权利要求14所述的重组Ad4载体，其中所述S蛋白的氨基酸序列与SEQ ID NO:2至少99％相同。
16.根据权利要求14或15所述的重组Ad4载体，其中所述S蛋白的氨基酸序列包含SEQID NO:2或由其组成。
17.根据权利要求14所述的重组Ad4载体，其中所述S蛋白的氨基酸序列包含至少一个使该蛋白在融合前构象下稳定的修饰。
18.根据权利要求17所述的重组Ad4，其中所述至少一个修饰包含K986P和V987P取代。
19.根据权利要求17或18所述的重组Ad4，其中所述S蛋白的氨基酸序列包含SEQ IDNO:3、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ IDNO:12，或由其组成。
20.根据权利要求14-19中的任一项所述的重组Ad4载体，其中所述E3区中的缺失包括23.3K、19K、24.8K、6.3K、29.7K、10.4K、14.5K和14.7K开放阅读框(ORF)的缺失。
21.根据权利要求14-20中的任一项所述的重组Ad4载体，其中所述SARS-CoV-2S的编码序列被插入至E3区缺失的位置。
22.根据权利要求14-21中的任一项所述的重组Ad4载体，其中所述S蛋白由密码子优化的核酸序列编码。
23.根据权利要求22所述的重组Ad4载体，其中所述密码子优化的核酸序列包含SEQ IDNO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18或SEQID NO:19，或由其组成。
24.根据权利要求14-16中的任一项所述的重组Ad4载体，其中所述载体的核苷酸序列与SEQ ID NO:1至少95％相同。
25.根据权利要求14-16中的任一项所述的重组Ad4载体，其中所述载体的核苷酸序列与SEQ ID NO:1至少99％相同。
26.根据权利要求14-16中的任一项所述的重组Ad4载体，其中所述载体的核苷酸序列包含SEQ ID NO:1或由其组成。
27.免疫原性组合物，包含权利要求1-13中的任一项所述的重组Ad4或权利要求14-26中的任一项所述的重组Ad4载体，和药学上可接受的载体。
28.在受试者中诱发针对SARS-CoV-2的免疫反应的方法，包括向受试者施用治疗有效量的权利要求1-13中的任一项所述的重组Ad4、权利要求14-26中的任一项所述的重组的具有复制能力的Ad4载体，或权利要求27所述的免疫原性组合物，从而在受试者中诱发针对SARS-CoV-2的免疫反应。
29.使受试者针对SARS-CoV-2的感染免疫的方法，包括向受试者施用治疗有效量的权利要求1-13中的任一项所述的重组Ad4、权利要求14-26中的任一项所述的重组的具有复制能力的Ad4载体，或权利要求27所述的免疫原性组合物，从而使受试者针对SARS-CoV-2的感染免疫。
30.根据权利要求28或29所述的方法，其中施用包含鼻内施用。
31.根据权利要求30所述的方法，其中鼻内施用包含施用气溶胶，该气溶胶包含直径大于10微米的颗粒。
32.根据权利要求28-31中的任一项所述的方法，其包含施用约104至约106个重组Ad4颗粒的剂量。
33.根据权利要求32所述的方法，其包含施用约105个重组的Ad4的颗粒的剂量。
34.根据权利要求28-33中的任一项所述的方法，其中所述重组Ad4、所述重组Ad4载体或所述免疫原性组合物以单剂施用。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202163138221P | 2021-01-15 | 2021-01-15 | |
| US63/138,221 | 2021-01-15 | ||
| PCT/US2022/012530 WO2022155476A1 (en) | 2021-01-15 | 2022-01-14 | Replication-competent adenovirus type 4 sars-cov-2 vaccines and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117412769A true CN117412769A (zh) | 2024-01-16 |
Family
ID=80222188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280010458.8A Pending CN117412769A (zh) | 2021-01-15 | 2022-01-14 | 具有复制能力的4型腺病毒sars-cov-2疫苗及其用途 |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP4277656A1 (zh) |
| JP (1) | JP2024503482A (zh) |
| KR (1) | KR20230132816A (zh) |
| CN (1) | CN117412769A (zh) |
| AU (1) | AU2022208035A1 (zh) |
| CA (1) | CA3205052A1 (zh) |
| WO (1) | WO2022155476A1 (zh) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5643578A (en) | 1992-03-23 | 1997-07-01 | University Of Massachusetts Medical Center | Immunization by inoculation of DNA transcription unit |
| US5593972A (en) | 1993-01-26 | 1997-01-14 | The Wistar Institute | Genetic immunization |
| EP2296700A2 (en) * | 2008-06-03 | 2011-03-23 | Vaxin, Inc. | Intranasal administration of receptor-binding ligands or genes encoding such ligands as a therapeutic regimen for mitigating infections caused by respiratory pathogens |
| DK3205353T3 (da) * | 2011-03-21 | 2021-04-06 | Altimmune Inc | Hurtig- og langtidsvirkende immunologisk terapeutisk middel |
-
2022
- 2022-01-14 KR KR1020237027608A patent/KR20230132816A/ko unknown
- 2022-01-14 AU AU2022208035A patent/AU2022208035A1/en active Pending
- 2022-01-14 JP JP2023543164A patent/JP2024503482A/ja active Pending
- 2022-01-14 CN CN202280010458.8A patent/CN117412769A/zh active Pending
- 2022-01-14 CA CA3205052A patent/CA3205052A1/en active Pending
- 2022-01-14 WO PCT/US2022/012530 patent/WO2022155476A1/en active Application Filing
- 2022-01-14 EP EP22703165.5A patent/EP4277656A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR20230132816A (ko) | 2023-09-18 |
| AU2022208035A1 (en) | 2023-07-13 |
| WO2022155476A1 (en) | 2022-07-21 |
| JP2024503482A (ja) | 2024-01-25 |
| CA3205052A1 (en) | 2022-07-21 |
| EP4277656A1 (en) | 2023-11-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11759516B2 (en) | Nucleic acid vaccine against the SARS-CoV-2 coronavirus | |
| CN111088283B (zh) | mVSV病毒载体及其病毒载体疫苗、一种基于mVSV介导的新冠肺炎疫苗 | |
| BE1023087B1 (fr) | Antigenes du cytomegalovirus et leurs utilisations | |
| US5741492A (en) | Preparation and use of viral vectors for mixed envelope protein vaccines against human immunodeficiency viruses | |
| EP2961846B1 (en) | Crimean-congo haemorrhagic fever virus antigenic composition | |
| KR20170102905A (ko) | 신규 다가 나노입자 기반 백신 | |
| KR20220016137A (ko) | 변형된 아데노바이러스 | |
| KR20210090650A (ko) | 알파바이러스 신생항원 벡터 및 인터페론 억제제 | |
| KR20220041844A (ko) | Hiv 항원 및 mhc 복합체 | |
| CN113666990A (zh) | 一种诱导广谱抗冠状病毒的t细胞疫苗免疫原及其应用 | |
| JP2023534421A (ja) | 触媒反応が不活性化されたアンジオテンシン変換酵素２（ａｃｅ２）変異型とその利用 | |
| EP4205761A1 (en) | Novel coronavirus recombinant spike protein, polynucleotide encoding same, vector comprising polynucleotide, and vaccine for preventing or treating coronavirus infection, comprising vector | |
| US20230405109A1 (en) | Nucleic acids, proteins, and vaccines of sars-cov-2 | |
| CA2539864A1 (en) | Hiv pharmaccines | |
| KR20230006825A (ko) | 전염성 질병 항원 및 백신 | |
| CN111148528A (zh) | 流感疫苗 | |
| KR20230005265A (ko) | Sars-cov-2에 대한 백신 및 이의 제조 | |
| CN114891830B (zh) | 基于水痘-带状疱疹病毒的重组表达载体、重组病毒及用途 | |
| CN117412769A (zh) | 具有复制能力的4型腺病毒sars-cov-2疫苗及其用途 | |
| WO2014151687A2 (en) | Compositions and methods to treat aids | |
| WO2021198701A1 (en) | Influenza vaccines | |
| JP2002501369A (ja) | Ｆｉｖワクチン | |
| US6723558B1 (en) | Preparation and use of viral vectors for mixed envelope protein vaccines against human immunodeficiency viruses | |
| CN117716036A (zh) | 用于病毒性疾病的温度可控型自我复制rna疫苗 |
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 |