CN113527509B - 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 - Google Patents
含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 Download PDFInfo
- Publication number
- CN113527509B CN113527509B CN202010307681.1A CN202010307681A CN113527509B CN 113527509 B CN113527509 B CN 113527509B CN 202010307681 A CN202010307681 A CN 202010307681A CN 113527509 B CN113527509 B CN 113527509B
- Authority
- CN
- China
- Prior art keywords
- ser
- gly
- protein
- adenovirus
- fragment
- 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.)
- Active
Links
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 title claims abstract description 91
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 title claims abstract description 91
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 78
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 74
- 230000001681 protective effect Effects 0.000 title claims abstract description 38
- 201000005243 lung squamous cell carcinoma Diseases 0.000 title claims description 6
- 241000701161 unidentified adenovirus Species 0.000 claims abstract description 130
- 210000004072 lung Anatomy 0.000 claims abstract description 78
- 210000004027 cell Anatomy 0.000 claims abstract description 53
- 239000012634 fragment Substances 0.000 claims abstract description 51
- 101710189104 Fibritin Proteins 0.000 claims abstract description 35
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims abstract description 34
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims abstract description 34
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 claims abstract description 30
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 claims abstract description 30
- 241001515965 unidentified phage Species 0.000 claims abstract description 27
- 102000018697 Membrane Proteins Human genes 0.000 claims abstract description 20
- 108010052285 Membrane Proteins Proteins 0.000 claims abstract description 20
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 102000035035 immunoglobulin-like cell adhesion molecules Human genes 0.000 claims abstract description 20
- 108091005483 immunoglobulin-like cell adhesion molecules Proteins 0.000 claims abstract description 20
- 108010084938 adenovirus receptor Proteins 0.000 claims abstract description 19
- 239000013598 vector Substances 0.000 claims description 70
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 27
- 102000039446 nucleic acids Human genes 0.000 claims description 24
- 108020004707 nucleic acids Proteins 0.000 claims description 24
- 150000007523 nucleic acids Chemical class 0.000 claims description 24
- 229920001184 polypeptide Polymers 0.000 claims description 23
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 23
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 239000002773 nucleotide Substances 0.000 claims description 8
- 125000003729 nucleotide group Chemical group 0.000 claims description 8
- 239000002131 composite material Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 2
- 206010041823 squamous cell carcinoma Diseases 0.000 abstract description 67
- 238000010362 genome editing Methods 0.000 abstract description 20
- 230000028993 immune response Effects 0.000 abstract description 12
- 238000011160 research Methods 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 208000015181 infectious disease Diseases 0.000 description 19
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 18
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 17
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 16
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 14
- 241000880493 Leptailurus serval Species 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 108091033409 CRISPR Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 108010026333 seryl-proline Proteins 0.000 description 11
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 101100076418 Homo sapiens MECOM gene Proteins 0.000 description 9
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 9
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 9
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 9
- 108010064235 lysylglycine Proteins 0.000 description 9
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 8
- 101710094396 Hexon protein Proteins 0.000 description 8
- 101150044538 MECOM gene Proteins 0.000 description 8
- 108010079364 N-glycylalanine Proteins 0.000 description 8
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 8
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 8
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 7
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 7
- 238000001415 gene therapy Methods 0.000 description 7
- 210000004185 liver Anatomy 0.000 description 7
- 108010003137 tyrosyltyrosine Proteins 0.000 description 7
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 6
- 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 6
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 108010081404 acein-2 Proteins 0.000 description 6
- 108010087924 alanylproline Proteins 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 108010017391 lysylvaline Proteins 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- OQCWXQJLCDPRHV-UWVGGRQHSA-N Arg-Gly-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O OQCWXQJLCDPRHV-UWVGGRQHSA-N 0.000 description 5
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 5
- GFFRWIJAFFMQGM-NUMRIWBASA-N Asn-Glu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GFFRWIJAFFMQGM-NUMRIWBASA-N 0.000 description 5
- VIRHEUMYXXLCBF-WDSKDSINSA-N Asp-Gly-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O VIRHEUMYXXLCBF-WDSKDSINSA-N 0.000 description 5
- 102100025278 Coxsackievirus and adenovirus receptor Human genes 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 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 5
- KZKBJEUWNMQTLV-XDTLVQLUSA-N Gln-Ala-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZKBJEUWNMQTLV-XDTLVQLUSA-N 0.000 description 5
- MCAVASRGVBVPMX-FXQIFTODSA-N Gln-Glu-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MCAVASRGVBVPMX-FXQIFTODSA-N 0.000 description 5
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 5
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 5
- UZWUBBRJWFTHTD-LAEOZQHASA-N Glu-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O UZWUBBRJWFTHTD-LAEOZQHASA-N 0.000 description 5
- 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 5
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 5
- 108020005004 Guide RNA Proteins 0.000 description 5
- 101000858031 Homo sapiens Coxsackievirus and adenovirus receptor Proteins 0.000 description 5
- UIEZQYNXCYHMQS-BJDJZHNGSA-N Ile-Lys-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)O)N UIEZQYNXCYHMQS-BJDJZHNGSA-N 0.000 description 5
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 5
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 5
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 5
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 5
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 5
- 108010003201 RGH 0205 Proteins 0.000 description 5
- 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 5
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 5
- 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 5
- ZUXQFMVPAYGPFJ-JXUBOQSCSA-N Thr-Ala-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN ZUXQFMVPAYGPFJ-JXUBOQSCSA-N 0.000 description 5
- 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 5
- PAPWZOJOLKZEFR-AVGNSLFASA-N Val-Arg-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N PAPWZOJOLKZEFR-AVGNSLFASA-N 0.000 description 5
- DJEVQCWNMQOABE-RCOVLWMOSA-N Val-Gly-Asp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N DJEVQCWNMQOABE-RCOVLWMOSA-N 0.000 description 5
- 108010089804 glycyl-threonine Proteins 0.000 description 5
- 108010057821 leucylproline Proteins 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 4
- XQGIRPGAVLFKBJ-CIUDSAMLSA-N Ala-Asn-Lys Chemical compound N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)O XQGIRPGAVLFKBJ-CIUDSAMLSA-N 0.000 description 4
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 4
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 4
- DPXDVGDLWJYZBH-GUBZILKMSA-N Arg-Asn-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O DPXDVGDLWJYZBH-GUBZILKMSA-N 0.000 description 4
- QQJSJIBESHAJPM-IHRRRGAJSA-N Arg-Cys-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QQJSJIBESHAJPM-IHRRRGAJSA-N 0.000 description 4
- 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 4
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 4
- XEOXPCNONWHHSW-AVGNSLFASA-N Arg-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N XEOXPCNONWHHSW-AVGNSLFASA-N 0.000 description 4
- 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 4
- HFPXZWPUVFVNLL-GUBZILKMSA-N Asn-Leu-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HFPXZWPUVFVNLL-GUBZILKMSA-N 0.000 description 4
- 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 4
- VZNOVQKGJQJOCS-SRVKXCTJSA-N Asp-Asp-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VZNOVQKGJQJOCS-SRVKXCTJSA-N 0.000 description 4
- SMZCLQGDQMGESY-ACZMJKKPSA-N Asp-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N SMZCLQGDQMGESY-ACZMJKKPSA-N 0.000 description 4
- VHQOCWWKXIOAQI-WDSKDSINSA-N Asp-Gln-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VHQOCWWKXIOAQI-WDSKDSINSA-N 0.000 description 4
- ZSJFGGSPCCHMNE-LAEOZQHASA-N Asp-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N ZSJFGGSPCCHMNE-LAEOZQHASA-N 0.000 description 4
- CJUKAWUWBZCTDQ-SRVKXCTJSA-N Asp-Leu-Lys Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O CJUKAWUWBZCTDQ-SRVKXCTJSA-N 0.000 description 4
- HJCGDIGVVWETRO-ZPFDUUQYSA-N Asp-Lys-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O)C(O)=O HJCGDIGVVWETRO-ZPFDUUQYSA-N 0.000 description 4
- JUWISGAGWSDGDH-KKUMJFAQSA-N Asp-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=CC=C1 JUWISGAGWSDGDH-KKUMJFAQSA-N 0.000 description 4
- ZVGRHIRJLWBWGJ-ACZMJKKPSA-N Asp-Ser-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZVGRHIRJLWBWGJ-ACZMJKKPSA-N 0.000 description 4
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 4
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 4
- VNCLJDOTEPPBBD-GUBZILKMSA-N Gln-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)N)N VNCLJDOTEPPBBD-GUBZILKMSA-N 0.000 description 4
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 4
- QKWBEMCLYTYBNI-GVXVVHGQSA-N Gln-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(N)=O QKWBEMCLYTYBNI-GVXVVHGQSA-N 0.000 description 4
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 4
- VXEFAWJTFAUDJK-AVGNSLFASA-N Glu-Tyr-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O VXEFAWJTFAUDJK-AVGNSLFASA-N 0.000 description 4
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 4
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 4
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 4
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 4
- FOKISINOENBSDM-WLTAIBSBSA-N Gly-Thr-Tyr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O FOKISINOENBSDM-WLTAIBSBSA-N 0.000 description 4
- 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 4
- LEHPJMKVGFPSSP-ZQINRCPSSA-N Ile-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 LEHPJMKVGFPSSP-ZQINRCPSSA-N 0.000 description 4
- LBRCLQMZAHRTLV-ZKWXMUAHSA-N Ile-Gly-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LBRCLQMZAHRTLV-ZKWXMUAHSA-N 0.000 description 4
- TWPSALMCEHCIOY-YTFOTSKYSA-N Ile-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)O)N TWPSALMCEHCIOY-YTFOTSKYSA-N 0.000 description 4
- CQQGCWPXDHTTNF-GUBZILKMSA-N Leu-Ala-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O CQQGCWPXDHTTNF-GUBZILKMSA-N 0.000 description 4
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 4
- LVTJJOJKDCVZGP-QWRGUYRKSA-N Leu-Lys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LVTJJOJKDCVZGP-QWRGUYRKSA-N 0.000 description 4
- HGUUMQWGYCVPKG-DCAQKATOSA-N Leu-Pro-Cys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N HGUUMQWGYCVPKG-DCAQKATOSA-N 0.000 description 4
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 4
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 4
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 4
- ZAENPHCEQXALHO-GUBZILKMSA-N Lys-Cys-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZAENPHCEQXALHO-GUBZILKMSA-N 0.000 description 4
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 4
- YWJQHDDBFAXNIR-MXAVVETBSA-N Lys-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCCN)N YWJQHDDBFAXNIR-MXAVVETBSA-N 0.000 description 4
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 4
- KVNLHIXLLZBAFQ-RWMBFGLXSA-N Lys-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N KVNLHIXLLZBAFQ-RWMBFGLXSA-N 0.000 description 4
- UDXSLGLHFUBRRM-OEAJRASXSA-N Lys-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCCCN)N)O UDXSLGLHFUBRRM-OEAJRASXSA-N 0.000 description 4
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 4
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 4
- 108700020796 Oncogene Proteins 0.000 description 4
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 4
- APKRGYLBSCWJJP-FXQIFTODSA-N Pro-Ala-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O APKRGYLBSCWJJP-FXQIFTODSA-N 0.000 description 4
- 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 4
- CLJLVCYFABNTHP-DCAQKATOSA-N Pro-Leu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O CLJLVCYFABNTHP-DCAQKATOSA-N 0.000 description 4
- 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 4
- XQPHBAKJJJZOBX-SRVKXCTJSA-N Pro-Lys-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O XQPHBAKJJJZOBX-SRVKXCTJSA-N 0.000 description 4
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 4
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 4
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 4
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 4
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 4
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 4
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 4
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 4
- DOBIBIXIHJKVJF-XKBZYTNZSA-N Thr-Ser-Gln Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O DOBIBIXIHJKVJF-XKBZYTNZSA-N 0.000 description 4
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 4
- GQPQJNMVELPZNQ-GBALPHGKSA-N Thr-Ser-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N)O GQPQJNMVELPZNQ-GBALPHGKSA-N 0.000 description 4
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 4
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 4
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 4
- IEESWNWYUOETOT-BVSLBCMMSA-N Trp-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(O)=O IEESWNWYUOETOT-BVSLBCMMSA-N 0.000 description 4
- OSMTVLSRTQDWHJ-JBACZVJFSA-N Tyr-Glu-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=C(O)C=C1 OSMTVLSRTQDWHJ-JBACZVJFSA-N 0.000 description 4
- XJPXTYLVMUZGNW-IHRRRGAJSA-N Tyr-Pro-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O XJPXTYLVMUZGNW-IHRRRGAJSA-N 0.000 description 4
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 4
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 4
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 4
- 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 4
- YMTOEGGOCHVGEH-IHRRRGAJSA-N Val-Lys-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O YMTOEGGOCHVGEH-IHRRRGAJSA-N 0.000 description 4
- JSOXWWFKRJKTMT-WOPDTQHZSA-N Val-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N JSOXWWFKRJKTMT-WOPDTQHZSA-N 0.000 description 4
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 108010078144 glutaminyl-glycine Proteins 0.000 description 4
- 108010025306 histidylleucine Proteins 0.000 description 4
- 108010092114 histidylphenylalanine Proteins 0.000 description 4
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 4
- 108010054155 lysyllysine Proteins 0.000 description 4
- 108010077112 prolyl-proline Proteins 0.000 description 4
- 108010070643 prolylglutamic acid Proteins 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 210000005084 renal tissue Anatomy 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 108010080629 tryptophan-leucine Proteins 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 108010029599 tyrosyl-glutamyl-tryptophan Proteins 0.000 description 4
- 238000011870 unpaired t-test Methods 0.000 description 4
- 108010015385 valyl-prolyl-proline Proteins 0.000 description 4
- 208000010370 Adenoviridae Infections Diseases 0.000 description 3
- 206010060931 Adenovirus infection Diseases 0.000 description 3
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 3
- 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 3
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 3
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 3
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 3
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 3
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 3
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 3
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 3
- NSNUZSPSADIMJQ-WDSKDSINSA-N Gln-Gly-Asp Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NSNUZSPSADIMJQ-WDSKDSINSA-N 0.000 description 3
- DNPCBMNFQVTHMA-DCAQKATOSA-N Glu-Leu-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O DNPCBMNFQVTHMA-DCAQKATOSA-N 0.000 description 3
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 3
- GWCRIHNSVMOBEQ-BQBZGAKWSA-N Gly-Arg-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O GWCRIHNSVMOBEQ-BQBZGAKWSA-N 0.000 description 3
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 3
- ZNTSGDNUITWTRA-WDSOQIARSA-N His-Trp-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O ZNTSGDNUITWTRA-WDSOQIARSA-N 0.000 description 3
- 241001135569 Human adenovirus 5 Species 0.000 description 3
- 108010065920 Insulin Lispro Proteins 0.000 description 3
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 3
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 3
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 3
- ABHVWYPPHDYFNY-WDSOQIARSA-N Met-His-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CN=CN1 ABHVWYPPHDYFNY-WDSOQIARSA-N 0.000 description 3
- SSSFPISOZOLQNP-GUBZILKMSA-N Pro-Arg-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSFPISOZOLQNP-GUBZILKMSA-N 0.000 description 3
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 3
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 3
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 3
- FHXGMDRKJHKLKW-QWRGUYRKSA-N Ser-Tyr-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 FHXGMDRKJHKLKW-QWRGUYRKSA-N 0.000 description 3
- 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 3
- UKBSDLHIKIXJKH-HJGDQZAQSA-N Thr-Arg-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UKBSDLHIKIXJKH-HJGDQZAQSA-N 0.000 description 3
- 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 3
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 3
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe 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](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 3
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 3
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 3
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 3
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 3
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 3
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 3
- 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 3
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 3
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 3
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 3
- VVIZITNVZUAEMI-DLOVCJGASA-N Val-Val-Gln Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCC(N)=O VVIZITNVZUAEMI-DLOVCJGASA-N 0.000 description 3
- 208000011589 adenoviridae infectious disease Diseases 0.000 description 3
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000036952 cancer formation Effects 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000006780 non-homologous end joining Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000005829 trimerization reaction Methods 0.000 description 3
- 108010038745 tryptophylglycine Proteins 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 102100033714 40S ribosomal protein S6 Human genes 0.000 description 2
- QDRGPQWIVZNJQD-CIUDSAMLSA-N Ala-Arg-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QDRGPQWIVZNJQD-CIUDSAMLSA-N 0.000 description 2
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 2
- BLTRAARCJYVJKV-QEJZJMRPSA-N Ala-Lys-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1ccccc1)C(O)=O BLTRAARCJYVJKV-QEJZJMRPSA-N 0.000 description 2
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 2
- QDGMZAOSMNGBLP-MRFFXTKBSA-N Ala-Trp-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N QDGMZAOSMNGBLP-MRFFXTKBSA-N 0.000 description 2
- DEAGTWNKODHUIY-MRFFXTKBSA-N Ala-Tyr-Trp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DEAGTWNKODHUIY-MRFFXTKBSA-N 0.000 description 2
- KMSHNDWHPWXPEC-BQBZGAKWSA-N Arg-Asp-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KMSHNDWHPWXPEC-BQBZGAKWSA-N 0.000 description 2
- CYXCAHZVPFREJD-LURJTMIESA-N Arg-Gly-Gly Chemical compound NC(=N)NCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O CYXCAHZVPFREJD-LURJTMIESA-N 0.000 description 2
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 2
- OWSMKCJUBAPHED-JYJNAYRXSA-N Arg-Pro-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OWSMKCJUBAPHED-JYJNAYRXSA-N 0.000 description 2
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 2
- KXEGPPNPXOKKHK-ZLUOBGJFSA-N Asn-Asp-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O KXEGPPNPXOKKHK-ZLUOBGJFSA-N 0.000 description 2
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 2
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 238000010354 CRISPR gene editing Methods 0.000 description 2
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 2
- SHERTACNJPYHAR-ACZMJKKPSA-N Gln-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O SHERTACNJPYHAR-ACZMJKKPSA-N 0.000 description 2
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 2
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 2
- IOFDDSNZJDIGPB-GVXVVHGQSA-N Gln-Leu-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IOFDDSNZJDIGPB-GVXVVHGQSA-N 0.000 description 2
- JRHPEMVLTRADLJ-AVGNSLFASA-N Gln-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JRHPEMVLTRADLJ-AVGNSLFASA-N 0.000 description 2
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 2
- 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 2
- TZOVVRJYUDETQG-RCOVLWMOSA-N Gly-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN TZOVVRJYUDETQG-RCOVLWMOSA-N 0.000 description 2
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 2
- 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 2
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 2
- 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 2
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 2
- PYFIQROSWQERAS-LBPRGKRZSA-N Gly-Trp-Gly Chemical compound C1=CC=C2C(C[C@H](NC(=O)CN)C(=O)NCC(O)=O)=CNC2=C1 PYFIQROSWQERAS-LBPRGKRZSA-N 0.000 description 2
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 2
- 206010019851 Hepatotoxicity Diseases 0.000 description 2
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 2
- IIVZNQCUUMBBKF-GVXVVHGQSA-N His-Gln-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CN=CN1 IIVZNQCUUMBBKF-GVXVVHGQSA-N 0.000 description 2
- BZKDJRSZWLPJNI-SRVKXCTJSA-N His-His-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O BZKDJRSZWLPJNI-SRVKXCTJSA-N 0.000 description 2
- 101000656896 Homo sapiens 40S ribosomal protein S6 Proteins 0.000 description 2
- BLFXHAFTNYZEQE-VKOGCVSHSA-N Ile-Trp-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N BLFXHAFTNYZEQE-VKOGCVSHSA-N 0.000 description 2
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 2
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 2
- BABSVXFGKFLIGW-UWVGGRQHSA-N Leu-Gly-Arg Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N BABSVXFGKFLIGW-UWVGGRQHSA-N 0.000 description 2
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 2
- SSJBMGCZZXCGJJ-DCAQKATOSA-N Lys-Asp-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O SSJBMGCZZXCGJJ-DCAQKATOSA-N 0.000 description 2
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 2
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 2
- FVKRQMQQFGBXHV-QXEWZRGKSA-N Met-Asp-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O FVKRQMQQFGBXHV-QXEWZRGKSA-N 0.000 description 2
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 2
- LRALLISKBZNSKN-BQBZGAKWSA-N Met-Gly-Ser Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LRALLISKBZNSKN-BQBZGAKWSA-N 0.000 description 2
- BMHIFARYXOJDLD-WPRPVWTQSA-N Met-Gly-Val Chemical compound [H]N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O BMHIFARYXOJDLD-WPRPVWTQSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010066427 N-valyltryptophan Proteins 0.000 description 2
- 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 2
- 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 2
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 2
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@@H]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 2
- QGMLKFGTGXWAHF-IHRRRGAJSA-N Ser-Arg-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGMLKFGTGXWAHF-IHRRRGAJSA-N 0.000 description 2
- WOUIMBGNEUWXQG-VKHMYHEASA-N Ser-Gly Chemical compound OC[C@H](N)C(=O)NCC(O)=O WOUIMBGNEUWXQG-VKHMYHEASA-N 0.000 description 2
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 2
- 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 2
- IOVBCLGAJJXOHK-SRVKXCTJSA-N Ser-His-His Chemical compound C([C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 IOVBCLGAJJXOHK-SRVKXCTJSA-N 0.000 description 2
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 2
- 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 2
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 2
- DCLBXIWHLVEPMQ-JRQIVUDYSA-N Thr-Asp-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DCLBXIWHLVEPMQ-JRQIVUDYSA-N 0.000 description 2
- ZSPQUTWLWGWTPS-HJGDQZAQSA-N Thr-Lys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZSPQUTWLWGWTPS-HJGDQZAQSA-N 0.000 description 2
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 2
- BPGDJSUFQKWUBK-KJEVXHAQSA-N Thr-Val-Tyr Chemical compound C[C@@H](O)[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 BPGDJSUFQKWUBK-KJEVXHAQSA-N 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- NLMXVDDEQFKQQU-CFMVVWHZSA-N Tyr-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NLMXVDDEQFKQQU-CFMVVWHZSA-N 0.000 description 2
- 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 2
- UMSZZGTXGKHTFJ-SRVKXCTJSA-N Tyr-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UMSZZGTXGKHTFJ-SRVKXCTJSA-N 0.000 description 2
- 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 2
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 2
- 238000004873 anchoring Methods 0.000 description 2
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 230000007686 hepatotoxicity Effects 0.000 description 2
- 108010028295 histidylhistidine Proteins 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 108010005942 methionylglycine Proteins 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000003007 single stranded DNA break Effects 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 1
- UFBURHXMKFQVLM-CIUDSAMLSA-N Arg-Glu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UFBURHXMKFQVLM-CIUDSAMLSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- NTWOPSIUJBMNRI-KKUMJFAQSA-N Asn-Lys-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTWOPSIUJBMNRI-KKUMJFAQSA-N 0.000 description 1
- KNMRXHIAVXHCLW-ZLUOBGJFSA-N Asp-Asn-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O KNMRXHIAVXHCLW-ZLUOBGJFSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- 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 1
- SAKCBXNPWDRWPE-BQBZGAKWSA-N Asp-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)O)N SAKCBXNPWDRWPE-BQBZGAKWSA-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
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 1
- PLNJUJGNLDSFOP-UWJYBYFXSA-N Asp-Tyr-Ala 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](C)C(O)=O PLNJUJGNLDSFOP-UWJYBYFXSA-N 0.000 description 1
- GYNUXDMCDILYIQ-QRTARXTBSA-N Asp-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N GYNUXDMCDILYIQ-QRTARXTBSA-N 0.000 description 1
- 101710172824 CRISPR-associated endonuclease Cas9 Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- DCJNIJAWIRPPBB-CIUDSAMLSA-N Cys-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N DCJNIJAWIRPPBB-CIUDSAMLSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 1
- ROHVCXBMIAAASL-HJGDQZAQSA-N Gln-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)N)O ROHVCXBMIAAASL-HJGDQZAQSA-N 0.000 description 1
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 1
- IRDASPPCLZIERZ-XHNCKOQMSA-N Glu-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N IRDASPPCLZIERZ-XHNCKOQMSA-N 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- IWAXHBCACVWNHT-BQBZGAKWSA-N Gly-Asp-Arg Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IWAXHBCACVWNHT-BQBZGAKWSA-N 0.000 description 1
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 1
- YXTFLTJYLIAZQG-FJXKBIBVSA-N Gly-Thr-Arg Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YXTFLTJYLIAZQG-FJXKBIBVSA-N 0.000 description 1
- FXTUGWXZTFMTIV-GJZGRUSLSA-N Gly-Trp-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)CN FXTUGWXZTFMTIV-GJZGRUSLSA-N 0.000 description 1
- JYGYNWYVKXENNE-OALUTQOASA-N Gly-Tyr-Trp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JYGYNWYVKXENNE-OALUTQOASA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 1
- HDOYNXLPTRQLAD-JBDRJPRFSA-N Ile-Ala-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)O)N HDOYNXLPTRQLAD-JBDRJPRFSA-N 0.000 description 1
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 1
- 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 1
- WLRJHVNFGAOYPS-HJPIBITLSA-N Ile-Ser-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N WLRJHVNFGAOYPS-HJPIBITLSA-N 0.000 description 1
- JERJIYYCOGBAIJ-OBAATPRFSA-N Ile-Tyr-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JERJIYYCOGBAIJ-OBAATPRFSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- UQRZFMQQXXJTTF-AVGNSLFASA-N Lys-Lys-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O UQRZFMQQXXJTTF-AVGNSLFASA-N 0.000 description 1
- 108700024831 MDS1 and EVI1 Complex Locus Proteins 0.000 description 1
- 102000046015 MDS1 and EVI1 Complex Locus Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- CAODKDAPYGUMLK-FXQIFTODSA-N Met-Asn-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CAODKDAPYGUMLK-FXQIFTODSA-N 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 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 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- KLSOMAFWRISSNI-OSUNSFLBSA-N Pro-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]1CCCN1 KLSOMAFWRISSNI-OSUNSFLBSA-N 0.000 description 1
- QDDJNKWPTJHROJ-UFYCRDLUSA-N Pro-Tyr-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 QDDJNKWPTJHROJ-UFYCRDLUSA-N 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 1
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- 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 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr 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=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- NRUPKQSXTJNQGD-XGEHTFHBSA-N Thr-Cys-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NRUPKQSXTJNQGD-XGEHTFHBSA-N 0.000 description 1
- 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 1
- 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 1
- WYLAVUAWOUVUCA-XVSYOHENSA-N Thr-Phe-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WYLAVUAWOUVUCA-XVSYOHENSA-N 0.000 description 1
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 1
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 1
- NXQAOORHSYJRGH-AAEUAGOBSA-N Trp-Gly-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 NXQAOORHSYJRGH-AAEUAGOBSA-N 0.000 description 1
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 1
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 1
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 1
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe 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](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 1
- 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 1
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 1
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 230000010530 Virus Neutralization Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000007614 genetic variation Effects 0.000 description 1
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108010079317 prolyl-tyrosine Proteins 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010029020 prolylglycine Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6839—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6875—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin
- A61K47/6879—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody being a hybrid immunoglobulin the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
-
- 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
- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10341—Use of virus, viral particle or viral elements as a vector
- C12N2710/10343—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
- C12N2800/00—Nucleic acids vectors
- C12N2800/10—Plasmid DNA
- C12N2800/106—Plasmid DNA for vertebrates
- C12N2800/107—Plasmid DNA for vertebrates for mammalian
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Virology (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Pulmonology (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明提出了含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用,所述重组蛋白包括:上皮细胞黏附分子抗体片段;腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;以及T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段的两端分别连接所述上皮细胞黏附分子抗体片段和腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;所述保护蛋白包括:腺病毒表面蛋白Hexon抗体片段;以及T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段与所述腺病毒表面蛋白Hexon抗体片段相连。本发明的复合物既可以特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,也可以降低机体对腺病毒的免疫反应,从而实现腺病毒基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
Description
技术领域
本发明涉及生物医药领域。具体地,本发明涉及含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用。
背景技术
肺癌在世界范围内都是致死率较高的肿瘤类型,其中肺鳞癌占肺癌诊断病例的30%。肺鳞癌好发于男性,与吸烟密切相关。我国是全球吸烟人数最多的国家,亦是肺鳞癌患者最多的国家。肺鳞癌常在肺部中央发病,确诊时多为晚期,手术难度大,预后效果较差。肺鳞癌通常发生大量驱动基因变异,但目前适用于肺鳞癌的靶向治疗药物很少。因此开发针对肺鳞癌变异驱动基因的新型疗法是急需解决的关键问题。
近年来发展了第三代基因组编辑技术,CRISPR/Cas9系统对基因靶点的高效修改使其成为抑制肿瘤细胞驱动基因功能的有力手段。该系统由两个组分构成:RNA导向的核酸内切酶Cas9和单链导向RNA(sgRNA)。导向RNA结合Cas9,并介导Cas9与其互补基因组序列的结合和剪切。Cas9的剪切产生了双链DNA断裂(DSB),机体会通过非同源末端连接(NHEJ)或同源重组(HDR)方式修复,从而导致靶序列的破坏或修改。其中通过NHEJ方式敲除癌基因,可以简便地使其失活,达到抑制癌基因功能的目标。
虽然目前已有众多针对罕见病的基因编辑疗法处于临床前或临床试验阶段,例如地中海贫血和脊髓性肌萎缩症等,但针对恶性肿瘤的成功基因编辑疗法仍然很少。最重要的原因是缺乏有效的递送手段。肿瘤细胞的表面蛋白谱与同组织的正常细胞相比已发生显著变化,目前常用的基因治疗载体对肿瘤细胞的感染效率明显下降。另外包括肺鳞癌在内的多种恶性肿瘤灶都位于体内脏器,目前基因治疗载体的局部注射方式无法对全部肿瘤灶形成有效感染和治疗。因此改造基因治疗载体,提高其对目标肿瘤细胞的感染效率和特异性,使其能够以静脉或腹腔注射等系统性方式给药,是成功开发肺鳞癌和其他恶性肿瘤基因编辑疗法的重要前提。
目前肿瘤基因治疗临床试验最常用的载体为5型腺病毒载体(ADV5),约占临床试验总数的22%。例如通过ADV5载体表达抑癌基因P53,用于治疗头颈部肿瘤。但它的受体免疫球蛋白样细胞黏附分子(CXADR)广泛表达于各种细胞表面,使其对肿瘤细胞缺乏感染特异性。而且ADV5载体的免疫原性较强,大部分人体内都已存在IgM抗体,会介导病毒中和效应,降低基因治疗的疗效。
因此,目前适于基因编辑治疗肺鳞癌的载体仍有待研究。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。
在本发明的一个方面,本发明提出了一种重组蛋白。根据本发明的实施例,所述重组蛋白包括:上皮细胞黏附分子抗体片段;腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;以及T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段的两端分别连接上皮细胞黏附分子抗体片段和腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段。
上皮细胞黏附分子(EpCAM)是肺鳞癌细胞表面的蛋白,该重组蛋白中含有其抗体片段,从而特异性地识别并结合到肺鳞癌细胞表面。腺病毒受体免疫球蛋白样细胞黏附分子(CXADR)的胞外区片段(ECAR)能够与腺病毒载体表面的Knob蛋白相结合,从而锚定到腺病毒上。T4噬菌体Fibritin片段连接上述两种蛋白片段,可使重组蛋白分子形成三聚化,起到稳定重组蛋白结构的作用。由此,根据本发明实施例的重组蛋白一端与腺病毒相连,另一端特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,从而实现腺病毒基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,上述重组蛋白还可以具有下列附加技术特征:
根据本发明的实施例,所述上皮细胞黏附分子抗体片段具有如SEQ ID NO:1所示的氨基酸序列。
根据本发明的实施例,所述腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段具有如SEQ ID NO:2所示的氨基酸序列。
根据本发明的实施例,所述T4噬菌体Fibritin片段具有如SEQ ID NO:3所示的氨基酸序列。
根据本发明的实施例,所述重组蛋白具有如SEQ ID NO:4所示的氨基酸序列。
在本发明的另一方面,本发明提出了一种核酸。根据本发明的实施例,所述核酸可操作地连接有编码上皮细胞黏附分子抗体的片段、编码腺病毒受体免疫球蛋白样细胞黏附分子的胞外区的片段以及编码T4噬菌体Fibritin的片段。由此,利用根据本发明实施例的核酸编码的重组蛋白一端与腺病毒相连,另一端特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,从而实现腺病毒基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,所述核酸具有如SEQ ID NO:5所示的核苷酸序列。
在本发明的又一方面,本发明提出了一种复合物。根据本发明的实施例,所述复合物包括:前面所述重组蛋白或由前面所述核酸编码的重组蛋白;以及保护蛋白,所述保护蛋白包括:腺病毒表面蛋白Hexon抗体片段;以及T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段与腺病毒表面蛋白Hexon抗体片段相连。如前所述,重组蛋白可以特异性识别并结合肺鳞癌细胞上。该保护蛋白上含有腺病毒表面蛋白Hexon抗体片段,能够特异性识别腺病毒表面的Hexon蛋白,在特异性感染肺鳞癌细胞的同时,将降低机体对腺病毒的免疫反应,从而使得腺病毒能够更好地发挥基因编辑治疗效果。由此,根据本发明实施例的复合物能够特异性感染肺鳞癌细胞,且降低机体对腺病毒的免疫反应,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,所述腺病毒表面蛋白Hexon抗体片段具有如SEQ ID NO:6所示的氨基酸序列。
根据本发明的实施例,所述T4噬菌体Fibritin片段具有如SEQ ID NO:3所示的氨基酸序列。
根据本发明的实施例,所述保护蛋白具有如SEQ ID NO:7所示的氨基酸序列,编码所述保护蛋白的核酸具有如SEQ ID NO:8所示的核苷酸序列。
在本发明的又一方面,本发明提出了一种重组腺病毒载体。根据本发明的实施例,所述重组腺病毒载体包括:携带有前面所述重组蛋白或由前面所述核酸编码的重组蛋白的腺病毒载体。由此,根据本发明实施例的重组腺病毒载体能够特异性高效感染肺鳞癌细胞,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,所述腺病毒载体进一步携带有保护蛋白,所述保护蛋白包括:腺病毒表面蛋白Hexon抗体片段;以及T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段与所述腺病毒表面蛋白Hexon抗体片段相连。
根据本发明的实施例,所述腺病毒表面蛋白Hexon抗体片段具有如SEQ ID NO:6所示的氨基酸序列。
根据本发明的实施例,所述T4噬菌体Fibritin片段具有如SEQ ID NO:3所示的氨基酸序列。
根据本发明的实施例,所述保护蛋白具有如SEQ ID NO:7所示的氨基酸序列。
根据本发明的实施例,所述重组蛋白和保护蛋白是以前面所述复合物的形式提供的。
根据本发明的实施例,所述重组蛋白与所述腺病毒载体表面的Knob蛋白结合,所述保护蛋白与所述腺病毒载体表面的Hexon蛋白结合。
根据本发明的实施例,所述腺病毒载体选自ADV5腺病毒,可表达Cas9酶、目的基因导向RNA、Knob蛋白和Hexon蛋白。
在本发明的又一方面,本发明提出了一种制备前面所述重组腺病毒载体的方法。根据本发明的实施例,所述方法包括:将前面所述重组蛋白或者前面所述复合物与腺病毒载体共孵育,以便使得所述重组蛋白或复合物与腺病毒载体结合,得到重组腺病毒载体。由此,根据本发明实施例的方法所得到的重组腺病毒载体能够特异性高效感染肺鳞癌细胞,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
在本发明的又一方面,本发明提出了前面所述重组蛋白、由前面所述核酸编码的重组蛋白、前面所述复合物或重组腺病毒载体在制备药物中的用途。根据本发明的实施例,所述药物用于治疗肺鳞癌。如前所述,重组蛋白或复合物能够特异性高效感染肺鳞癌细胞,并可以降低机体对重组腺病毒载体的免疫反应,实现更好地治疗目的。
根据本发明的实施例,所述肺鳞癌细胞表达上皮细胞黏附分子。
在本发明的又一方面,本发明提出了一种药物组合物。根据本发明的实施例,所述药物组合物包括:前面所述重组蛋白、复合物或重组腺病毒载体;以及药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。由此,根据本发明实施例的药物组合物能够特异性高效感染肺鳞癌细胞,并可以降低机体对该药物组合物的免疫反应,实现更好地治疗肺鳞癌的目的。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1显示了本发明一个实施例的重组蛋白对腺病毒在肺鳞癌细胞H520中的感染效率影响示意图;
图2显示了根据本发明一个实施例的重组腺病毒载体结构示意图;
图3显示了根据本发明一个实施例的重组蛋白和保护蛋白对腺病毒的感染特异性的比较示意图;
图4显示了根据本发明一个实施例的保护蛋白对腺病毒免疫反应的影响示意图;
图5显示了根据本发明一个实施例的保护蛋白对腺病毒肝毒性影响示意图;
图6显示了根据本发明一个实施例的以靶向EpCAM腺病毒为载体敲除MECOM基因抑制肺鳞癌PDX肿瘤生长,其中,A为肺鳞癌PDX模型的肿瘤生长曲线;B为观察终点肿瘤照片;C为病毒注射7天后的MECOM基因位点编辑状况;D为病毒注射7天后的MECOM基因和下游信号分子RPS6的表达和磷酸化状况;E为观察终点小鼠肝、肺、肾组织的HE染色。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。
本发明提出了重组蛋白、核酸、复合物、重组腺病毒载体及其制备方法和用途,下面将分别对其进行详细描述。
重组蛋白
在本发明的一个方面,本发明提出了一种重组蛋白。根据本发明的实施例,所述重组蛋白包括:上皮细胞黏附分子抗体片段;腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;以及T4噬菌体Fibritin片段,T4噬菌体Fibritin片段的两端分别连接上皮细胞黏附分子抗体片段和腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段。
上皮细胞黏附分子(EpCAM)是肺鳞癌细胞表面的蛋白,该重组蛋白中含有其抗体片段,从而特异性地识别并结合到肺鳞癌细胞表面。腺病毒受体免疫球蛋白样细胞黏附分子(CXADR)的胞外区片段(ECAR)能够与腺病毒载体表面的Knob蛋白相结合,从而锚定到腺病毒上。T4噬菌体Fibritin片段连接上述两种蛋白片段,可使重组蛋白分子形成三聚化,起到稳定重组蛋白结构的作用。由此,根据本发明实施例的重组蛋白一端与腺病毒相连,另一端特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,从而实现腺病毒基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,上皮细胞黏附分子抗体片段具有如SEQ ID NO:1所示的氨基酸序列。发明人对人源上皮细胞黏附分子EpCAM单链抗体(scFv)序列进行密码子优化及合成,发现具有SEQ ID NO:1所示氨基酸序列的上皮细胞黏附分子抗体片段可以特异性识别并结合到肺鳞癌细胞表面的上皮细胞黏附分子,从而提高感染效率。
GGGGSGGGGSGGGGSGGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLEIKGGGGSGGGGSGGGGSEVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSG(SEQ ID NO:1)
根据本发明的实施例,腺病毒受体免疫球蛋白样细胞黏附分子(CXADR)的胞外区片段(ECAR)具有如SEQ ID NO:2所示的氨基酸序列。由此,可以特异性地与腺病毒表面的Knob蛋白结合。
MALLLCFVLLCGVVDFARSLSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLVVLVKPSGARCYVDGSEEIGSDFKIKCEPKEGSLPLQYEWQKLSDSQKMPTSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNVVPPSNKAG(SEQ ID NO:2)
根据本发明的实施例,T4噬菌体Fibritin片段具有如SEQ ID NO:3所示的氨基酸序列。Fibritin片段连接上皮细胞黏附分子EpCAM抗体和腺病毒受体免疫球蛋白样细胞黏附分子(CXADR)的胞外区(ECAR)这两种蛋白片段,可使重组蛋白分子形成三聚化,起到稳定重组蛋白结构的作用。
RGLTNSIKANETNIASVTQEVNTAKGNISSLQGDVQALQEAGYIPEAPRDGQAYVRKDGEWVFLSTFLSPA(SEQ ID NO:3)
根据本发明的实施例,重组蛋白具有如SEQ ID NO:4所示的氨基酸序列。由此,该重组蛋白一端与腺病毒相连,另一端特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,从而更好地使腺病毒发挥基因编辑治疗目的。
MALLLCFVLLCGVVDFARSLSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLVVLVKPSGARCYVDGSEEIGSDFKIKCEPKEGSLPLQYEWQKLSDSQKMPTSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNVVPPSNKAGRGLTNSIKANETNIASVTQEVNTAKGNISSLQGDVQALQEAGYIPEAPRDGQAYVRKDGEWVFLSTFLSPAGGGGSGGGGSGGGGSGGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLEIKGGGGSGGGGSGGGGSEVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSG(SEQ ID NO:4)
核酸
在本发明的另一方面,本发明提出了一种核酸。根据本发明的实施例,该核酸可操作地连接有编码上皮细胞黏附分子抗体的片段、编码腺病毒受体免疫球蛋白样细胞黏附分子的胞外区的片段以及编码T4噬菌体Fibritin的片段。由此,利用根据本发明实施例的核酸编码的重组蛋白一端与腺病毒相连,另一端特异性识别肺鳞癌细胞,提高感染肺鳞癌细胞效率,从而实现腺病毒基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,核酸具有如SEQ ID NO:5所示的核苷酸序列。
ATGGCGCTCCTGCTGTGCTTCGTGCTCCTGTGCGGAGTAGTGGATTTCGCCAGAAGTTTGAGTATCACTACTCCTGAAGAGATGATTGAAAAAGCCAAAGGGGAAACTGCCTATCTGCCATGCAAATTTACGCTTAGTCCCGAAGACCAGGGACCGCTGGACATCGAGTGGCTGATATCACCAGCTGATAATCAGAAGGTGGATCAAGTGATTATTTTATATTCTGGAGACAAAATTTATGATGACTACTATCCAGATCTGAAAGGCCGAGTACATTTTACGAGTAATGATCTCAAATCTGGTGATGCATCAATAAATGTAACGAATTTACAACTGTCAGATATTGGCACATATCAGTGCAAAGTGAAAAAAGCTCCTGGTGTTGCAAATAAGAAGATTCATCTGGTAGTTCTTGTTAAGCCTTCAGGTGCGAGATGTTACGTTGATGGATCTGAAGAAATTGGAAGTGACTTTAAGATAAAATGTGAACCAAAAGAAGGTTCACTTCCATTACAGTATGAGTGGCAAAAATTGTCTGACTCACAGAAAATGCCCACTTCATGGTTAGCAGAAATGACTTCATCTGTTATATCTGTAAAAAATGCCTCTTCTGAGTACTCTGGGACATACAGCTGTACAGTCAGAAACAGAGTGGGCTCTGATCAGTGCCTGTTGCGTCTAAACGTTGTCCCTCCTTCAAATAAAGCTGGACGCGGATTAACCAATTCAATAAAAGCTAACGAAACTAACATTGCATCAGTTACACAAGAAGTGAATACAGCTAAAGGCAATATATCTTCTTTACAAGGTGATGTTCAAGCTCTCCAAGAAGCCGGTTATATTCCTGAAGCTCCAAGAGATGGGCAAGCTTACGTTCGTAAAGATGGCGAATGGGTATTCCTTTCTACCTTTTTATCACCAGCAGGCGGAGGGGGATCAGGAGGCGGAGGGTCAGGAGGAGGCGGAAGCGGAGGGGGAGGCAGCGAGCTGCAGATGACTCAGAGCCCTTCCTCACTGTCTGCCAGTGTGGGCGACCGAGTCACCATCACATGCCGGACCTCACAGAGCATTAGCTCCTACCTGAACTGGTATCAGCAGAAACCTGGACAGCCCCCTAAGCTGCTGATCTACTGGGCAAGCACCAGAGAGTCCGGAGTGCCAGACAGGTTCTCCGGATCTGGCAGTGGGACAGATTTTACTCTGACCATTTCTAGTCTGCAGCCCGAGGACTCTGCTACTTACTATTGCCAGCAGAGCTACGATATCCCTTATACTTTCGGACAGGGCACCAAACTGGAAATTAAGGGCGGGGGAGGCTCAGGAGGAGGAGGGAGCGGCGGAGGAGGCAGCGAGGTGCAGCTGCTGGAAAGCGGAGGAGGAGTGGTCCAGCCAGGACGATCTCTGAGACTGAGTTGTGCCGCTTCAGGCTTCACATTTTCAAGCTATGGAATGCACTGGGTGCGACAGGCACCTGGAAAGGGACTGGAGTGGGTGGCTGTCATCAGCTACGACGGCTCCAACAAATACTATGCAGATAGCGTGAAGGGGAGGTTTACCATTTCTCGCGATAACAGTAAAAATACACTGTACCTGCAGATGAATAGCCTGAGGGCCGAAGACACTGCTGTGTACTATTGCGCTAAGGATATGGGATGGGGGTCCGGATGGCGACCATACTATTACTATGGGATGGACGTGTGGGGCCAGGGGACCACCGTGACCGTGTCCTCAGGGTAA(SEQID NO:5)
复合物
在本发明的又一方面,本发明提出了一种复合物。根据本发明的实施例,该复合物包括:前面所述重组蛋白或由前面所述核酸编码的重组蛋白;以及保护蛋白,保护蛋白包括:腺病毒表面蛋白Hexon抗体片段;以及T4噬菌体Fibritin片段,T4噬菌体Fibritin片段与腺病毒表面蛋白Hexon抗体片段相连。如前所述,重组蛋白可以特异性识别并结合肺鳞癌细胞上。保护蛋白上含有腺病毒表面蛋白Hexon抗体片段,能够特异性识别腺病毒表面的Hexon蛋白,在特异性感染肺鳞癌细胞的同时,将降低机体对腺病毒的免疫反应,从而使得腺病毒能够更好地发挥基因编辑治疗效果。同时,连接上T4噬菌体Fibritin片段起到稳定保护蛋白结构的作用。由此,根据本发明实施例的复合物能够特异性感染肺鳞癌细胞,且降低机体对腺病毒的免疫反应,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
需要说明的是,本发明所描述的复合物中,重组蛋白与保护蛋白之间的位置关系不作严格限定,既可以是无接触的,也可以是有连接关系。
根据本发明的实施例,腺病毒表面蛋白Hexon抗体(scFv)片段具有如SEQ ID NO:6所示的氨基酸序列。由此,可以特异性地识别腺病毒表面的Hexon蛋白结合,提高感染肺鳞癌细胞的特异性,且降低机体对腺病毒的免疫反应。
MGSSHHHHHHSSGLVPRGSHQVQLVQSGAEDKKPGASVKVSCKVSGFSLGRYGVHWVRQAPGQGLEWMGVIWRGGTTDYNAKFQGRVTITKDDSKSTVYMELSSLRSEDTAVYYCARQGSNFPLAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLSASVGDRVTITCKASQSVTNDAAWYQKKPGKAPKLLIYQASTRYTGVPSRFSGSGYGTDFTLTISSLQPEDFATYFCHQDYSSPLTFGQGTKVEIKRGGGGSGGGGSGGGGS(SEQ ID NO:6)
根据本发明的实施例,T4噬菌体Fibritin片段具有如SEQ ID NO:3所示的氨基酸序列。
根据本发明的实施例,保护蛋白具有如SEQ ID NO:7所示的氨基酸序列,编码保护蛋白的核酸具有如SEQ ID NO:8所示的核苷酸序列。
MGSSHHHHHHSSGLVPRGSHQVQLVQSGAEDKKPGASVKVSCKVSGFSLGRYGVHWVRQAPGQGLEWMGVIWRGGTTDYNAKFQGRVTITKDDSKSTVYMELSSLRSEDTAVYYCARQGSNFPLAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLSASVGDRVTITCKASQSVTNDAAWYQKKPGKAPKLLIYQASTRYTGVPSRFSGSGYGTDFTLTISSLQPEDFATYFCHQDYSSPLTFGQGTKVEIKRGGGGSGGGGSGGGGSRGLTNSIKANETNIASVTQEVNTAKGNISSLQGDVQALQEAGYIPEAPRDGQAYVRKDGEWVFLSTFLSPA(SEQ ID NO:7)
ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGCAGCCATCAAGTACAACTCGTACAATCCGGCGCCGAAGACAAAAAACCCGGCGCCTCCGTAAAAGTATCCTGCAAAGTATCAGGATTCTCCCTAGGCCGATACGGCGTACACTGGGTACGACAAGCCCCCGGCCAAGGCCTAGAATGGATGGGAGTCATCTGGCGCGGCGGAACCACAGACTACAACGCCAAATTCCAAGGCCGAGTAACCATCACCAAAGACGACTCCAAATCAACCGTATACATGGAACTATCCTCACTCCGCTCCGAAGACACCGCCGTATACTACTGCGCCCGACAAGGCTCCAACTTCCCCCTAGCCTACTGGGGCCAAGGCACCCTAGTAACCGTATCCTCAGGCGGAGGGGGATCAGGAGGCGGAGGGTCAGGAGGAGGCGGAAGCGATATCGTAATGACCCAATCCCCCTCCTCACTCTCCGCCTCCGTAGGCGACCGAGTAACCATCACCTGCAAAGCCTCCCAATCCGTAACCAACGACGCCGCCTGGTACCAAAAAAAACCCGGCAAAGCCCCCAAACTACTAATCTACCAAGCCTCCACCCGATACACCGGCGTACCCTCCCGATTCTCCGGCTCAGGCTACGGCACCGACTTCACACTCACCATCTCCTCACTCCAACCCGAAGACTTCGCCACCTACTTCTGCCACCAAGACTACTCCTCACCCCTAACATTCGGCCAAGGAACAAAAGTAGAAATAAAACGCGGAGGCGGAGGGTCAGGAGGAGGCGGAAGCGGAGGGGGAGGCAGCCGCGGATTAACCAATTCAATAAAAGCTAACGAAACTAACATTGCATCAGTTACACAAGAAGTGAATACAGCTAAAGGCAATATATCTTCTTTACAAGGTGATGTTCAAGCTCTCCAAGAAGCCGGTTATATTCCTGAAGCTCCAAGAGATGGGCAAGCTTACGTTCGTAAAGATGGCGAATGGGTATTCCTTTCTACCTTTTTATCACCAGCATGA(SEQ ID NO:8)
重组腺病毒载体
在本发明的又一方面,本发明提出了一种重组腺病毒载体。根据本发明的实施例,该重组腺病毒载体包括:携带有前面所述重组蛋白或由前面所述核酸编码的重组蛋白的腺病毒载体。由此,根据本发明实施例的重组腺病毒载体能够特异性高效感染肺鳞癌细胞,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
根据本发明的实施例,腺病毒载体进一步携带有保护蛋白。该保护蛋白与前面所述复合物中针对保护蛋白所描述的特征和优点一致,在此不再赘述。
需要说明的是,重组腺病毒载体中重组蛋白和保护蛋白的存在形式不作严格限定,既可以单独存在,发挥各自的功能,也可以以复合物(复合蛋白)的形式作为一个整体来提供,具体可以根据实际情况灵活选择,在此不再赘述。
根据本发明的实施例,重组蛋白与腺病毒载体表面的Knob蛋白结合,保护蛋白与腺病毒载体表面的Hexon蛋白结合。重组蛋白可通过ECAR片段与腺病毒载体表面的Knob蛋白结合,保护蛋白可通过Hexon scFv片段与腺病毒载体表面的Hexon蛋白结合。
根据本发明的实施例,腺病毒载体选自ADV5腺病毒,可表达Cas9酶、目的基因导向RNA、Knob蛋白和Hexon蛋白。由此,该腺病毒载体可以与重组蛋白和保护蛋白结合,从而特异性高效感染肺鳞癌细胞,并在Cas9酶和目的基因导向RNA的作用下作用于肺鳞癌细胞中靶序列,从而起到治疗目的。
本领域技术人员能够理解的是,前面针对重组蛋白、核酸和复合物所描述的特征和优点,同样适用于该重组腺病毒载体,在此不再赘述。
制备重组腺病毒载体的方法
在本发明的又一方面,本发明提出了一种制备前面所述重组腺病毒载体的方法。根据本发明的实施例,该方法包括:将前面所述重组蛋白、重组蛋白和重组腺病毒载体中的所述保护蛋白或者前面所述复合物与腺病毒载体共孵育,以便使得重组蛋白或复合物与腺病毒载体结合,得到重组腺病毒载体。由此,根据本发明实施例的方法所得到的重组腺病毒载体能够特异性高效感染肺鳞癌细胞,从而实现基因编辑治疗,为肺鳞癌治疗提供了科学研究和临床应用基础,应用前景好。
本领域技术人员能够理解的是,前面针对重组蛋白和复合物所描述的特征和优点,同样适用于该制备重组腺病毒载体的方法,在此不再赘述。
用途
在本发明的又一方面,本发明提出了前面所述重组蛋白、由前面所述核酸编码的重组蛋白、前面所述复合物或重组腺病毒载体在制备药物中的用途。根据本发明的实施例,该药物用于治疗肺鳞癌。如前所述,重组蛋白或复合物能够特异性高效感染肺鳞癌细胞,并可以降低机体对重组腺病毒载体的免疫反应,实现更好地治疗目的。
根据本发明的实施例,肺鳞癌细胞表达上皮细胞黏附分子。由此,重组蛋白才可以特异性识别并结合到肺鳞癌细胞上。
本领域技术人员能够理解的是,前面针对重组蛋白、核酸和复合物所描述的特征和优点,同样适用于该用途,在此不再赘述。
药物组合物
在本发明的又一方面,本发明提出了一种药物组合物。根据本发明的实施例,所述药物组合物包括:前面所述重组蛋白、复合物或重组腺病毒载体;以及药学上可接受的辅料、载体、赋形剂、溶媒或它们的组合。由此,根据本发明实施例的药物组合物能够特异性高效感染肺鳞癌细胞,并可以降低机体对该药物组合物的免疫反应,实现更好地治疗肺鳞癌的目的。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的,和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病,包括:(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生;(b)抑制疾病,例如阻滞疾病发展;或(c)缓解疾病,例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药,包括但不限于将含本文所述化合物的药物给予有需要的个体。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1
1、3种重组蛋白对腺病毒感染效率的影响
表达GFP的5型腺病毒(ADV5)分别与3种重组蛋白按比例(1×10-7pmol/VP)混合后室温预孵育2小时,然后感染EpCAM阳性表达的肺鳞癌细胞系H520。48小时后通过流式细胞仪检测GFP阳性细胞的比例(感染效率)。
结果如图1所示,其为2次实验的平均值,*为非配对T检验P<0.05。可以看出,重组蛋白1对腺病毒的感染效率有最显著的上调。
重组蛋白1:具有SEQ ID NO:4所示的氨基酸序列。
重组蛋白2:具有SEQ ID NO:9所示的氨基酸序列。
重组蛋白3:具有SEQ ID NO:10所示的氨基酸序列。
MALLLCFVLLCGVVDFARSLSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLVVLVKPSGARCYVDGSEEIGSDFKIKCEPKEGSLPLQYEWQKLSDSQKMPTSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNVVPPSNKAGRGLTNSIKANETNIASVTQEVNTAKGNISSLQGDVQALQEAGYIPEAPRDGQAYVRKDGEWVFLSTFLSPAGGGGSGGGGSGGGGSGGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSESGTNYTLTISSLQPEDFATYFCQQSDSLPITFGQGTRLDIQGGGGSGGGGSGGGGSEVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSSG(SEQ ID NO:9)
MALLLCFVLLCGVVDFARSLSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLVVLVKPSGARCYVDGSEEIGSDFKIKCEPKEGSLPLQYEWQKLSDSQKMPTSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNVVPPSNKAGRGLTNSIKANETNIASVTQEVNTAKGNISSLQGDVQALQEAGYIPEAPRDGQAYVRKDGEWVFLSTFLSPAGGGGSGGGGSGGGGSGGGGSELQMTQSPSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLEIKGGGGSGGGGSGGGGSEVQLLESGGVVVQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKKEGYWGQGTLVTVSSG(SEQ ID NO:10)
2、重组蛋白1和保护蛋白提高腺病毒的感染特异性
裸鼠皮下注射肺鳞癌细胞系H520,成瘤后,瘤内或尾静脉注射腺病毒(ADV,1×1010VP)或其与重组蛋白1(3×10-5pmol/VP)和保护蛋白(3×10-5pmol/VP)的复合物(参见图2)。48小时后收集肿瘤、肝、肺和肾组织,通过Real-time PCR检测各种组织中腺病毒基因组DNA的丰度。
如图3所示,其为2次平行实验的平均值,*为非配对T检验P<0.05,腺病毒相对丰度是Realtime PCR检测到的各种组织中腺病毒DNA和内参基因Glucagon DNA丰度的比值,i.t.和i.v.分别指瘤内和尾静脉注射病毒。两种蛋白能显著提高腺病毒对肿瘤组织的感染,并降低其对肝、肺、肾组织的感染,尤其是降低对肝脏的感染。直接注射腺病毒静脉时主要感染肝脏,这种非特异性感染是限制该病毒临床应用的一个主要原因,另一个是免疫原性。采用重组蛋白和保护蛋白与腺病毒结合,可以显著提高其对EpCAM阳性肺鳞癌肿瘤的感染特异性。
3、保护蛋白降低腺病毒的免疫反应
表达GFP的5型腺病毒(ADV5)与靶向EpCAM的重组蛋白1(1×10-7pmol/VP)和保护蛋白(5×10-7pmol/VP)混合后室温预孵育2小时,然后感染EpCAM阳性表达的肺鳞癌细胞系H520。48小时后通过流式细胞仪检测GFP阳性细胞的比例。
图4结果为2次实验的平均值,*为非配对T检验P<0.05,图4A中相对感染效率是腺病毒和蛋白复合物感染H520细胞后GFP阳性细胞比率与普通腺病毒感染后GFP阳性细胞比率的比值。可以看出,1×10-7pmol/VP的重组蛋白1与ADV5混合物,可以显著上调ADV对H520细胞的感染效率。加入5μL肺癌患者血清会引起抗体中和反应,显著抑制重组蛋白与病毒复合物的感染效率。而5×10-7pmol/VP的保护蛋白与重组蛋白和腺病毒形成的复合物可以有效抵抗肺癌患者血清的中和反应,维持ADV对H520细胞的感染效率。
C57BL6小鼠皮下注射鼠肺癌细胞LEWIS,成瘤后,瘤内或尾静脉注射腺病毒(ADV,1×1010VP)或其与重组蛋白1(3×10-5pmol/VP)和保护蛋白(3×10-5pmol/VP)的复合物。7天后收集血清,通过ELISA检测ADV抗体。如图4B所示,单独注射ADV或其与重组蛋白的复合物都诱导抗ADV抗体的生成,加入保护蛋白能显著降低抗体的生成。
4、保护蛋白降低腺病毒的肝毒性
C57BL6小鼠皮下注射鼠肺癌细胞LEWIS,成瘤后,瘤内或尾静脉注射腺病毒(ADV,1×1010VP)或其与重组蛋白1(3×10-5pmol/VP)和保护蛋白(3×10-5pmol/VP)的复合物。7天后收集肝组织,通过HE染色和血清转氨酶浓度来检测肝脏损伤程度。如图5A所示,ADV及其与重组蛋白的复合物都会引起肝细胞的膨胀和变形,这是肝脏炎症反应的指征。加入保护蛋白能保护肝细胞,避免发生炎症反应。另外,保护蛋白能降低ADV引起的血清转氨酶上升(图5B,为2次平行实验的平均值,*为非配对T检验P<0.05)。
5、以靶向EpCAM的腺病毒为载体,在肺鳞癌PDX鼠模型中特异性敲除MECOM基因的效果
在LUSC021PDX鼠模型中尾静脉注射表达SaCas9和MECOM基因导向RNA(gRNA)的腺病毒(1×1010VP)、靶向EpCAM的重组蛋白1(3×10-5pmol/VP)和保护蛋白(3×10-5pmol/VP)的复合物(MECOM-KO),或对照病毒蛋白复合物(NT)。每12天注射一次,观察肿瘤生长状况,共52天,每组4只小鼠。病毒注射7天后取肿瘤组织,通过T7E1和免疫印迹实验检测MECOM基因敲除效果。肿瘤生长曲线和第52天的肿瘤大小测量结果显示,与对照病毒组(NT)相比,MECOM基因敲除组肿瘤生长均受到显著抑制(图6A和6B,单因素方差分析P<0.05)。T7E1和免疫印迹结果显示靶向EpCAM的腺病毒蛋白复合物能够在肺鳞癌肿瘤组织中有效编辑MECOM基因,下调其基因表达和下游信号分子RPS6的表达和磷酸化水平(图6C和6D)。第52天的肝、肺、肾组织HE染色显示尾静脉注射的腺病毒蛋白复合物并未引起重要组织损伤(图6E)。这些结果表明以靶向EpCAM的腺病毒载体对MECOM进行基因编辑,能显著抑制肺鳞癌生长,并保证安全性。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
SEQUENCE LISTING
<110> 深圳华大生命科学研究院
<120> 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用
<130> PIDC3202058
<160> 10
<170> PatentIn version 3.5
<210> 1
<211> 270
<212> PRT
<213> Artificial Sequence
<220>
<223> 1
<400> 1
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Glu Leu Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Ser
35 40 45
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
50 55 60
Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
100 105 110
Asp Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
130 135 140
Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu
145 150 155 160
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met
165 170 175
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val
180 185 190
Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly
195 200 205
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
210 215 220
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
225 230 235 240
Asp Met Gly Trp Gly Ser Gly Trp Arg Pro Tyr Tyr Tyr Tyr Gly Met
245 250 255
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
260 265 270
<210> 2
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> 2
<400> 2
Met Ala Leu Leu Leu Cys Phe Val Leu Leu Cys Gly Val Val Asp Phe
1 5 10 15
Ala Arg Ser Leu Ser Ile Thr Thr Pro Glu Glu Met Ile Glu Lys Ala
20 25 30
Lys Gly Glu Thr Ala Tyr Leu Pro Cys Lys Phe Thr Leu Ser Pro Glu
35 40 45
Asp Gln Gly Pro Leu Asp Ile Glu Trp Leu Ile Ser Pro Ala Asp Asn
50 55 60
Gln Lys Val Asp Gln Val Ile Ile Leu Tyr Ser Gly Asp Lys Ile Tyr
65 70 75 80
Asp Asp Tyr Tyr Pro Asp Leu Lys Gly Arg Val His Phe Thr Ser Asn
85 90 95
Asp Leu Lys Ser Gly Asp Ala Ser Ile Asn Val Thr Asn Leu Gln Leu
100 105 110
Ser Asp Ile Gly Thr Tyr Gln Cys Lys Val Lys Lys Ala Pro Gly Val
115 120 125
Ala Asn Lys Lys Ile His Leu Val Val Leu Val Lys Pro Ser Gly Ala
130 135 140
Arg Cys Tyr Val Asp Gly Ser Glu Glu Ile Gly Ser Asp Phe Lys Ile
145 150 155 160
Lys Cys Glu Pro Lys Glu Gly Ser Leu Pro Leu Gln Tyr Glu Trp Gln
165 170 175
Lys Leu Ser Asp Ser Gln Lys Met Pro Thr Ser Trp Leu Ala Glu Met
180 185 190
Thr Ser Ser Val Ile Ser Val Lys Asn Ala Ser Ser Glu Tyr Ser Gly
195 200 205
Thr Tyr Ser Cys Thr Val Arg Asn Arg Val Gly Ser Asp Gln Cys Leu
210 215 220
Leu Arg Leu Asn Val Val Pro Pro Ser Asn Lys Ala Gly
225 230 235
<210> 3
<211> 71
<212> PRT
<213> Artificial Sequence
<220>
<223> 3
<400> 3
Arg Gly Leu Thr Asn Ser Ile Lys Ala Asn Glu Thr Asn Ile Ala Ser
1 5 10 15
Val Thr Gln Glu Val Asn Thr Ala Lys Gly Asn Ile Ser Ser Leu Gln
20 25 30
Gly Asp Val Gln Ala Leu Gln Glu Ala Gly Tyr Ile Pro Glu Ala Pro
35 40 45
Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Phe Leu
50 55 60
Ser Thr Phe Leu Ser Pro Ala
65 70
<210> 4
<211> 578
<212> PRT
<213> Artificial Sequence
<220>
<223> 4
<400> 4
Met Ala Leu Leu Leu Cys Phe Val Leu Leu Cys Gly Val Val Asp Phe
1 5 10 15
Ala Arg Ser Leu Ser Ile Thr Thr Pro Glu Glu Met Ile Glu Lys Ala
20 25 30
Lys Gly Glu Thr Ala Tyr Leu Pro Cys Lys Phe Thr Leu Ser Pro Glu
35 40 45
Asp Gln Gly Pro Leu Asp Ile Glu Trp Leu Ile Ser Pro Ala Asp Asn
50 55 60
Gln Lys Val Asp Gln Val Ile Ile Leu Tyr Ser Gly Asp Lys Ile Tyr
65 70 75 80
Asp Asp Tyr Tyr Pro Asp Leu Lys Gly Arg Val His Phe Thr Ser Asn
85 90 95
Asp Leu Lys Ser Gly Asp Ala Ser Ile Asn Val Thr Asn Leu Gln Leu
100 105 110
Ser Asp Ile Gly Thr Tyr Gln Cys Lys Val Lys Lys Ala Pro Gly Val
115 120 125
Ala Asn Lys Lys Ile His Leu Val Val Leu Val Lys Pro Ser Gly Ala
130 135 140
Arg Cys Tyr Val Asp Gly Ser Glu Glu Ile Gly Ser Asp Phe Lys Ile
145 150 155 160
Lys Cys Glu Pro Lys Glu Gly Ser Leu Pro Leu Gln Tyr Glu Trp Gln
165 170 175
Lys Leu Ser Asp Ser Gln Lys Met Pro Thr Ser Trp Leu Ala Glu Met
180 185 190
Thr Ser Ser Val Ile Ser Val Lys Asn Ala Ser Ser Glu Tyr Ser Gly
195 200 205
Thr Tyr Ser Cys Thr Val Arg Asn Arg Val Gly Ser Asp Gln Cys Leu
210 215 220
Leu Arg Leu Asn Val Val Pro Pro Ser Asn Lys Ala Gly Arg Gly Leu
225 230 235 240
Thr Asn Ser Ile Lys Ala Asn Glu Thr Asn Ile Ala Ser Val Thr Gln
245 250 255
Glu Val Asn Thr Ala Lys Gly Asn Ile Ser Ser Leu Gln Gly Asp Val
260 265 270
Gln Ala Leu Gln Glu Ala Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly
275 280 285
Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Phe Leu Ser Thr Phe
290 295 300
Leu Ser Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln Ser Pro
325 330 335
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
340 345 350
Thr Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
355 360 365
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
370 375 380
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
385 390 395 400
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys
405 410 415
Gln Gln Ser Tyr Asp Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
420 425 430
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro
450 455 460
Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
465 470 475 480
Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
485 490 495
Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
500 505 510
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
515 520 525
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
530 535 540
Tyr Cys Ala Lys Asp Met Gly Trp Gly Ser Gly Trp Arg Pro Tyr Tyr
545 550 555 560
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
565 570 575
Ser Gly
<210> 5
<211> 1737
<212> DNA
<213> Artificial Sequence
<220>
<223> 5
<400> 5
atggcgctcc tgctgtgctt cgtgctcctg tgcggagtag tggatttcgc cagaagtttg 60
agtatcacta ctcctgaaga gatgattgaa aaagccaaag gggaaactgc ctatctgcca 120
tgcaaattta cgcttagtcc cgaagaccag ggaccgctgg acatcgagtg gctgatatca 180
ccagctgata atcagaaggt ggatcaagtg attattttat attctggaga caaaatttat 240
gatgactact atccagatct gaaaggccga gtacatttta cgagtaatga tctcaaatct 300
ggtgatgcat caataaatgt aacgaattta caactgtcag atattggcac atatcagtgc 360
aaagtgaaaa aagctcctgg tgttgcaaat aagaagattc atctggtagt tcttgttaag 420
ccttcaggtg cgagatgtta cgttgatgga tctgaagaaa ttggaagtga ctttaagata 480
aaatgtgaac caaaagaagg ttcacttcca ttacagtatg agtggcaaaa attgtctgac 540
tcacagaaaa tgcccacttc atggttagca gaaatgactt catctgttat atctgtaaaa 600
aatgcctctt ctgagtactc tgggacatac agctgtacag tcagaaacag agtgggctct 660
gatcagtgcc tgttgcgtct aaacgttgtc cctccttcaa ataaagctgg acgcggatta 720
accaattcaa taaaagctaa cgaaactaac attgcatcag ttacacaaga agtgaataca 780
gctaaaggca atatatcttc tttacaaggt gatgttcaag ctctccaaga agccggttat 840
attcctgaag ctccaagaga tgggcaagct tacgttcgta aagatggcga atgggtattc 900
ctttctacct ttttatcacc agcaggcgga gggggatcag gaggcggagg gtcaggagga 960
ggcggaagcg gagggggagg cagcgagctg cagatgactc agagcccttc ctcactgtct 1020
gccagtgtgg gcgaccgagt caccatcaca tgccggacct cacagagcat tagctcctac 1080
ctgaactggt atcagcagaa acctggacag ccccctaagc tgctgatcta ctgggcaagc 1140
accagagagt ccggagtgcc agacaggttc tccggatctg gcagtgggac agattttact 1200
ctgaccattt ctagtctgca gcccgaggac tctgctactt actattgcca gcagagctac 1260
gatatccctt atactttcgg acagggcacc aaactggaaa ttaagggcgg gggaggctca 1320
ggaggaggag ggagcggcgg aggaggcagc gaggtgcagc tgctggaaag cggaggagga 1380
gtggtccagc caggacgatc tctgagactg agttgtgccg cttcaggctt cacattttca 1440
agctatggaa tgcactgggt gcgacaggca cctggaaagg gactggagtg ggtggctgtc 1500
atcagctacg acggctccaa caaatactat gcagatagcg tgaaggggag gtttaccatt 1560
tctcgcgata acagtaaaaa tacactgtac ctgcagatga atagcctgag ggccgaagac 1620
actgctgtgt actattgcgc taaggatatg ggatgggggt ccggatggcg accatactat 1680
tactatggga tggacgtgtg gggccagggg accaccgtga ccgtgtcctc agggtaa 1737
<210> 6
<211> 275
<212> PRT
<213> Artificial Sequence
<220>
<223> 6
<400> 6
Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro
1 5 10 15
Arg Gly Ser His Gln Val Gln Leu Val Gln Ser Gly Ala Glu Asp Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Ser
35 40 45
Leu Gly Arg Tyr Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Met Gly Val Ile Trp Arg Gly Gly Thr Thr Asp Tyr Asn
65 70 75 80
Ala Lys Phe Gln Gly Arg Val Thr Ile Thr Lys Asp Asp Ser Lys Ser
85 90 95
Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gln Gly Ser Asn Phe Pro Leu Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro
145 150 155 160
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
165 170 175
Ala Ser Gln Ser Val Thr Asn Asp Ala Ala Trp Tyr Gln Lys Lys Pro
180 185 190
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gln Ala Ser Thr Arg Tyr Thr
195 200 205
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Thr
210 215 220
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys
225 230 235 240
His Gln Asp Tyr Ser Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
245 250 255
Glu Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
260 265 270
Gly Gly Ser
275
<210> 7
<211> 346
<212> PRT
<213> Artificial Sequence
<220>
<223> 7
<400> 7
Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro
1 5 10 15
Arg Gly Ser His Gln Val Gln Leu Val Gln Ser Gly Ala Glu Asp Lys
20 25 30
Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Phe Ser
35 40 45
Leu Gly Arg Tyr Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly
50 55 60
Leu Glu Trp Met Gly Val Ile Trp Arg Gly Gly Thr Thr Asp Tyr Asn
65 70 75 80
Ala Lys Phe Gln Gly Arg Val Thr Ile Thr Lys Asp Asp Ser Lys Ser
85 90 95
Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gln Gly Ser Asn Phe Pro Leu Ala Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro
145 150 155 160
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
165 170 175
Ala Ser Gln Ser Val Thr Asn Asp Ala Ala Trp Tyr Gln Lys Lys Pro
180 185 190
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gln Ala Ser Thr Arg Tyr Thr
195 200 205
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Thr
210 215 220
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys
225 230 235 240
His Gln Asp Tyr Ser Ser Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
245 250 255
Glu Ile Lys Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
260 265 270
Gly Gly Ser Arg Gly Leu Thr Asn Ser Ile Lys Ala Asn Glu Thr Asn
275 280 285
Ile Ala Ser Val Thr Gln Glu Val Asn Thr Ala Lys Gly Asn Ile Ser
290 295 300
Ser Leu Gln Gly Asp Val Gln Ala Leu Gln Glu Ala Gly Tyr Ile Pro
305 310 315 320
Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp
325 330 335
Val Phe Leu Ser Thr Phe Leu Ser Pro Ala
340 345
<210> 8
<211> 1041
<212> DNA
<213> Artificial Sequence
<220>
<223> 8
<400> 8
atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60
caagtacaac tcgtacaatc cggcgccgaa gacaaaaaac ccggcgcctc cgtaaaagta 120
tcctgcaaag tatcaggatt ctccctaggc cgatacggcg tacactgggt acgacaagcc 180
cccggccaag gcctagaatg gatgggagtc atctggcgcg gcggaaccac agactacaac 240
gccaaattcc aaggccgagt aaccatcacc aaagacgact ccaaatcaac cgtatacatg 300
gaactatcct cactccgctc cgaagacacc gccgtatact actgcgcccg acaaggctcc 360
aacttccccc tagcctactg gggccaaggc accctagtaa ccgtatcctc aggcggaggg 420
ggatcaggag gcggagggtc aggaggaggc ggaagcgata tcgtaatgac ccaatccccc 480
tcctcactct ccgcctccgt aggcgaccga gtaaccatca cctgcaaagc ctcccaatcc 540
gtaaccaacg acgccgcctg gtaccaaaaa aaacccggca aagcccccaa actactaatc 600
taccaagcct ccacccgata caccggcgta ccctcccgat tctccggctc aggctacggc 660
accgacttca cactcaccat ctcctcactc caacccgaag acttcgccac ctacttctgc 720
caccaagact actcctcacc cctaacattc ggccaaggaa caaaagtaga aataaaacgc 780
ggaggcggag ggtcaggagg aggcggaagc ggagggggag gcagccgcgg attaaccaat 840
tcaataaaag ctaacgaaac taacattgca tcagttacac aagaagtgaa tacagctaaa 900
ggcaatatat cttctttaca aggtgatgtt caagctctcc aagaagccgg ttatattcct 960
gaagctccaa gagatgggca agcttacgtt cgtaaagatg gcgaatgggt attcctttct 1020
acctttttat caccagcatg a 1041
<210> 9
<211> 578
<212> PRT
<213> Artificial Sequence
<220>
<223> 9
<400> 9
Met Ala Leu Leu Leu Cys Phe Val Leu Leu Cys Gly Val Val Asp Phe
1 5 10 15
Ala Arg Ser Leu Ser Ile Thr Thr Pro Glu Glu Met Ile Glu Lys Ala
20 25 30
Lys Gly Glu Thr Ala Tyr Leu Pro Cys Lys Phe Thr Leu Ser Pro Glu
35 40 45
Asp Gln Gly Pro Leu Asp Ile Glu Trp Leu Ile Ser Pro Ala Asp Asn
50 55 60
Gln Lys Val Asp Gln Val Ile Ile Leu Tyr Ser Gly Asp Lys Ile Tyr
65 70 75 80
Asp Asp Tyr Tyr Pro Asp Leu Lys Gly Arg Val His Phe Thr Ser Asn
85 90 95
Asp Leu Lys Ser Gly Asp Ala Ser Ile Asn Val Thr Asn Leu Gln Leu
100 105 110
Ser Asp Ile Gly Thr Tyr Gln Cys Lys Val Lys Lys Ala Pro Gly Val
115 120 125
Ala Asn Lys Lys Ile His Leu Val Val Leu Val Lys Pro Ser Gly Ala
130 135 140
Arg Cys Tyr Val Asp Gly Ser Glu Glu Ile Gly Ser Asp Phe Lys Ile
145 150 155 160
Lys Cys Glu Pro Lys Glu Gly Ser Leu Pro Leu Gln Tyr Glu Trp Gln
165 170 175
Lys Leu Ser Asp Ser Gln Lys Met Pro Thr Ser Trp Leu Ala Glu Met
180 185 190
Thr Ser Ser Val Ile Ser Val Lys Asn Ala Ser Ser Glu Tyr Ser Gly
195 200 205
Thr Tyr Ser Cys Thr Val Arg Asn Arg Val Gly Ser Asp Gln Cys Leu
210 215 220
Leu Arg Leu Asn Val Val Pro Pro Ser Asn Lys Ala Gly Arg Gly Leu
225 230 235 240
Thr Asn Ser Ile Lys Ala Asn Glu Thr Asn Ile Ala Ser Val Thr Gln
245 250 255
Glu Val Asn Thr Ala Lys Gly Asn Ile Ser Ser Leu Gln Gly Asp Val
260 265 270
Gln Ala Leu Gln Glu Ala Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly
275 280 285
Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Phe Leu Ser Thr Phe
290 295 300
Leu Ser Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln Ser Pro
325 330 335
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
340 345 350
Thr Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
355 360 365
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
370 375 380
Gly Val Pro Asp Arg Phe Ser Gly Ser Glu Ser Gly Thr Asn Tyr Thr
385 390 395 400
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys
405 410 415
Gln Gln Ser Asp Ser Leu Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu
420 425 430
Asp Ile Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Val Val Gln Pro
450 455 460
Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
465 470 475 480
Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
485 490 495
Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
500 505 510
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
515 520 525
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
530 535 540
Tyr Cys Ala Lys Asp Met Gly Trp Gly Ser Gly Trp Arg Pro Tyr Tyr
545 550 555 560
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
565 570 575
Ser Gly
<210> 10
<211> 564
<212> PRT
<213> Artificial Sequence
<220>
<223> 10
<400> 10
Met Ala Leu Leu Leu Cys Phe Val Leu Leu Cys Gly Val Val Asp Phe
1 5 10 15
Ala Arg Ser Leu Ser Ile Thr Thr Pro Glu Glu Met Ile Glu Lys Ala
20 25 30
Lys Gly Glu Thr Ala Tyr Leu Pro Cys Lys Phe Thr Leu Ser Pro Glu
35 40 45
Asp Gln Gly Pro Leu Asp Ile Glu Trp Leu Ile Ser Pro Ala Asp Asn
50 55 60
Gln Lys Val Asp Gln Val Ile Ile Leu Tyr Ser Gly Asp Lys Ile Tyr
65 70 75 80
Asp Asp Tyr Tyr Pro Asp Leu Lys Gly Arg Val His Phe Thr Ser Asn
85 90 95
Asp Leu Lys Ser Gly Asp Ala Ser Ile Asn Val Thr Asn Leu Gln Leu
100 105 110
Ser Asp Ile Gly Thr Tyr Gln Cys Lys Val Lys Lys Ala Pro Gly Val
115 120 125
Ala Asn Lys Lys Ile His Leu Val Val Leu Val Lys Pro Ser Gly Ala
130 135 140
Arg Cys Tyr Val Asp Gly Ser Glu Glu Ile Gly Ser Asp Phe Lys Ile
145 150 155 160
Lys Cys Glu Pro Lys Glu Gly Ser Leu Pro Leu Gln Tyr Glu Trp Gln
165 170 175
Lys Leu Ser Asp Ser Gln Lys Met Pro Thr Ser Trp Leu Ala Glu Met
180 185 190
Thr Ser Ser Val Ile Ser Val Lys Asn Ala Ser Ser Glu Tyr Ser Gly
195 200 205
Thr Tyr Ser Cys Thr Val Arg Asn Arg Val Gly Ser Asp Gln Cys Leu
210 215 220
Leu Arg Leu Asn Val Val Pro Pro Ser Asn Lys Ala Gly Arg Gly Leu
225 230 235 240
Thr Asn Ser Ile Lys Ala Asn Glu Thr Asn Ile Ala Ser Val Thr Gln
245 250 255
Glu Val Asn Thr Ala Lys Gly Asn Ile Ser Ser Leu Gln Gly Asp Val
260 265 270
Gln Ala Leu Gln Glu Ala Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly
275 280 285
Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val Phe Leu Ser Thr Phe
290 295 300
Leu Ser Pro Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Gln Met Thr Gln Ser Pro
325 330 335
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
340 345 350
Thr Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
355 360 365
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser
370 375 380
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
385 390 395 400
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys
405 410 415
Gln Gln Ser Tyr Asp Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu
420 425 430
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Val Val Val Gln Pro
450 455 460
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp
465 470 475 480
Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
485 490 495
Trp Val Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
500 505 510
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
515 520 525
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
530 535 540
Tyr Cys Ala Lys Lys Glu Gly Tyr Trp Gly Gln Gly Thr Leu Val Thr
545 550 555 560
Val Ser Ser Gly
Claims (14)
1.一种复合物,其特征在于,包括:
重组蛋白;以及
保护蛋白,
所述保护蛋白由下列物质组成:
腺病毒表面蛋白Hexon抗体片段;以及
T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段与所述腺病毒表面蛋白Hexon抗体片段相连;
所述重组蛋白由下列物质组成:
上皮细胞黏附分子抗体片段;
腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;以及
T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段的两端分别连接所述上皮细胞黏附分子抗体片段和腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;
所述T4噬菌体Fibritin片段为SEQ ID NO:3所示的氨基酸序列。
2.根据权利要求1所述的复合物,其特征在于,所述上皮细胞黏附分子抗体片段为SEQID NO:1所示的氨基酸序列。
3.根据权利要求1所述的复合物,其特征在于,所述腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段为SEQ ID NO:2所示的氨基酸序列。
4.根据权利要求1所述的复合物,其特征在于,所述重组蛋白为SEQ ID NO:4所示的氨基酸序列,编码所述重组蛋白的核酸为SEQ ID NO:5所示的核苷酸序列。
5.根据权利要求1所述的复合物,其特征在于,所述腺病毒表面蛋白Hexon抗体片段为SEQ ID NO:6所示的氨基酸序列。
6.根据权利要求1所述的复合物,其特征在于,所述保护蛋白为SEQ ID NO:7所示的氨基酸序列,编码所述保护蛋白的核酸为SEQ ID NO:8所示的核苷酸序列。
7.一种重组腺病毒载体,其特征在于,包括:携带有重组蛋白和保护蛋白的腺病毒载体;
所述保护蛋白由下列物质组成:
腺病毒表面蛋白Hexon抗体片段;以及
T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段与所述腺病毒表面蛋白Hexon抗体片段相连;
所述重组蛋白由下列物质组成:
上皮细胞黏附分子抗体片段;
腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;以及
T4噬菌体Fibritin片段,所述T4噬菌体Fibritin片段的两端分别连接所述上皮细胞黏附分子抗体片段和腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段;
所述T4噬菌体Fibritin片段为SEQ ID NO:3所示的氨基酸序列。
8.根据权利要求7所述的重组腺病毒载体,其特征在于,所述上皮细胞黏附分子抗体片段为SEQ ID NO:1所示的氨基酸序列;
所述腺病毒受体免疫球蛋白样细胞黏附分子的胞外区片段为SEQ ID NO:2所示的氨基酸序列;
所述腺病毒表面蛋白Hexon抗体片段为SEQ ID NO:6所示的氨基酸序列;
所述保护蛋白为SEQ ID NO:7所示的氨基酸序列,编码所述保护蛋白的核酸为SEQ IDNO:8所示的核苷酸序列。
9.根据权利要求7所述的重组腺病毒载体,其特征在于,所述重组蛋白为SEQ ID NO:4所示的氨基酸序列,编码所述重组蛋白的核酸为SEQ ID NO:5所示的核苷酸序列。
10.一种制备权利要求7-9任一项所述重组腺病毒载体的方法,其特征在于,包括:
将权利要求7-9任一项所述重组腺病毒载体中的重组蛋白和保护蛋白与腺病毒载体共孵育,以便使得所述重组蛋白和保护蛋白与腺病毒载体结合,得到重组腺病毒载体。
11.权利要求1-6任一项所述复合物或权利要求7-9任一项所述重组腺病毒载体在制备药物中的用途,其特征在于,所述药物用于治疗肺鳞癌;
所述肺鳞癌细胞表达上皮细胞黏附分子。
12.一种药物组合物,其特征在于,包括:
权利要求1-6任一项所述复合物或者权利要求7-9任一项所述重组腺病毒载体;以及
药学上可接受的辅料。
13.根据权利要求12所述的药物组合物,其特征在于,所述辅料为赋形剂。
14.根据权利要求13所述的药物组合物,其特征在于,所述赋形剂为载体、溶媒或它们的组合。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010307681.1A CN113527509B (zh) | 2020-04-17 | 2020-04-17 | 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010307681.1A CN113527509B (zh) | 2020-04-17 | 2020-04-17 | 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113527509A CN113527509A (zh) | 2021-10-22 |
CN113527509B true CN113527509B (zh) | 2023-09-26 |
Family
ID=78123441
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010307681.1A Active CN113527509B (zh) | 2020-04-17 | 2020-04-17 | 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113527509B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105017428A (zh) * | 2014-05-13 | 2015-11-04 | 中国人民解放军军事医学科学院基础医学研究所 | 双靶向融合蛋白及其编码基因与应用 |
CN105949323A (zh) * | 2016-06-24 | 2016-09-21 | 安徽未名细胞治疗有限公司 | 一种EpCAM特异性嵌合抗原受体及其编码基因、应用 |
CN106967717A (zh) * | 2017-03-14 | 2017-07-21 | 西南医科大学 | 一种适配体介导腺病毒靶向给药系统及其构建方法 |
CN110291187A (zh) * | 2017-02-17 | 2019-09-27 | 万科斯蒙股份有限公司 | 新型的靶向vegfr-2的免疫治疗方法 |
-
2020
- 2020-04-17 CN CN202010307681.1A patent/CN113527509B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105017428A (zh) * | 2014-05-13 | 2015-11-04 | 中国人民解放军军事医学科学院基础医学研究所 | 双靶向融合蛋白及其编码基因与应用 |
CN105949323A (zh) * | 2016-06-24 | 2016-09-21 | 安徽未名细胞治疗有限公司 | 一种EpCAM特异性嵌合抗原受体及其编码基因、应用 |
CN110291187A (zh) * | 2017-02-17 | 2019-09-27 | 万科斯蒙股份有限公司 | 新型的靶向vegfr-2的免疫治疗方法 |
CN106967717A (zh) * | 2017-03-14 | 2017-07-21 | 西南医科大学 | 一种适配体介导腺病毒靶向给药系统及其构建方法 |
Non-Patent Citations (3)
Title |
---|
Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors;Heideman等;《Cancer Gene Ther》;20011231;第8卷(第5期);第342-351页 * |
肿瘤靶向性腺病毒研究进展;况舸等;《国外医学.肿瘤学分册》;20050420(第04期);第243-246页 * |
谢秀琼等.《中药新制剂开发与应用 第3版》.人民卫生出版社,2006,第138-141页. * |
Also Published As
Publication number | Publication date |
---|---|
CN113527509A (zh) | 2021-10-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112480217B (zh) | 基于SARS-CoV-2的S抗原蛋白的疫苗和组合物 | |
AU696495B2 (en) | Adenoviral vectors of animal origin and use in gene therapy | |
CN100390292C (zh) | 甲胎蛋白表达细胞的腺病毒载体及其使用方法 | |
DE69826661T2 (de) | Antitumorale zusammenstellung von immunogene polypetiden mit veränderter zellokalisierung | |
CN111467489B (zh) | 一种治疗肿瘤的药物 | |
AU766403C (en) | Treatment of cervical cancer | |
WO2016106178A1 (en) | Multitargeting onocolytic adenovirus, methods of use, and methods of making | |
CN113842453B (zh) | 一种抑制SARS-CoV-2的纳米捕集剂 | |
AU721970B2 (en) | Liposomal-viral DNA complexes for treating disease | |
JP2001503617A (ja) | 標的化腫瘍遺伝子治療のためのレセプターを介した遺伝子移送系 | |
WO2023051701A1 (zh) | 抗SARS-CoV-2感染的mRNA、蛋白以及抗SARS-CoV-2感染的疫苗 | |
Rueda et al. | Influence of flanking sequences on presentation efficiency of a CD8+ cytotoxic T-cell epitope delivered by parvovirus-like particles | |
CN113527509B (zh) | 含有重组蛋白和保护蛋白的复合物在治疗肺鳞癌中的应用 | |
WO2008154867A1 (en) | Material with immunogenicity | |
EP1446479B1 (en) | Recombinant adenovirus with enhanced therapeutic effect and pharmaceutical composition comprising said recombinant adenovirus | |
CA2170882A1 (en) | Vector for gene therapy of the liver | |
WO2006125381A1 (fr) | Virus du gene de ciblage tumoral zd55-il-24, son procede de construction et son application | |
KR100686356B1 (ko) | 중공 나노입자를 형성하는 단백질에 질환 치료용 세포도입 물질을 융합시킨 약제 | |
EP1642981B1 (en) | RECOMBINANT GENE MEDICINE OF ADENOVIRUS VECTOR AND GENE p53 FOR TREATING PROLIFERATIVE DISEASES | |
CN1517437B (zh) | 特异性治疗肿瘤或胞内感染的疫苗及应用 | |
Fu et al. | Potential adenovirus-mediated gene therapy of glioma cancer | |
JP2002544236A (ja) | 組換えパラポックスウイルスに基づくとりわけ肝の慢性ウイルス感染症ならびに炎症性、変性性および増殖性疾患ならびに癌のための器官、組織および細胞特異的免疫治療薬 | |
WO2023083315A1 (zh) | 一种以RBD靶向递送shRNA的nCOVsiRNA药物及合成方法和应用 | |
US20060165726A1 (en) | Remedies with the use of hollow protein nanoparticles presenting growth factor or the like | |
CN116789750A (zh) | 预防和/或治疗宫颈癌的多肽及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |