KR101235934B1 - 글루카곤 수용체 길항제 - Google Patents
글루카곤 수용체 길항제 Download PDFInfo
- Publication number
- KR101235934B1 KR101235934B1 KR1020107021297A KR20107021297A KR101235934B1 KR 101235934 B1 KR101235934 B1 KR 101235934B1 KR 1020107021297 A KR1020107021297 A KR 1020107021297A KR 20107021297 A KR20107021297 A KR 20107021297A KR 101235934 B1 KR101235934 B1 KR 101235934B1
- Authority
- KR
- South Korea
- Prior art keywords
- ser
- leu
- val
- thr
- gly
- Prior art date
Links
- 229940122904 Glucagon receptor antagonist Drugs 0.000 title description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims abstract description 71
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims abstract description 71
- 230000027455 binding Effects 0.000 claims abstract description 37
- 108010063919 Glucagon Receptors Proteins 0.000 claims abstract description 36
- 102100040890 Glucagon receptor Human genes 0.000 claims abstract description 35
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims abstract description 34
- 102000051325 Glucagon Human genes 0.000 claims abstract description 30
- 108060003199 Glucagon Proteins 0.000 claims abstract description 30
- 229960004666 glucagon Drugs 0.000 claims abstract description 30
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 10
- 241000282414 Homo sapiens Species 0.000 claims description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 102000005962 receptors Human genes 0.000 abstract description 23
- 108020003175 receptors Proteins 0.000 abstract description 23
- 238000011282 treatment Methods 0.000 abstract description 8
- 239000005557 antagonist Substances 0.000 abstract description 5
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 abstract description 3
- 108010021625 Immunoglobulin Fragments Proteins 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 229940088597 hormone Drugs 0.000 abstract description 3
- 239000005556 hormone Substances 0.000 abstract description 3
- 229920001184 polypeptide Polymers 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 241000880493 Leptailurus serval Species 0.000 description 40
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 31
- 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 29
- 210000004027 cell Anatomy 0.000 description 29
- 108010050848 glycylleucine Proteins 0.000 description 27
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 26
- 108010089804 glycyl-threonine Proteins 0.000 description 26
- 241000700159 Rattus Species 0.000 description 23
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 23
- 108010073969 valyllysine Proteins 0.000 description 23
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 21
- 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 21
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 20
- 108091028043 Nucleic acid sequence Proteins 0.000 description 20
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 20
- 108010087924 alanylproline Proteins 0.000 description 20
- 235000001014 amino acid Nutrition 0.000 description 20
- 238000001727 in vivo Methods 0.000 description 20
- FUTAPPOITCCWTH-WHFBIAKZSA-N Gly-Asp-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O FUTAPPOITCCWTH-WHFBIAKZSA-N 0.000 description 19
- WCNWGAUZWWSYDG-SVSWQMSJSA-N Ile-Thr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)O)N WCNWGAUZWWSYDG-SVSWQMSJSA-N 0.000 description 19
- 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 19
- 125000003275 alpha amino acid group Chemical group 0.000 description 19
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 18
- 108010034529 leucyl-lysine Proteins 0.000 description 18
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 17
- 108010008355 arginyl-glutamine Proteins 0.000 description 17
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 17
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 16
- 108020004414 DNA Proteins 0.000 description 16
- 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 16
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 16
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 16
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 16
- 108010092854 aspartyllysine Proteins 0.000 description 16
- 108010070643 prolylglutamic acid Proteins 0.000 description 16
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 15
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 15
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 15
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 15
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 15
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 15
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 15
- 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 15
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 15
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 15
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 15
- LNICFEXCAHIJOR-DCAQKATOSA-N Pro-Ser-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LNICFEXCAHIJOR-DCAQKATOSA-N 0.000 description 15
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 15
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 15
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 15
- 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 15
- 108010026333 seryl-proline Proteins 0.000 description 15
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 15
- 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 14
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 14
- UESYBOXFJWJVSB-AVGNSLFASA-N Gln-Phe-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O UESYBOXFJWJVSB-AVGNSLFASA-N 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 14
- 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 14
- IGOYNRWLWHWAQO-JTQLQIEISA-N Gly-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IGOYNRWLWHWAQO-JTQLQIEISA-N 0.000 description 14
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 14
- 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 14
- 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 14
- DLZBBDSPTJBOOD-BPNCWPANSA-N Pro-Tyr-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O DLZBBDSPTJBOOD-BPNCWPANSA-N 0.000 description 14
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 14
- 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 14
- 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 14
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 14
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 13
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 13
- 241001529936 Murinae Species 0.000 description 13
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 13
- 238000006467 substitution reaction Methods 0.000 description 13
- QLQHWWCSCLZUMA-KKUMJFAQSA-N Leu-Asp-Tyr Chemical compound CC(C)C[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 QLQHWWCSCLZUMA-KKUMJFAQSA-N 0.000 description 12
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 11
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 11
- 108010010147 glycylglutamine Proteins 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 10
- NGBGZCUWFVVJKC-IRXDYDNUSA-N Gly-Tyr-Tyr Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NGBGZCUWFVVJKC-IRXDYDNUSA-N 0.000 description 10
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 10
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 10
- 108010031719 prolyl-serine Proteins 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 9
- 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 9
- 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 9
- 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 9
- 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 9
- 241000282567 Macaca fascicularis Species 0.000 description 9
- 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 9
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 9
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 9
- 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 9
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 9
- 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 9
- 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 9
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 9
- 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 9
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 9
- 108010081404 acein-2 Proteins 0.000 description 9
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 9
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 9
- 108010047857 aspartylglycine Proteins 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 108010017391 lysylvaline Proteins 0.000 description 9
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 9
- 239000013598 vector Substances 0.000 description 9
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 8
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 8
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 8
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 8
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 8
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 8
- 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 8
- 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 8
- GJLXZITZLUUXMJ-NHCYSSNCSA-N Gln-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N GJLXZITZLUUXMJ-NHCYSSNCSA-N 0.000 description 8
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 8
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 8
- NTXIJPDAHXSHNL-ONGXEEELSA-N His-Gly-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O NTXIJPDAHXSHNL-ONGXEEELSA-N 0.000 description 8
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 8
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-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](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 8
- 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 8
- 108010065920 Insulin Lispro Proteins 0.000 description 8
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 8
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 8
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 8
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 8
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 8
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 8
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 8
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 8
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 8
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 8
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 8
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 8
- 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 8
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 8
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 8
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 8
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 8
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 8
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 8
- AGDDLOQMXUQPDY-BZSNNMDCSA-N Tyr-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O AGDDLOQMXUQPDY-BZSNNMDCSA-N 0.000 description 8
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 8
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 8
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 8
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 8
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 8
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 8
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 8
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 8
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 8
- 108010064235 lysylglycine Proteins 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 108010051242 phenylalanylserine Proteins 0.000 description 8
- 108010077112 prolyl-proline Proteins 0.000 description 8
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 8
- 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 7
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 7
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 7
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 7
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 7
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 7
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 7
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 7
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 7
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 7
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 7
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 7
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 7
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 7
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 7
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 7
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 7
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 7
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 7
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 7
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 7
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 7
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 7
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 7
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 7
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 7
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 7
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 7
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 7
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 7
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 7
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 7
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 7
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 7
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 7
- 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 7
- 241001465754 Metazoa Species 0.000 description 7
- 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 7
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 7
- 102100040918 Pro-glucagon Human genes 0.000 description 7
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 7
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 7
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 7
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 7
- 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 7
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 7
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 7
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 7
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 7
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 7
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 7
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 7
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 7
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 7
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 7
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 7
- QARCDOCCDOLJSF-HJPIBITLSA-N Tyr-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QARCDOCCDOLJSF-HJPIBITLSA-N 0.000 description 7
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 7
- 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 7
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-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](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 7
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 7
- 108010078144 glutaminyl-glycine Proteins 0.000 description 7
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 7
- 238000010606 normalization Methods 0.000 description 7
- 108010073101 phenylalanylleucine Proteins 0.000 description 7
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 7
- 108010051110 tyrosyl-lysine Proteins 0.000 description 7
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 7
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 6
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 6
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 6
- ULUQBUKAPDUKOC-GVXVVHGQSA-N Lys-Glu-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O ULUQBUKAPDUKOC-GVXVVHGQSA-N 0.000 description 6
- 101001040081 Rattus norvegicus Glucagon receptor Proteins 0.000 description 6
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 6
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 6
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 6
- FIRUOPRJKCBLST-KKUMJFAQSA-N Tyr-His-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O FIRUOPRJKCBLST-KKUMJFAQSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 5
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 5
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 5
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 5
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 5
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 5
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 5
- 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 5
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 5
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 5
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 5
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 5
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- RCYUBVHMVUHEBM-RCWTZXSCSA-N Pro-Pro-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RCYUBVHMVUHEBM-RCWTZXSCSA-N 0.000 description 5
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 5
- 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 5
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 5
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 5
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 5
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 5
- CCZXBOFIBYQLEV-IHPCNDPISA-N Trp-Leu-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(O)=O CCZXBOFIBYQLEV-IHPCNDPISA-N 0.000 description 5
- GULIUBBXCYPDJU-CQDKDKBSSA-N Tyr-Leu-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CC1=CC=C(O)C=C1 GULIUBBXCYPDJU-CQDKDKBSSA-N 0.000 description 5
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 5
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 5
- HWNYVQMOLCYHEA-IHRRRGAJSA-N Val-Ser-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N HWNYVQMOLCYHEA-IHRRRGAJSA-N 0.000 description 5
- 108010070944 alanylhistidine Proteins 0.000 description 5
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000002821 scintillation proximity assay Methods 0.000 description 5
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 5
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 5
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 5
- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 4
- LJFNNUBZSZCZFN-WHFBIAKZSA-N Ala-Gly-Cys Chemical compound N[C@@H](C)C(=O)NCC(=O)N[C@@H](CS)C(=O)O LJFNNUBZSZCZFN-WHFBIAKZSA-N 0.000 description 4
- PMQXMXAASGFUDX-SRVKXCTJSA-N Ala-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCCN PMQXMXAASGFUDX-SRVKXCTJSA-N 0.000 description 4
- FUKFQILQFQKHLE-DCAQKATOSA-N Ala-Lys-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O FUKFQILQFQKHLE-DCAQKATOSA-N 0.000 description 4
- IHMCQESUJVZTKW-UBHSHLNASA-N Ala-Phe-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 IHMCQESUJVZTKW-UBHSHLNASA-N 0.000 description 4
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound 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 MUGAESARFRGOTQ-IGNZVWTISA-N 0.000 description 4
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 4
- GOVUDFOGXOONFT-VEVYYDQMSA-N Asn-Arg-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GOVUDFOGXOONFT-VEVYYDQMSA-N 0.000 description 4
- SEKBHZJLARBNPB-GHCJXIJMSA-N Asn-Ile-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O SEKBHZJLARBNPB-GHCJXIJMSA-N 0.000 description 4
- DJIMLSXHXKWADV-CIUDSAMLSA-N Asn-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O DJIMLSXHXKWADV-CIUDSAMLSA-N 0.000 description 4
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-N 0.000 description 4
- WKGJGVGTEZGFSW-FXQIFTODSA-N Asp-Asn-Met Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O WKGJGVGTEZGFSW-FXQIFTODSA-N 0.000 description 4
- HKEZZWQWXWGASX-KKUMJFAQSA-N Asp-Leu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HKEZZWQWXWGASX-KKUMJFAQSA-N 0.000 description 4
- UMHUHHJMEXNSIV-CIUDSAMLSA-N Asp-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UMHUHHJMEXNSIV-CIUDSAMLSA-N 0.000 description 4
- LTCKTLYKRMCFOC-KKUMJFAQSA-N Asp-Phe-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LTCKTLYKRMCFOC-KKUMJFAQSA-N 0.000 description 4
- BPHKULHWEIUDOB-FXQIFTODSA-N Cys-Gln-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BPHKULHWEIUDOB-FXQIFTODSA-N 0.000 description 4
- OWAFTBLVZNSIFO-SRVKXCTJSA-N Cys-His-His Chemical compound N[C@@H](CS)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O OWAFTBLVZNSIFO-SRVKXCTJSA-N 0.000 description 4
- KCPOQGRVVXYLAC-KKUMJFAQSA-N Cys-Leu-Phe Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CS)N KCPOQGRVVXYLAC-KKUMJFAQSA-N 0.000 description 4
- DTFJUSWYECELTM-BPUTZDHNSA-N Cys-Pro-Trp Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O DTFJUSWYECELTM-BPUTZDHNSA-N 0.000 description 4
- YNJBLTDKTMKEET-ZLUOBGJFSA-N Cys-Ser-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O YNJBLTDKTMKEET-ZLUOBGJFSA-N 0.000 description 4
- YWEHYKGJWHPGPY-XGEHTFHBSA-N Cys-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N)O YWEHYKGJWHPGPY-XGEHTFHBSA-N 0.000 description 4
- XEZWLWNGUMXAJI-QEJZJMRPSA-N Gln-Cys-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)N)C(O)=O)=CNC2=C1 XEZWLWNGUMXAJI-QEJZJMRPSA-N 0.000 description 4
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 4
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 4
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 4
- NZOAFWHVAFJERA-OALUTQOASA-N Gly-Phe-Trp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O NZOAFWHVAFJERA-OALUTQOASA-N 0.000 description 4
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 4
- QIVPRLJQQVXCIY-HGNGGELXSA-N His-Ala-Gln Chemical compound C[C@H](NC(=O)[C@@H](N)Cc1cnc[nH]1)C(=O)N[C@@H](CCC(N)=O)C(O)=O QIVPRLJQQVXCIY-HGNGGELXSA-N 0.000 description 4
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 4
- RWYCOSAAAJBJQL-KCTSRDHCSA-N Ile-Gly-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RWYCOSAAAJBJQL-KCTSRDHCSA-N 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 4
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 4
- MJWVXZABPOKJJF-ACRUOGEOSA-N Leu-Phe-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MJWVXZABPOKJJF-ACRUOGEOSA-N 0.000 description 4
- SXOFUVGLPHCPRQ-KKUMJFAQSA-N Leu-Tyr-Cys Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(O)=O SXOFUVGLPHCPRQ-KKUMJFAQSA-N 0.000 description 4
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 4
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 4
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 4
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 0.000 description 4
- LLGTYVHITPVGKR-RYUDHWBXSA-N Phe-Gln-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O LLGTYVHITPVGKR-RYUDHWBXSA-N 0.000 description 4
- PSKRILMFHNIUAO-JYJNAYRXSA-N Phe-Glu-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N PSKRILMFHNIUAO-JYJNAYRXSA-N 0.000 description 4
- NPLGQVKZFGJWAI-QWHCGFSZSA-N Phe-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O NPLGQVKZFGJWAI-QWHCGFSZSA-N 0.000 description 4
- KBVJZCVLQWCJQN-KKUMJFAQSA-N Phe-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KBVJZCVLQWCJQN-KKUMJFAQSA-N 0.000 description 4
- GPLWGAYGROGDEN-BZSNNMDCSA-N Phe-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O GPLWGAYGROGDEN-BZSNNMDCSA-N 0.000 description 4
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 4
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 4
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 4
- MAWSJXHRLWVJEZ-ACZMJKKPSA-N Ser-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N MAWSJXHRLWVJEZ-ACZMJKKPSA-N 0.000 description 4
- VMVNCJDKFOQOHM-GUBZILKMSA-N Ser-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N VMVNCJDKFOQOHM-GUBZILKMSA-N 0.000 description 4
- QMCDMHWAKMUGJE-IHRRRGAJSA-N Ser-Phe-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O QMCDMHWAKMUGJE-IHRRRGAJSA-N 0.000 description 4
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 4
- YBXMGKCLOPDEKA-NUMRIWBASA-N Thr-Asp-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YBXMGKCLOPDEKA-NUMRIWBASA-N 0.000 description 4
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 4
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 4
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 4
- KULBQAVOXHQLIY-HSCHXYMDSA-N Trp-Ile-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 KULBQAVOXHQLIY-HSCHXYMDSA-N 0.000 description 4
- RWAYYYOZMHMEGD-XIRDDKMYSA-N Trp-Leu-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 RWAYYYOZMHMEGD-XIRDDKMYSA-N 0.000 description 4
- NWQCKAPDGQMZQN-IHPCNDPISA-N Trp-Lys-Leu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O NWQCKAPDGQMZQN-IHPCNDPISA-N 0.000 description 4
- GQNCRIFNDVFRNF-BPUTZDHNSA-N Trp-Pro-Asp Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O GQNCRIFNDVFRNF-BPUTZDHNSA-N 0.000 description 4
- ARJASMXQBRNAGI-YESZJQIVSA-N Tyr-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N ARJASMXQBRNAGI-YESZJQIVSA-N 0.000 description 4
- CWVHKVVKAQIJKY-ACRUOGEOSA-N Tyr-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CC=C(C=C2)O)N CWVHKVVKAQIJKY-ACRUOGEOSA-N 0.000 description 4
- KWKJGBHDYJOVCR-SRVKXCTJSA-N Tyr-Ser-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O KWKJGBHDYJOVCR-SRVKXCTJSA-N 0.000 description 4
- SYFHQHYTNCQCCN-MELADBBJSA-N Tyr-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O SYFHQHYTNCQCCN-MELADBBJSA-N 0.000 description 4
- JHDZONWZTCKTJR-KJEVXHAQSA-N Tyr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JHDZONWZTCKTJR-KJEVXHAQSA-N 0.000 description 4
- NAHUCETZGZZSEX-IHPCNDPISA-N Tyr-Trp-Asp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NAHUCETZGZZSEX-IHPCNDPISA-N 0.000 description 4
- 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 4
- COYSIHFOCOMGCF-WPRPVWTQSA-N Val-Arg-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-WPRPVWTQSA-N 0.000 description 4
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 4
- IWZYXFRGWKEKBJ-GVXVVHGQSA-N Val-Gln-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N IWZYXFRGWKEKBJ-GVXVVHGQSA-N 0.000 description 4
- LKUDRJSNRWVGMS-QSFUFRPTSA-N Val-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LKUDRJSNRWVGMS-QSFUFRPTSA-N 0.000 description 4
- XNLUVJPMPAZHCY-JYJNAYRXSA-N Val-Val-Phe Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 XNLUVJPMPAZHCY-JYJNAYRXSA-N 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 4
- 108010091092 arginyl-glycyl-proline Proteins 0.000 description 4
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 4
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 4
- 108010068265 aspartyltyrosine Proteins 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- 239000002299 complementary DNA Chemical group 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 108010050343 histidyl-alanyl-glutamine Proteins 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 108010043322 lysyl-tryptophyl-alpha-lysine Proteins 0.000 description 4
- 108010005942 methionylglycine Proteins 0.000 description 4
- 230000009871 nonspecific binding Effects 0.000 description 4
- 108010012581 phenylalanylglutamate Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 108010079317 prolyl-tyrosine Proteins 0.000 description 4
- 108010053725 prolylvaline Proteins 0.000 description 4
- 108010048818 seryl-histidine Proteins 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 108010044292 tryptophyltyrosine Proteins 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- RWCLSUOSKWTXLA-FXQIFTODSA-N Arg-Asp-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RWCLSUOSKWTXLA-FXQIFTODSA-N 0.000 description 3
- FTNRWCPWDWRPAV-BZSNNMDCSA-N Asn-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FTNRWCPWDWRPAV-BZSNNMDCSA-N 0.000 description 3
- YNQMEIJEWSHOEO-SRVKXCTJSA-N Asn-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O YNQMEIJEWSHOEO-SRVKXCTJSA-N 0.000 description 3
- XUZQMPGBGFQJMY-SRVKXCTJSA-N Gln-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N XUZQMPGBGFQJMY-SRVKXCTJSA-N 0.000 description 3
- FGWRYRAVBVOHIB-XIRDDKMYSA-N Gln-Pro-Trp Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)N)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O FGWRYRAVBVOHIB-XIRDDKMYSA-N 0.000 description 3
- WOSRKEJQESVHGA-CIUDSAMLSA-N Glu-Arg-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O WOSRKEJQESVHGA-CIUDSAMLSA-N 0.000 description 3
- PCBBLFVHTYNQGG-LAEOZQHASA-N Glu-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N PCBBLFVHTYNQGG-LAEOZQHASA-N 0.000 description 3
- QXPRJQPCFXMCIY-NKWVEPMBSA-N Gly-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN QXPRJQPCFXMCIY-NKWVEPMBSA-N 0.000 description 3
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 3
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- GAZGFPOZOLEYAJ-YTFOTSKYSA-N Ile-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N GAZGFPOZOLEYAJ-YTFOTSKYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- ZDBMWELMUCLUPL-QEJZJMRPSA-N Leu-Phe-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 ZDBMWELMUCLUPL-QEJZJMRPSA-N 0.000 description 3
- WIVCOAKLPICYGY-KKUMJFAQSA-N Phe-Asp-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N WIVCOAKLPICYGY-KKUMJFAQSA-N 0.000 description 3
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 3
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 3
- DWAMXBFJNZIHMC-KBPBESRZSA-N Tyr-Leu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O DWAMXBFJNZIHMC-KBPBESRZSA-N 0.000 description 3
- VVZDBPBZHLQPPB-XVKPBYJWSA-N Val-Glu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VVZDBPBZHLQPPB-XVKPBYJWSA-N 0.000 description 3
- 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 3
- AOILQMZPNLUXCM-AVGNSLFASA-N Val-Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN AOILQMZPNLUXCM-AVGNSLFASA-N 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 108010094001 arginyl-tryptophyl-arginine Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 3
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 108010030617 leucyl-phenylalanyl-valine Proteins 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007523 nucleic acids Chemical group 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 108010003137 tyrosyltyrosine Proteins 0.000 description 3
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 2
- LBYMZCVBOKYZNS-CIUDSAMLSA-N Ala-Leu-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O LBYMZCVBOKYZNS-CIUDSAMLSA-N 0.000 description 2
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 2
- 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 2
- DHONNEYAZPNGSG-UBHSHLNASA-N Ala-Val-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DHONNEYAZPNGSG-UBHSHLNASA-N 0.000 description 2
- SGYSTDWPNPKJPP-GUBZILKMSA-N Arg-Ala-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SGYSTDWPNPKJPP-GUBZILKMSA-N 0.000 description 2
- YFWTXMRJJDNTLM-LSJOCFKGSA-N Arg-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YFWTXMRJJDNTLM-LSJOCFKGSA-N 0.000 description 2
- YUGFLWBWAJFGKY-BQBZGAKWSA-N Arg-Cys-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O YUGFLWBWAJFGKY-BQBZGAKWSA-N 0.000 description 2
- GNYUVVJYGJFKHN-RVMXOQNASA-N Arg-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N GNYUVVJYGJFKHN-RVMXOQNASA-N 0.000 description 2
- LLUGJARLJCGLAR-CYDGBPFRSA-N Arg-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LLUGJARLJCGLAR-CYDGBPFRSA-N 0.000 description 2
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 2
- SLQQPJBDBVPVQV-JYJNAYRXSA-N Arg-Phe-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O SLQQPJBDBVPVQV-JYJNAYRXSA-N 0.000 description 2
- AIFHRTPABBBHKU-RCWTZXSCSA-N Arg-Thr-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AIFHRTPABBBHKU-RCWTZXSCSA-N 0.000 description 2
- QUBKBPZGMZWOKQ-SZMVWBNQSA-N Arg-Trp-Arg Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 QUBKBPZGMZWOKQ-SZMVWBNQSA-N 0.000 description 2
- KEZVOBAKAXHMOF-GUBZILKMSA-N Arg-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N KEZVOBAKAXHMOF-GUBZILKMSA-N 0.000 description 2
- CMLGVVWQQHUXOZ-GHCJXIJMSA-N Asn-Ala-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CMLGVVWQQHUXOZ-GHCJXIJMSA-N 0.000 description 2
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 2
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 2
- HAFCJCDJGIOYPW-WDSKDSINSA-N Asp-Gly-Gln Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O HAFCJCDJGIOYPW-WDSKDSINSA-N 0.000 description 2
- DWOSGXZMLQNDBN-FXQIFTODSA-N Asp-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CS)C(=O)O DWOSGXZMLQNDBN-FXQIFTODSA-N 0.000 description 2
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 2
- 102100021277 Beta-secretase 2 Human genes 0.000 description 2
- 101710150190 Beta-secretase 2 Proteins 0.000 description 2
- AVFGSUXQKHIQJS-QEJZJMRPSA-N Cys-Gln-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CS)N)C(O)=O)=CNC2=C1 AVFGSUXQKHIQJS-QEJZJMRPSA-N 0.000 description 2
- SKSJPIBFNFPTJB-NKWVEPMBSA-N Cys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CS)N)C(=O)O SKSJPIBFNFPTJB-NKWVEPMBSA-N 0.000 description 2
- SBDVXRYCOIEYNV-YUMQZZPRSA-N Cys-His-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CS)N SBDVXRYCOIEYNV-YUMQZZPRSA-N 0.000 description 2
- HKALUUKHYNEDRS-GUBZILKMSA-N Cys-Leu-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HKALUUKHYNEDRS-GUBZILKMSA-N 0.000 description 2
- CMYVIUWVYHOLRD-ZLUOBGJFSA-N Cys-Ser-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CMYVIUWVYHOLRD-ZLUOBGJFSA-N 0.000 description 2
- IXPSSIBVVKSOIE-SRVKXCTJSA-N Cys-Ser-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N)O IXPSSIBVVKSOIE-SRVKXCTJSA-N 0.000 description 2
- 102220502941 Geranylgeranyl transferase type-2 subunit alpha_D10E_mutation Human genes 0.000 description 2
- RZSLYUUFFVHFRQ-FXQIFTODSA-N Gln-Ala-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O RZSLYUUFFVHFRQ-FXQIFTODSA-N 0.000 description 2
- NKCZYEDZTKOFBG-GUBZILKMSA-N Gln-Gln-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NKCZYEDZTKOFBG-GUBZILKMSA-N 0.000 description 2
- KHNJVFYHIKLUPD-SRVKXCTJSA-N Gln-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N KHNJVFYHIKLUPD-SRVKXCTJSA-N 0.000 description 2
- RWQCWSGOOOEGPB-FXQIFTODSA-N Gln-Ser-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O RWQCWSGOOOEGPB-FXQIFTODSA-N 0.000 description 2
- SGVGIVDZLSHSEN-RYUDHWBXSA-N Gln-Tyr-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O SGVGIVDZLSHSEN-RYUDHWBXSA-N 0.000 description 2
- UBRQJXFDVZNYJP-AVGNSLFASA-N Gln-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)N)N)O UBRQJXFDVZNYJP-AVGNSLFASA-N 0.000 description 2
- AUTNXSQEVVHSJK-YVNDNENWSA-N Glu-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O AUTNXSQEVVHSJK-YVNDNENWSA-N 0.000 description 2
- KRGZZKWSBGPLKL-IUCAKERBSA-N Glu-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N KRGZZKWSBGPLKL-IUCAKERBSA-N 0.000 description 2
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 2
- PAWIVEIWWYGBAM-YUMQZZPRSA-N Gly-Leu-Ala Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O PAWIVEIWWYGBAM-YUMQZZPRSA-N 0.000 description 2
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 2
- CSMYMGFCEJWALV-WDSKDSINSA-N Gly-Ser-Gln Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O CSMYMGFCEJWALV-WDSKDSINSA-N 0.000 description 2
- KBBFOULZCHWGJX-KBPBESRZSA-N Gly-Tyr-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)CN)O KBBFOULZCHWGJX-KBPBESRZSA-N 0.000 description 2
- 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 2
- MJNWEIMBXKKCSF-XVYDVKMFSA-N His-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N MJNWEIMBXKKCSF-XVYDVKMFSA-N 0.000 description 2
- VBOFRJNDIOPNDO-YUMQZZPRSA-N His-Gly-Asn Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N VBOFRJNDIOPNDO-YUMQZZPRSA-N 0.000 description 2
- FYTCLUIYTYFGPT-YUMQZZPRSA-N His-Gly-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FYTCLUIYTYFGPT-YUMQZZPRSA-N 0.000 description 2
- YAALVYQFVJNXIV-KKUMJFAQSA-N His-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 YAALVYQFVJNXIV-KKUMJFAQSA-N 0.000 description 2
- YVCGJPIKRMGNPA-LSJOCFKGSA-N His-Met-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O YVCGJPIKRMGNPA-LSJOCFKGSA-N 0.000 description 2
- XHQYFGPIRUHQIB-PBCZWWQYSA-N His-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CN=CN1 XHQYFGPIRUHQIB-PBCZWWQYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- UWLHDGMRWXHFFY-HPCHECBXSA-N Ile-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1CCC[C@@H]1C(=O)O)N UWLHDGMRWXHFFY-HPCHECBXSA-N 0.000 description 2
- XQLGNKLSPYCRMZ-HJWJTTGWSA-N Ile-Phe-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)O)N XQLGNKLSPYCRMZ-HJWJTTGWSA-N 0.000 description 2
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 2
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-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
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 description 2
- 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 2
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 2
- KWTVLKBOQATPHJ-SRVKXCTJSA-N Leu-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N KWTVLKBOQATPHJ-SRVKXCTJSA-N 0.000 description 2
- YOZCKMXHBYKOMQ-IHRRRGAJSA-N Leu-Arg-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOZCKMXHBYKOMQ-IHRRRGAJSA-N 0.000 description 2
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 2
- UBZGNBKMIJHOHL-BZSNNMDCSA-N Leu-Leu-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 UBZGNBKMIJHOHL-BZSNNMDCSA-N 0.000 description 2
- FMFNIDICDKEMOE-XUXIUFHCSA-N Leu-Val-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FMFNIDICDKEMOE-XUXIUFHCSA-N 0.000 description 2
- 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 2
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 2
- HAUUXTXKJNVIFY-ONGXEEELSA-N Lys-Gly-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HAUUXTXKJNVIFY-ONGXEEELSA-N 0.000 description 2
- TVHCDSBMFQYPNA-RHYQMDGZSA-N Lys-Thr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TVHCDSBMFQYPNA-RHYQMDGZSA-N 0.000 description 2
- FJVJLMZUIGMFFU-BQBZGAKWSA-N Met-Asp-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O FJVJLMZUIGMFFU-BQBZGAKWSA-N 0.000 description 2
- QMIXOTQHYHOUJP-KKUMJFAQSA-N Met-Gln-Tyr Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N QMIXOTQHYHOUJP-KKUMJFAQSA-N 0.000 description 2
- CHDYFPCQVUOJEB-ULQDDVLXSA-N Met-Leu-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CHDYFPCQVUOJEB-ULQDDVLXSA-N 0.000 description 2
- 108010066427 N-valyltryptophan Proteins 0.000 description 2
- DMEYUTSDVRCWRS-ULQDDVLXSA-N Phe-Lys-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 DMEYUTSDVRCWRS-ULQDDVLXSA-N 0.000 description 2
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 2
- SGCZFWSQERRKBD-BQBZGAKWSA-N Pro-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 SGCZFWSQERRKBD-BQBZGAKWSA-N 0.000 description 2
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 241000700162 Rattus sp. Species 0.000 description 2
- BTKUIVBNGBFTTP-WHFBIAKZSA-N Ser-Ala-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(O)=O BTKUIVBNGBFTTP-WHFBIAKZSA-N 0.000 description 2
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 2
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 2
- QUGRFWPMPVIAPW-IHRRRGAJSA-N Ser-Pro-Phe Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QUGRFWPMPVIAPW-IHRRRGAJSA-N 0.000 description 2
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 2
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-N 0.000 description 2
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 2
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 2
- YXGCIEUDOHILKR-IHRRRGAJSA-N Ser-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CO)N YXGCIEUDOHILKR-IHRRRGAJSA-N 0.000 description 2
- WYKJENSCCRJLRC-ZDLURKLDSA-N Thr-Gly-Cys Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)O WYKJENSCCRJLRC-ZDLURKLDSA-N 0.000 description 2
- 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 2
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 2
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 2
- FHVCMIMUGUFIOJ-IHPCNDPISA-N Trp-His-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)N[C@@H](CC4=CN=CN4)C(=O)O)N FHVCMIMUGUFIOJ-IHPCNDPISA-N 0.000 description 2
- 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 2
- AKLNEFNQWLHIGY-QWRGUYRKSA-N Tyr-Gly-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N)O AKLNEFNQWLHIGY-QWRGUYRKSA-N 0.000 description 2
- GFJXBLSZOFWHAW-JYJNAYRXSA-N Tyr-His-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GFJXBLSZOFWHAW-JYJNAYRXSA-N 0.000 description 2
- GQVZBMROTPEPIF-SRVKXCTJSA-N Tyr-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GQVZBMROTPEPIF-SRVKXCTJSA-N 0.000 description 2
- YMZYSCDRTXEOKD-IHPCNDPISA-N Tyr-Trp-Asn Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N YMZYSCDRTXEOKD-IHPCNDPISA-N 0.000 description 2
- KRXFXDCNKLANCP-CXTHYWKRSA-N Tyr-Tyr-Ile Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 KRXFXDCNKLANCP-CXTHYWKRSA-N 0.000 description 2
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 2
- PYXQBKJPHNCTNW-CYDGBPFRSA-N Val-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N PYXQBKJPHNCTNW-CYDGBPFRSA-N 0.000 description 2
- JZWZACGUZVCQPS-RNJOBUHISA-N Val-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N JZWZACGUZVCQPS-RNJOBUHISA-N 0.000 description 2
- MHHAWNPHDLCPLF-ULQDDVLXSA-N Val-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=CC=C1 MHHAWNPHDLCPLF-ULQDDVLXSA-N 0.000 description 2
- JXWGBRRVTRAZQA-ULQDDVLXSA-N Val-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N JXWGBRRVTRAZQA-ULQDDVLXSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000002998 immunogenetic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010000761 leucylarginine Proteins 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 108010063431 methionyl-aspartyl-glycine Proteins 0.000 description 2
- 108700023046 methionyl-leucyl-phenylalanine Proteins 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- GJLXVWOMRRWCIB-MERZOTPQSA-N (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanamide Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=C(O)C=C1 GJLXVWOMRRWCIB-MERZOTPQSA-N 0.000 description 1
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N 2-{[3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- JYCQQPHGFMYQCF-UHFFFAOYSA-N 4-tert-Octylphenol monoethoxylate Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCO)C=C1 JYCQQPHGFMYQCF-UHFFFAOYSA-N 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- 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
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 1
- JTKLCCFLSLCCST-SZMVWBNQSA-N Arg-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(O)=O)=CNC2=C1 JTKLCCFLSLCCST-SZMVWBNQSA-N 0.000 description 1
- DCGLNNVKIZXQOJ-FXQIFTODSA-N Arg-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N DCGLNNVKIZXQOJ-FXQIFTODSA-N 0.000 description 1
- 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 1
- 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 1
- FFEUXEAKYRCACT-PEDHHIEDSA-N Arg-Ile-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(O)=O FFEUXEAKYRCACT-PEDHHIEDSA-N 0.000 description 1
- YBZMTKUDWXZLIX-UWVGGRQHSA-N Arg-Leu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YBZMTKUDWXZLIX-UWVGGRQHSA-N 0.000 description 1
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 1
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 1
- 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 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 1
- VILLWIDTHYPSLC-PEFMBERDSA-N Asp-Glu-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VILLWIDTHYPSLC-PEFMBERDSA-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
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 1
- NALWOULWGHTVDA-UWVGGRQHSA-N Asp-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NALWOULWGHTVDA-UWVGGRQHSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100021935 C-C motif chemokine 26 Human genes 0.000 description 1
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 102220479740 Cell division cycle protein 123 homolog_S11I_mutation Human genes 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000027582 GPCRs class B Human genes 0.000 description 1
- 108091008883 GPCRs class B Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102220502946 Geranylgeranyl transferase type-2 subunit alpha_D10N_mutation Human genes 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- 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
- QBEWLBKBGXVVPD-RYUDHWBXSA-N Gln-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)N)N QBEWLBKBGXVVPD-RYUDHWBXSA-N 0.000 description 1
- QENSHQJGWGRPQS-QEJZJMRPSA-N Gln-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)N)C(O)=O)=CNC2=C1 QENSHQJGWGRPQS-QEJZJMRPSA-N 0.000 description 1
- NSEKYCAADBNQFE-XIRDDKMYSA-N Gln-Trp-Arg Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(N)=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 NSEKYCAADBNQFE-XIRDDKMYSA-N 0.000 description 1
- CMFBOXUBWMZZMD-BPUTZDHNSA-N Gln-Trp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N CMFBOXUBWMZZMD-BPUTZDHNSA-N 0.000 description 1
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 1
- CVPXINNKRTZBMO-CIUDSAMLSA-N Glu-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)CN=C(N)N CVPXINNKRTZBMO-CIUDSAMLSA-N 0.000 description 1
- NLKVNZUFDPWPNL-YUMQZZPRSA-N Glu-Arg-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O NLKVNZUFDPWPNL-YUMQZZPRSA-N 0.000 description 1
- KKCUFHUTMKQQCF-SRVKXCTJSA-N Glu-Arg-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O KKCUFHUTMKQQCF-SRVKXCTJSA-N 0.000 description 1
- KEBACWCLVOXFNC-DCAQKATOSA-N Glu-Arg-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O KEBACWCLVOXFNC-DCAQKATOSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- AFODTOLGSZQDSL-PEFMBERDSA-N Glu-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N AFODTOLGSZQDSL-PEFMBERDSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 1
- 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 1
- 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 1
- GXMXPCXXKVWOSM-KQXIARHKSA-N Glu-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N GXMXPCXXKVWOSM-KQXIARHKSA-N 0.000 description 1
- RBXSZQRSEGYDFG-GUBZILKMSA-N Glu-Lys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O RBXSZQRSEGYDFG-GUBZILKMSA-N 0.000 description 1
- BHXSLRDWXIFKTP-SRVKXCTJSA-N Glu-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N BHXSLRDWXIFKTP-SRVKXCTJSA-N 0.000 description 1
- BIYNPVYAZOUVFQ-CIUDSAMLSA-N Glu-Pro-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O BIYNPVYAZOUVFQ-CIUDSAMLSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 1
- UMZHHILWZBFPGL-LOKLDPHHSA-N Glu-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O UMZHHILWZBFPGL-LOKLDPHHSA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- PHONXOACARQMPM-BQBZGAKWSA-N Gly-Ala-Met Chemical compound [H]NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O PHONXOACARQMPM-BQBZGAKWSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 1
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 1
- 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 1
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 1
- OQQKUTVULYLCDG-ONGXEEELSA-N Gly-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)CN)C(O)=O OQQKUTVULYLCDG-ONGXEEELSA-N 0.000 description 1
- ABPRMMYHROQBLY-NKWVEPMBSA-N Gly-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)CN)C(=O)O ABPRMMYHROQBLY-NKWVEPMBSA-N 0.000 description 1
- 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 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- TVQGUFGDVODUIF-LSJOCFKGSA-N His-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N TVQGUFGDVODUIF-LSJOCFKGSA-N 0.000 description 1
- MJICNEVRDVQXJH-WDSOQIARSA-N His-Arg-Trp Chemical compound N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O MJICNEVRDVQXJH-WDSOQIARSA-N 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- PGRPSOUCWRBWKZ-DLOVCJGASA-N His-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CN=CN1 PGRPSOUCWRBWKZ-DLOVCJGASA-N 0.000 description 1
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 description 1
- 101500028775 Homo sapiens Glucagon Proteins 0.000 description 1
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 1
- WIZPFZKOFZXDQG-HTFCKZLJSA-N Ile-Ile-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O WIZPFZKOFZXDQG-HTFCKZLJSA-N 0.000 description 1
- RIVKTKFVWXRNSJ-GRLWGSQLSA-N Ile-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RIVKTKFVWXRNSJ-GRLWGSQLSA-N 0.000 description 1
- WYUHAXJAMDTOAU-IAVJCBSLSA-N Ile-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N WYUHAXJAMDTOAU-IAVJCBSLSA-N 0.000 description 1
- HXIDVIFHRYRXLZ-NAKRPEOUSA-N Ile-Ser-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)O)N HXIDVIFHRYRXLZ-NAKRPEOUSA-N 0.000 description 1
- YJRSIJZUIUANHO-NAKRPEOUSA-N Ile-Val-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)O)N YJRSIJZUIUANHO-NAKRPEOUSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- PBCHMHROGNUXMK-DLOVCJGASA-N Leu-Ala-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 PBCHMHROGNUXMK-DLOVCJGASA-N 0.000 description 1
- QPRQGENIBFLVEB-BJDJZHNGSA-N Leu-Ala-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O QPRQGENIBFLVEB-BJDJZHNGSA-N 0.000 description 1
- DLFAACQHIRSQGG-CIUDSAMLSA-N Leu-Asp-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DLFAACQHIRSQGG-CIUDSAMLSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- VPKIQULSKFVCSM-SRVKXCTJSA-N Leu-Gln-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VPKIQULSKFVCSM-SRVKXCTJSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- USLNHQZCDQJBOV-ZPFDUUQYSA-N Leu-Ile-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O USLNHQZCDQJBOV-ZPFDUUQYSA-N 0.000 description 1
- 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 1
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 1
- PKKMDPNFGULLNQ-AVGNSLFASA-N Leu-Met-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O PKKMDPNFGULLNQ-AVGNSLFASA-N 0.000 description 1
- FYPWFNKQVVEELI-ULQDDVLXSA-N Leu-Phe-Val Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 FYPWFNKQVVEELI-ULQDDVLXSA-N 0.000 description 1
- UCBPDSYUVAAHCD-UWVGGRQHSA-N Leu-Pro-Gly Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UCBPDSYUVAAHCD-UWVGGRQHSA-N 0.000 description 1
- 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 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
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- DCRWPTBMWMGADO-AVGNSLFASA-N Lys-Glu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DCRWPTBMWMGADO-AVGNSLFASA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 1
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 1
- QKXZCUCBFPEXNK-KKUMJFAQSA-N Lys-Leu-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 QKXZCUCBFPEXNK-KKUMJFAQSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- TUSOIZOVPJCMFC-FXQIFTODSA-N Met-Asp-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O TUSOIZOVPJCMFC-FXQIFTODSA-N 0.000 description 1
- JPCHYAUKOUGOIB-HJGDQZAQSA-N Met-Glu-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPCHYAUKOUGOIB-HJGDQZAQSA-N 0.000 description 1
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 1
- 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 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- ULECEJGNDHWSKD-QEJZJMRPSA-N Phe-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 ULECEJGNDHWSKD-QEJZJMRPSA-N 0.000 description 1
- WMGVYPPIMZPWPN-SRVKXCTJSA-N Phe-Asp-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N WMGVYPPIMZPWPN-SRVKXCTJSA-N 0.000 description 1
- FENSZYFJQOFSQR-FIRPJDEBSA-N Phe-Phe-Ile Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FENSZYFJQOFSQR-FIRPJDEBSA-N 0.000 description 1
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 1
- FXEKNHAJIMHRFJ-ULQDDVLXSA-N Phe-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N FXEKNHAJIMHRFJ-ULQDDVLXSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- WSRWHZRUOCACLJ-UWVGGRQHSA-N Pro-Gly-His Chemical compound C([C@@H](C(=O)O)NC(=O)CNC(=O)[C@H]1NCCC1)C1=CN=CN1 WSRWHZRUOCACLJ-UWVGGRQHSA-N 0.000 description 1
- 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 1
- RWCOTTLHDJWHRS-YUMQZZPRSA-N Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 RWCOTTLHDJWHRS-YUMQZZPRSA-N 0.000 description 1
- KDBHVPXBQADZKY-GUBZILKMSA-N Pro-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KDBHVPXBQADZKY-GUBZILKMSA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- POQFNPILEQEODH-FXQIFTODSA-N Pro-Ser-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O POQFNPILEQEODH-FXQIFTODSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 1
- 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 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- FZXOPYUEQGDGMS-ACZMJKKPSA-N Ser-Ser-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O FZXOPYUEQGDGMS-ACZMJKKPSA-N 0.000 description 1
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 1
- SZRNDHWMVSFPSP-XKBZYTNZSA-N Ser-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N)O SZRNDHWMVSFPSP-XKBZYTNZSA-N 0.000 description 1
- FLMYSKVSDVHLEW-SVSWQMSJSA-N Ser-Thr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLMYSKVSDVHLEW-SVSWQMSJSA-N 0.000 description 1
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- 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 1
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- PXYJUECTGMGIDT-WDSOQIARSA-N Trp-Arg-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 PXYJUECTGMGIDT-WDSOQIARSA-N 0.000 description 1
- GZTKZDGIEBKZAH-XIRDDKMYSA-N Trp-Cys-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC3=CN=CN3)C(=O)O)N GZTKZDGIEBKZAH-XIRDDKMYSA-N 0.000 description 1
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 1
- 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 1
- YHRCLOURJWJABF-WDSOQIARSA-N Trp-His-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N YHRCLOURJWJABF-WDSOQIARSA-N 0.000 description 1
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-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
- SJWLQICJOBMOGG-PMVMPFDFSA-N Trp-Tyr-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC4=CN=CN4)C(=O)O)N SJWLQICJOBMOGG-PMVMPFDFSA-N 0.000 description 1
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 1
- VTFWAGGJDRSQFG-MELADBBJSA-N Tyr-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O VTFWAGGJDRSQFG-MELADBBJSA-N 0.000 description 1
- YWXMGBUGMLJMIP-IHPCNDPISA-N Tyr-Cys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC3=CC=C(C=C3)O)N YWXMGBUGMLJMIP-IHPCNDPISA-N 0.000 description 1
- OHOVFPKXPZODHS-SJWGOKEGSA-N Tyr-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OHOVFPKXPZODHS-SJWGOKEGSA-N 0.000 description 1
- AVIQBBOOTZENLH-KKUMJFAQSA-N Tyr-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N AVIQBBOOTZENLH-KKUMJFAQSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 1
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 1
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- UEOOXDLMQZBPFR-ZKWXMUAHSA-N Val-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N UEOOXDLMQZBPFR-ZKWXMUAHSA-N 0.000 description 1
- 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 1
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 1
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- PGQUDQYHWICSAB-NAKRPEOUSA-N Val-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N PGQUDQYHWICSAB-NAKRPEOUSA-N 0.000 description 1
- UJMCYJKPDFQLHX-XGEHTFHBSA-N Val-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N)O UJMCYJKPDFQLHX-XGEHTFHBSA-N 0.000 description 1
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 1
- 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 1
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 1
- RTJPAGFXOWEBAI-SRVKXCTJSA-N Val-Val-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RTJPAGFXOWEBAI-SRVKXCTJSA-N 0.000 description 1
- 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 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 238000012440 amplified luminescent proximity homogeneous assay Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 210000001728 clone cell Anatomy 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 208000007345 glycogen storage disease Diseases 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010033719 glycyl-histidyl-glycine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 108010016686 methionyl-alanyl-serine Proteins 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002571 pancreatic alpha cell Anatomy 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 108010093296 prolyl-prolyl-alanine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220083031 rs746990000 Human genes 0.000 description 1
- 102220322685 rs777811020 Human genes 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 210000005253 yeast cell 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
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Abstract
본 발명은 글루카곤 호르몬이 이의 수용체에 결합하는 것을 억제하는 글루카곤 수용체 폴리펩티드 길항제에 관한 것이다. 더욱 특히, 본 발명은 글루카곤이 이의 수용체에 결합하는 것을 억제하는 고친화력 글루카곤 수용체 항체 또는 이의 Fab 단편, 및 포유류 종에서의 제2형 당뇨병 (NIDDM) 및 관련 장애의 치료 또는 예방에서의 이의 용도에 관한 것이다.
Description
본 발명은 글루카곤 호르몬이 이의 수용체에 결합하는 것을 억제하는 글루카곤 수용체 폴리펩티드 길항제에 관한 것이다. 더욱 특히, 본 발명은 글루카곤이 이의 수용체에 결합하는 것을 억제하는 고친화력 글루카곤 수용체 항체 또는 이의 Fab 단편, 및 포유류 종에서의 제2형 당뇨병 (NIDDM) 및 관련 장애의 치료 또는 예방에서의 이의 용도에 관한 것이다.
글루카곤은 낮은 혈당 수준에 응답하여 췌장 α-세포에 의해 생산되는 아미노산 29개의 펩티드 호르몬이다. 글루카곤은 간세포 표면 상의 막-회합형 글루카곤 수용체에 결합하고, 이는 G-단백질 신호 전달 케스케이드를 촉발하여, 세포내 고리형 AMP를 활성화시키고 신생(denovo) 합성 (글루코스신합성) 및 글리코겐 파괴 (글리코겐분해)를 통한 글루코스의 방출에 이른다.
울슨(Unson) 등은 래트 수용체의 2개의 세포외 부분에 상응하는 합성 펩티드들에 대해 생성된 폴리클로날 항체를 개시하였다. 개시된 분석법에서, 아미노산 잔기 126-137 및 206-219에 대해 생성된 폴리클로날 항체가 래트 간 막 내의 수용체에 대한 글루카곤의 결합을 차단하는 것으로 발견되었다 ([Unson et al., PNAS Vol. 93, pp. 310-315, Jan 1996]).
버기(Buggy) 등은 시험관내 분석법에서 수용체의 호르몬 결합 부위에 대해 글루카곤과 경쟁하는 것으로 언급된 모노클로날 항체의 제제를 개시하였다 ([Buggy et al., Horm. Metab. Res. 28 (1996) 215-219]). 개시된 분석법에서, CIV395.7A라는 명칭이 주어진 항체는 인간 및 래트 글루카곤 수용체를 인식하였지만, 마우스에 대해서는 그렇지 않았다. 인간의 치료적 처치를 위한 항체를 개발하기 위해, 검증된 래트 및/또는 뮤린(murine) 동물 모델에서 전-임상 효능 및 안정성 연구를 수행하는 것이 통상적으로 필요하다. 그러므로, 래트, 뮤린 및 인간 형태의 글루카곤 수용체에 결합할 수 있는 전-임상 치료 항체 후보물을 제공하는 것은 치료 항체의 약물 개발을 매우 용이하게 할 것이고, 따라서 고도로 바람직할 것이다.
라이트(Wright) 등은 hGR-2 F6으로 지정된 모노클로날 항체 및 이의 Fab 단편의 아미노산 서열을 개시하였다. 이러한 항체는 인간 글루카곤 수용체에 대해 마우스에서 생성되었고, 개시된 분석법에서 이러한 수용체에서의 경쟁적 길항제로서 기술되었다 ([Wright et al., Acta Cryst. (2000) D56, 573-580). 본 출원인은 hGR-2 F6이 래트 및 뮤린 형태의 글루카곤 수용체에 낮은 친화력으로만 결합한다는 것을 발견하였고, 높은 용량에서 당뇨병 래트 생체내 모델에서 hGR-2F6에 대해 치료 효능이 발견되지 않았다. 특히, 이러한 항체는 래트 모델에서 어떠한 통계적 유의성으로도 혈청 글루코스를 감소시킬 수 없었다 (미공개).
본 출원인은 당뇨병, 바람직하게는 제2형 당뇨병 및 관련 장애의 효과적인 치료를 제공하기 위해, 글루카곤 수용체에 높은 친화력으로 결합하고, 이에 의해 이러한 수용체에 글루카곤이 결합하는 것을 억제할 치료적 모노클로날 항체를 제공할 필요가 있음을 확인하였다. 더욱이, 항체의 전-임상 약물 개발을 허용하기 위해, 필수적인 전-임상 안전 및 효능 연구를 착수하도록 인간, 래트 및 뮤린 형태의 글루카곤 수용체에 결합할 수 있는 모노클로날 항체를 제공하는 것이 명백히 바람직하다.
본 발명은 인간, 래트 및 뮤린 기원의 천연 글루카곤 수용체에 높은 친화력으로 특이적으로 결합할 수 있는 신규 모노클로날 항체 또는 이의 Fab 단편에 관한 것이다. 또한, 본 발명가들은 다중 기원의 글루카곤 수용체에 결합하는 모노클로날 항체 또는 이의 Fab 단편을 제공할 뿐만 아니라, 혈청 글루코스를 감소시키는 능력에서 생체내 효능을 나타내는, 글루카곤 수용체에 결합하는 모노클로날 항체를 최초로 제공한다.
첫번째 양상에서, 본 발명은 인간, 래트 및 뮤린 글루카곤 수용체에 결합할 수 있고 각각의 수용체에 대한 글루카곤 결합을 50 nM 미만의 Ki로 억제하는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체에 관한 것이다.
추가적인 뜻밖의 발견에서, 본 발명가들은 GLP-1의 생체내 혈청 농도를 유의하게 증가시킬 수 있는, 글루카곤 수용체에 특이적으로 결합할 수 있는 항체 또는 이의 Fab 단편을 최초로 제공한다. GLP-1의 혈청 수준을 증가시키는 것은 β-세포 기능을 강화하고, 글루카곤 분비를 감소시키며, 위 배출을 지연시키는 것으로 당업계에 공지되어 있고, 제2형 당뇨병 및 관련 용태의 치료에서 고도로 유리한 것으로 인식된다.
두번째 양상에서, 본 발명은 유효량의 본 발명에 따른 Fab 단편 또는 인간화 모노클로날 항체 및 제약상 허용가능한 부형제를 포함하는 제약 조성물에 관한 것이다.
세번째 양상에서, 본 발명은 유효량의 본 발명에 따른 Fab 단편 또는 인간화 모노클로날 항체를 제1형 또는 제2형 당뇨병의 치료 및 체중 감소 달성을 필요로 하는 환자에게 투여하는 단계를 포함하는, 인간에서 제1형 또는 제2형 당뇨병을 치료하고 체중 감소를 달성하는 방법을 제공한다.
본 발명의 네번째 양상은 의약으로서 사용하기 위한 본 발명에 따른 Fab 단편 또는 인간화 모노클로날 항체를 포함한다.
본 발명의 다섯번째 양상은 인간에서의 제1형 또는 제2형 당뇨병의 치료 또는 예방 또는 체중 감소 달성을 위한 의약의 제조에서의, 본 발명에 따른 Fab 단편 또는 인간화 모노클로날 항체의 용도에 관한 것이다.
본 발명은 인간, 래트 및 뮤린 글루카곤 수용체에 결합할 수 있고 각각의 수용체에 대한 글루카곤 결합을 50 nM 미만의 Ki로 억제하는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체에 관한 것이다.
본 발명은 인간, 래트 및 뮤린 기원의 글루카곤 수용체에 더하여, 사이노몰거스 원숭이의 글루카곤 수용체에 높은 친화력으로 또한 결합할 수 있는 모노클로날 항체를 또한 제공한다. 바람직하게는, 따라서 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 50 nM 미만의 Ki로 사이노몰거스 원숭이 글루카곤 수용체에 대한 글루카곤 결합을 또한 억제한다. 바람직하게는, Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 지명된 글루카곤 수용체 각각에서의 Ki가 30 nM 미만, 더욱 바람직하게는 20 nM 미만, 더 바람직하게는 10 nM 미만이다. 추가로 바람직하게는, Fab 단편은 래트, 뮤린 및 사이노몰거스 수용체에서의 시험관내 Ki가 20 nM 미만이고, 인간 수용체에서의 시험관내 Ki가 5 nM 미만이다. 더욱 바람직하게는, Fab 단편의 Ki, 특히 인간 글루카곤 수용체에서의 Ki는 0.1 nM 내지 15 nM, 가장 바람직하게는 1 내지 10 nM이다.
본 발명에 따른 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 바람직하게는 인간 및 래트 글루카곤 수용체에서의 기능적 결합 친화력 (Kb)이 적어도 100 nM이다. 더 바람직하게는, Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 이러한 수용체들에서의 기능적 결합 친화력이 적어도 50 nM, 더욱 바람직하게는 적어도 10 nM이다. 가장 바람직한 실시양태에서, Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 인간 및 래트 글루카곤 수용체에서의 기능적 결합 친화력이 1 내지 10 nM이다.
특히 뜻밖인 발견에서, 본 출원인은 본 발명에 따라 확인된 결합 성질을 지니는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체에 대한 생체내 노출 시 매우 빠른 속도로 혈청 GLP-1가 증가되고 혈청 혈당이 감소된다는 것을 주목하였다. 이러한 유리한 효과를 최대화하기 위해, Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체가 GLP 수용체에 감지할 수 있는 정도로 결합하지 않는 것, 즉 5000 nM을 초과하는 Ki가 바람직하다.
서열의 설명:
서열 1 내지 22는 표 1의 경쇄 및 중쇄 CDR을 지칭한다.
서열 23 내지 30은 본원에 기술된 바람직한 인간 프레임워크 영역을 지칭한다.
서열 31 및 32는 인간 GluR의 아미노산 및 cDNA 서열이다.
서열 33 및 34는 래트 GluR의 아미노산 및 cDNA 서열이다.
서열 35 및 36은 뮤린 GluR의 아미노산 및 cDNA 서열이다.
서열 37 및 38은 사이노몰거스 GluR의 아미노산 및 cDNA 서열이다.
서열 39 및 40은 예 1 (Ab1)의 가변 영역 아미노산 서열이다.
서열 41 및 42는 예 2 (Ab2)의 가변 영역 아미노산 서열이다.
서열 43 및 44는 예 3 (Ab3)의 가변 영역 아미노산 서열이다.
서열 45 및 46은 예 4 (Ab4)의 가변 영역 아미노산 서열이다.
서열 45 및 47은 예 5 (Ab5)의 가변 영역 아미노산 서열이다.
서열 45 및 48은 예 6 (Ab6)의 가변 영역 아미노산 서열이다.
서열 45 및 49는 예 7 (Ab7)의 가변 영역 아미노산 서열이다.
서열 50은 바람직한 카파 경쇄 IgG4 불변 영역을 지칭한다.
서열 51은 바람직한 중쇄 CH1 불변 도메인을 지칭한다.
서열 52는 바람직한 변형된 인간 IgG4 Fc 영역을 지칭한다.
서열 53 내지 55는 바람직한 경쇄 CDR을 지칭한다.
서열 56 내지 68은 바람직한 중쇄 CDR을 지칭한다.
서열 59 및 60은 예 1 (Ab1)의 경쇄 및 중쇄 단백질 서열이다.
서열 61 및 62는 예 2 (Ab2)의 경쇄 및 중쇄 단백질 서열이다.
서열 63 및 64는 예 3 (Ab3)의 경쇄 및 중쇄 단백질 서열이다.
서열 65 및 66은 예 4 (Ab4)의 경쇄 및 중쇄 단백질 서열이다.
서열 65 및 67은 예 5 (Ab5)의 경쇄 및 중쇄 단백질 서열이다.
서열 65 및 68은 예 6 (Ab6)의 경쇄 및 중쇄 단백질 서열이다.
서열 65 및 69는 예 7 (Ab7)의 경쇄 및 중쇄 단백질 서열이다.
서열 70 및 71은 예 1 (Ab1)의 경쇄 및 중쇄 DNA 서열이다.
서열 72 및 73은 예 2 (Ab2)의 경쇄 및 중쇄 DNA 서열이다.
서열 74 및 75는 예 3 (Ab3)의 경쇄 및 중쇄 DNA 서열이다.
서열 76 및 77은 예 4 (Ab4)의 경쇄 및 중쇄 DNA 서열이다.
서열 76 및 78은 예 5 (Ab5)의 경쇄 및 중쇄 DNA 서열이다.
서열 76 및 79는 예 6 (Ab6)의 경쇄 및 중쇄 DNA 서열이다.
서열 76 및 80은 예 7 (Ab7)의 경쇄 및 중쇄 DNA 서열이다.
정의:
"글루카곤 수용체" (본원에서 "GluR"로 또한 지칭됨)는 아미노 말단의 긴 세포외 도메인, 7개의 막횡단 절편 및 세포내 C-말단 도메인으로 구성된 G 단백질-커플링(coupled) 수용체 클래스 2 패밀리에 속한다. 글루카곤 수용체는 간세포의 표면에서 현저하게 발현되어, 이러한 표면에서 글루카곤에 결합하고 이에 의해 제공되는 신호를 세포 내로 변환시킨다. 래트 및 인간 기원의 글루카곤 수용체를 코딩하는 DNA 서열이 단리되었고, 당업계에 개시되어 있다 (EP0658200B1). 뮤린 및 사이노몰거스 원숭이 동족체 또한 단리되었고, 서열이 결정되었다 ([Burcelin, et al., Gene 164 (1995) 305-310]; [McNally et al., Peptides 25 (2004) 1171-1178]).
본 발명의 항체 또는 이의 Fab 단편의 활성과 관련하여 본원에서 사용된 용어 "억제하다"는 글루카곤 수용체의 생물학적 활성을 실질적으로 길항하는 능력을 의미한다. 이러한 능력은 본원에 기술된 [125I] 글루카곤 결합 분석법으로부터 계산된 Ki 값에서 반영된다.
본 발명의 모노클로날 항체와 관련하여 사용된 용어 "인간화"는 적어도 인간 프레임워크 및 불변 영역 (CL, CH 도메인 (예를 들어, CH1, CH2, CH3), 및 힌지), 및 글루카곤 수용체 결합 항체로부터 유래된 CDR이 있는 항체를 지칭한다. 인간 프레임워크는 인간 생식계열 서열, 뿐만 아니라 체세포 돌연변이가 있는 서열에 상응하는 프레임워크를 포함한다. 인간 프레임워크 및 불변 영역은 완전히 인간형일 수 있거나, 또는 하나 이상의 아미노산 치환, 말단 및 중간 부가 및 결실 등에 의해 천연 서열과 다를 수 있다. CDR은 임의의 항체 프레임워크의 환경 내의 본 출원에서의 글루카곤 특이적 수용체에 결합하는 하나 이상의 CDR로부터 유래될 수 있다. 예를 들어, 본 발명의 인간화 항체의 CDR은 마우스 항체 프레임워크의 환경 내의 글루카곤 수용체에 결합하는 CDR로부터 유래될 수 있고, 그후 인간 프레임워크의 환경 내에서 글루카곤 수용체에 결합하도록 조작된다.
용어 "모노클로날 항체"는 임의의 진핵생물, 원핵생물 또는 파지 클론이 예를 들어 포함되는 단일 카피 또는 클론으로부터 유래된 항체를 지칭하고, 항체가 생산되는 방법을 지칭하지 않는다. 바람직하게는, 본 발명의 모노클로날 항체는 균질하거나 실질적으로 균질한 집단으로 존재한다.
본 발명의 항체에 관하여 본원에서 사용된 용어 "생체내 효능"은 인간 또는 동물 모델에서 양성의 생물학적 효과를 부여하는 항체의 능력을 의미한다. 바람직하게는, 생체내 효능은 상승된 혈당을 나타내는 동물에 대한, 대조군 응답과 비교하여 본 발명의 항체에 대한 응답에서의 글루코스 정상화 효과를 지칭한다. 당뇨병성 주커(Zucker) 당뇨병 비만(fatty) 래트 (ZDF) 모델 ([Horm Metab Res. 2005 Feb;37(2):79-83])이 생체내 효능을 평가하는데 적합하게 사용될 수 있고, 이때 바람직하게는 생체내 효능은 ≤ 30 ㎎/㎏ 투여량의 본 발명에 따른 인간화 항체에 동물을 노출시켰을 때의 100％ 혈당 정상화를 의미한다. 더욱 바람직하게는, 생체내 효능은 ≤ 15 ㎎/㎏ 투여량의 항체, 더 바람직하게는 ≤ 10 ㎎/㎏ 투여량, 더욱 바람직하게는 0.1 내지 5 ㎎/㎏에 동물을 노출시켰을 때의 100％ 혈당 정상화를 의미한다. 가장 바람직한 실시양태에서, 생체내 효능은 1 내지 3 ㎎/㎏ 투여량의 본 발명에 따른 인간화 항체에 동물을 노출시켰을 때의 당뇨병성 ZDF 래트 모델에서의 100％ 혈당 정상화를 의미하도록 사용된다.
용어 "글루코스 정상화"는 120 ㎎/㎗ 미만, 바람직하게는 110 내지 120 ㎎/㎗ 범위의 ZDF 래트 모델에서의 평균 혈장 글루코스 값을 의미하는 것을 가리킨다. 혈장 글루코스는 [Etgen et al., Metabolism 2000;49(5):684-688]에 따라 결정될 수 있거나, 또는 [D'Orazio et al., Clin. Chem. Lab. Med. 2006;44(12):1486-1490]에 따라 전체 혈당 농도의 변환으로부터 계산될 수 있다.
본원에서 사용된 "Fab 단편"은 CL 및 CH1 도메인에 더하여 경쇄 및 중쇄 CDR 및 프레임워크 서열의 아미노산 잔기를 함유하는, 가변 영역 내의 항체 분자의 일부분을 지칭한다.
중쇄의 3개의 CDR은 본원에서 "CDRH1, CDRH2, 및 CDRH3"으로 지칭되고, 경쇄의 3개의 CDR은 "CDRL1, CDRL2 및 CDRL3"으로 지칭된다. 각각의 도메인에 대한 아미노산의 할당은 주지된 관례에 따른다 ([Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971)]; [Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)]). 항원-결합 도메인, 또는 항원-결합 도메인의 CDR은 토끼, 마우스, 래트 또는 햄스터를 포함하지만 이에 한정되지 않는 또다른 비-인간 종으로부터 유래될 수 있다.
본 발명가들은 뮤린, 래트, 사이노몰거스 원숭이 및 인간 기원의 글루카곤 수용체에 대해 특히 높은 친화력을 나타내는 항체 Fab 단편이 제조되도록 조합되어 사용될 수 있는 중쇄 및 경쇄 CDR 서열들을 확인하였다. Fab 단편은 바람직하게는 하기의 것들을 포함한다;
[식중
X = Y 또는 A X6 = W 또는 H
X1 = M 또는 I X7 = N, D 또는 E
X2 = N 또는 Y X8 = Y, Q, S 또는 V
X3 = Q 또는 L X9 = N, S 또는 I
X4 = Q 또는 W X10 = G 또는 A
X5 = L 또는 I X11 = M 또는 L].
더욱 바람직하게는, X는 Y 또는 A이고; X1은 I이고; X2는 Y이고; X3은 Q 또는 L이고; X4는 Q 또는 W이고; X5는 L 또는 I이고; X6은 W 또는 H이고; X7은 D 또는 E이고; X8은 Y, Q, S 또는 V이고; X9는 S이고; X10은 G 또는 A이고; X11은 L이다. 더 바람직하게는, X는 A이고; X1은 I이고; X2는 Y이고; X3은 Q이고; X4는 Q이고; X5는 L이고; X6은 H이고; X7은 D 또는 E이고; X8은 Y, Q 또는 S이고; X9는 S이고; X10은 G 또는 A이고; X11은 L이다.
바람직하게는, 본 발명의 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는
의 CDR 서열을 포함하고, 이때 상기 Fab 단편은
CDRL1: A2Y, I9M;
CDRL2: Y4N;
CDRL3: Q1L, Q2W, L6I;
CDRH1: H9W, D10E, D10N;
CDRH2: Y9Q, Y9S, Y9V, S11N, S11I;
CDRH3: G3A, L12M
으로 구성된 군으로부터 선택된 1개, 2개 또는 3개의 아미노산 치환을 갖는다.
더욱 바람직하게는, 상기 Fab 단편은 CDRH1: D10E; CDRH2: Y9Q, Y9S; CDRH3: G3A로부터 선택된 1개, 2개 또는 3개의 아미노산 치환을 포함한다.
바람직하게는, 본 발명에 따른 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 하기로부터 선택된 CDR 서열을 포함한다:
(i) 서열 2의 CDRL1; 서열 4의 CDRL2; 서열 7의 CDRL3이 있는 경쇄; 및 서열 11의 CDRH1; 서열 15의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(ii) 서열 1의 CDRL1; 서열 4의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 10의 CDRH1; 서열 16의 CDRH2; 서열 20의 CDRH3이 있는 중쇄;
(iii) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 8의 CDRL3이 있는 경쇄; 및 서열 11의 CDRH1; 서열 15의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(iv) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 15의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(v) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 17의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(vi) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 15의 CDRH2; 서열 22의 CDRH3이 있는 중쇄; 및
(vii) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 13의 CDRH1; 서열 18의 CDRH2; 서열 22의 CDRH3이 있는 중쇄.
본 발명에 따른 항체가 낮은 혈장 농도에서 생체내 효능을 나타내는 것이 특히 바람직하다. ZDF 래트 모델에서 30 ㎎/㎏의 투여량, 바람직하게는 15 ㎎/㎏ 미만의 투여량, 더욱 바람직하게는 5 ㎎/㎏ 미만, 더 바람직하게는 0.1 내지 5 ㎎/㎏ 범위에서 생체내 효능이 관찰되어야 한다. 가장 바람직하게는, 본 발명에 따른 항체는 약 1 내지 3 ㎎/㎏의 투여량에서 ZDF 래트 모델에서 100％ 글루코스 정상화를 달성한다. 특히 바람직한 본 발명에 따른 항체들은 3 ㎎/㎏의 낮은 투여량에서 생체내 ZDF 래트 모델에서 100％ 글루코스 정상화를 나타낼 수 있다는 것이 발견되었다. 따라서, 바람직하게는 본 발명은
(i) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 15의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(ii) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 17의 CDRH2; 서열 21의 CDRH3이 있는 중쇄;
(iii) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 15의 CDRH2; 서열 22의 CDRH3이 있는 중쇄; 또는
(iv) 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 13의 CDRH1; 서열 18의 CDRH2; 서열 22의 CDRH3이 있는 중쇄
를 포함하는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체를 포함한다.
추가적인 바람직한 실시양태에서, 본 발명은 서열 3의 CDRL1; 서열 5의 CDRL2; 서열 6의 CDRL3이 있는 경쇄; 및 서열 12의 CDRH1; 서열 17의 CDRH2; 서열 21의 CDRH3이 있는 중쇄를 포함하는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체에 관한 것이다. 기술된 부류 내의 또다른 유사한 항체들과 비교하여 이러한 실시양태에 따른 Fab 단편을 포함하는 항체가 장기간에 걸쳐 생체내 효능을 유지하는 특히 유리한 성질이 있다는 것이 발견되었다.
본 발명의 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 바람직하게는 인간 기원의 경쇄 및 중쇄 가변 사슬 프레임워크 영역을 포함한다. 또한, 다양한 상이한 인간 프레임워크 서열들이 본 발명의 인간화 면역글로불린에 대한 기초로서 단독으로 또는 조합되어 사용될 수 있다. 바람직하게는, 본 발명의 Fab 단편 또는 인간화 모노클로날 항체의 프레임워크 영역은 인간 기원의 영역이거나 또는 실질적으로 인간 기원의 영역이다 (적어도 95％, 97％ 또는 99％의 인간 기원). 인간 기원의 프레임워크 영역의 서열을 ImMunoGenetics (IMGT)로부터 이의 웹사이트 http://imgt.cines.fr/textes/IMGTindex/FR.html을 통해 또는 [The immunoglobulin Factsbook, Marie-Paule Lefranc, Gerard Lefranc, Academic Press 2001, ISBN 012441351]로부터 수득할 수 있다. 예를 들어, 생식계열 경쇄 프레임워크가 A11, A17, A18, A19, A20, A27, A30, LI, L1I, L12, L2, L5, L15 L6, L8, O12, O2, 및 O8로 구성된 군으로부터 선택될 수 있고, 생식계열 중쇄 프레임워크 영역이 VH2-5, VH2-26, VH2-70, VH3-20, VH3-72, VHI-46, VH3-9, VH3-66, VH3-74, VH4-31, VH I-18, VH I-69, VI-13-7, VH3-11, VH3-15, VH3-21, VH3-23, VH3-30, VH3-48, VH4-39, VH4-59, 및 VH5-5I로 구성된 군으로부터 선택될 수 있다.
본원에 개시된 특정 항체는 추가적인 본 발명의 항체를 제조하기 위한 주형 또는 어버이 항체로서 사용될 수 있다. 한 접근법에서, 어버이 항체 CDR이 어버이 항체 프레임워크와의 서열 동일성이 높은 인간 프레임워크 내로 그래프팅(grafting)된다. 새로운 프레임워크의 서열 동일성은 일반적으로 어버이 항체 내의 상응하는 프레임워크와 80％ 이상, 85％ 이상, 또는 90％ 이상일 것이다. 이러한 그래프팅은 어버이 항체와 비교하여 결합 친화력에서의 감소를 초래할 수 있다. 그러한 경우, [Queen et al., Proc. Natl. Acad. Sci. USA 88, 2869 (1991)]에 공개된 구체적인 기준을 기초로 특정 위치에서 프레임워크가 어버이 프레임워크로 역-돌연변이될 수 있다. 사용될 수 있는 추가적인 방법에는, 예를 들어, [Jones et al., Nature, 321:522 (1986)]; [Riechmann et al., Nature, 332:323-327 (1988)]; [Verhoeyen et al., Science, 239:1534 (1988)]이 포함된다.
가장 바람직하게는, 본 발명에 따른 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체는 FR1 서열 23; FR2 서열 24; FR3 서열 25; FR4 서열 26의 경쇄 프레임워크 (FR) 서열; 및 FR5 서열 27; FR6 서열 28; FR7 서열 29; FR8 서열 30의 중쇄 가변 사슬 프레임워크 서열을 포함하고, 이때 이들은 경쇄 가변 서열 FR1 - CDRL1 - FR2 - CDRL2 - FR3 - CDRL3 - FR4 및 중쇄 가변 서열 FR5 - CDRH1 - FR6 - CDRH2 - FR7 - CDRH3 - FR8로서 배열된다.
본 출원인은 시험관내 경쟁적 글루카곤 결합 분석법의 사용을 통해 글루카곤 수용체 길항작용 항체의 생체내 효능을 예측할 때, Fab 단편의 친화력이 생체내 효능과 양성으로 상관된다는 것을 뜻밖에 결정하였다. 역으로, 글루카곤 수용체에 대한 전장 항체의 결합 친화력 (Ki)은 반드시 생체내 효능의 유효한 예보물인 것은 아니다. 따라서 바람직하게는, 본원에서 추구되는 유리한 성질이 있는 모노클로날 항체의 제조 방법은 이종성으로 발현된 글루카곤 수용체 유전자를 사용하는 시험관내 경쟁적 글루카곤 결합 분석법에서 50 nM 미만의 Ki로 각각의 글루카곤 수용체에 결합하는 Fab 단편을 선택하는 단계를 포함한다. 더욱 바람직하게는, 상기 방법은 각각의 글루카곤 수용체에서의 시험관내 Ki가 30 nM 미만, 더욱 바람직하게는 20 nM 미만, 더 바람직하게는 10 nM 미만인 Fab 단편을 선택하는 단계를 포함한다. 더욱 바람직하게는, 래트, 뮤린 및 사이노몰거스 수용체에서의 20 nM 미만의 시험관내 Ki 및 인간 수용체에서의 5 nM 미만의 시험관내 Ki에 의해 Fab 단편이 선택된다. 더욱 바람직하게는, 선택된 Fab 단편의 Ki, 특히 인간 글루카곤 수용체에서의 Ki는 0.1 nM 내지 15 nM, 가장 바람직하게는 1 내지 10 nM이다. 그후, 이러한 방법에 의해 확인된 Fab 단편이 당업계에 통상적으로 공지된 기술에 의해 치료적 사용을 위한 전장 항체로서 적절하게 발현될 수 있다.
본 발명의 교시내용을 적용할 때, 당업자가 통상적인 기술, 예를 들어 부위 지정 돌연변이유발을 사용하여 본원에 개시된 특정 CDR 및 프레임워크 서열 내의 아미노산을 치환시킬 수 있고, 이렇게 함으로써 본원에서 제공된 서열로부터 유래된 가변 영역 아미노산 서열을 추가로 생성시킬 수 있는 것으로 이해될 것이다. 모두 20개까지의 별법적인 천연 발생 아미노산이 특정 치환 부위에서 도입될 수 있다. 그후, 상기에서 본원에 정의된 시험관내 선택 방법을 적절하게 사용하여, 청구된 교차 반응성 및 시험관내 Ki (생체내 효능을 가리키는 것으로 본 출원인에 의해 발견됨)를 지니는 Fab 단편에 대해 이러한 추가적인 가변 영역 아미노산 서열들을 스크리닝할 수 있다. 이러한 방식으로, 본 발명에 따른 인간화 항체의 제조에 적절한 추가적인 Fab 단편들이 확인된다. 바람직하게는, 프레임워크 내에서의 아미노산 치환은 본원에 개시된 프레임워크 서열 중 하나 또는 각각 내의 1개, 2개 또는 3개의 위치에 제한된다. 바람직하게는, CDR 내에서의 아미노산 치환은 CDR 중 하나 또는 각각 내의 1개 내지 3개의 위치에 제한되고, 더욱 바람직하게는, CDR 중 하나 또는 각각 내의 1개 또는 2개의 아미노산 위치에서의 치환이 수행된다. 더 바람직하게는, 아미노산 치환이 중쇄 가변 영역의 CDR들 내의 1개 또는 2개의 아미노산 위치에서 수행된다. 가장 바람직하게는, 아미노산 치환이 CDRH2 내의 1개 또는 2개의 아미노산 위치에서 수행된다.
본원에 기술된 항체를 어버이 항체로 사용하여, CDR 및 프레임워크 치환을 조합하여 별법적인 본 발명에 따른 항체를 제조하기 위한 적절한 방법이 [Wu et al., J. Mol. Biol., 294: 151-162]에 기술되어 있다.
본원에서 사용된, 면역글로불린의 Fc 부분은 비-공유결합성 상호작용 및 디술피드 결합을 통해 회합된 양쪽 중쇄로부터의 항체의 불변 영역을 지칭한다. Fc 부분은 힌지 영역을 포함할 수 있고, CH2 및 CH3 도메인을 지나 항체의 C-말단까지 연장될 수 있다. Fc 부분은 하나 이상의 글리코실화 부위를 추가로 포함할 수 있다. 본 발명의 모노클로날 항체에는 면역글로불린 클래스 IgA, IgD, IgG, IgM 및 IgE 중 임의의 것으로부터 선택된 중쇄 불변 영역이 있을 수 있다. 바람직하게는, 다른 IgG 아유형에 비해 FcγR 및 보체 인자에 결합하는 능력 감소로 인해, 본 발명의 항체는 인간 IgG4 Fc 영역으로부터 유래된 Fc 부분을 함유한다. 더욱 바람직하게는, 본 발명의 항체의 IgG4 Fc 영역은 이펙터 기능을 추가로 감소시키는 치환을 함유한다 ([Issacs et al., (1996) Clin. Exp. Immunol. 106:427-433]). 이는 잔기 233의 글루타메이트에 대한 프롤린, 잔기 234의 페닐알라닌에 대한 알라닌 또는 발린 및 알라닌 또는 잔기 235의 류신에 대한 알라닌 또는 글루타메이트를 포함하는 군 중 하나 이상으로부터 선택될 수 있다 (EU 번호매김, [Kabat, E.A. et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. U.S. Dept. of Health and Human Services, Bethesda, MD, NIH Publication no. 91-3242]). 이러한 잔기들은 서열 52에서의 위치 15, 16 및 17 및 서열 67의 위치 235, 236 및 237에 상응한다. 추가로, 서열 52의 위치 79에 상응하는 잔기 297 (EU 번호매김)의 Asn을 Ala로 치환함으로써 IgG4 Fc 영역 내의 N-연결 글리코실화 부위를 제거하는 것은 인간화 항체의 환경에서 잔류 이펙터 활성이 제거되는 것을 확실하게 하는 또다른 방식이다.
또한, 바람직하게는, 본 발명의 인간화 모노클로날 항체와 함께 사용하기 위한 IgG4 Fc 부분은 중쇄 이량체 형성을 안정화시키고 절반-IgG4 Fc 사슬의 형성을 방지하는 치환을 함유한다. 이러한 구축물은 228 위치 (EU 번호매김)의 세린이 프롤린으로 치환되어 구성된다 (서열 52에서의 아미노산 잔기 10). 천연 분자 내에 존재하는 C-말단 라이신 잔기가 본원에서 논의된 항체의 IgG4 유도체 Fc 부분에서 또한 결실될 수 있다 (서열 52의 위치 229; 결실된 라이신은 des-K로 지칭됨). 서열 67의 아미노산 221 내지 448에 의해 가장 바람직한 IgG4 Fc 부분이 제공된다.
추가로 본 발명은 본 발명의 항체를 코딩하는 단리된 핵산 서열; 이러한 핵산 (임의적으로, 벡터로 형질전환된 숙주 세포가 인식하는 제어 서열에 작동가능하게 연결됨)을 포함하는 벡터 (또는 벡터들); 이러한 벡터를 포함하는 숙주 세포; 핵산이 발현되도록 숙주 세포를 배양하는 단계 및 숙주 세포 배양 배지로부터 항체를 회수하는 임의적인 단계를 포함하는, 본 발명에 따른 항체 또는 이의 Fab 단편을 생산하는 방법에 관한 것이다.
또다른 실시양태에서, 본 발명은 본 발명의 Fab 단편 또는 인간화 모노클로날 항체를 포함하는 제약 조성물을 제공한다. 본 발명의 제약 조성물은 제약상 허용가능한 담체를 추가로 포함할 수 있다. 상기 제약 조성물에서, 본 발명의 Fab 단편 또는 인간화 모노클로날 항체는 유효 성분이다. 바람직하게는, 제약 조성물은 본 발명의 Fab 단편 또는 인간화 모노클로날 항체의 균질한 또는 실질적으로 균질한 집단을 포함한다. 치료적 용도를 위한 조성물은 무균성이어야 하고, 동결건조될 수 있으며, 임의적으로는 적합한 희석제가 보충된다.
본 발명의 추가적인 실시양태는 임의의 본 발명의 단리된 폴리뉴클레오티드 또는 본 발명의 HCVR, LCVR, 모노클로날 항체 또는 Fab 단편을 코딩하는 서열을 포함하는 임의의 재조합 벡터(들)의 수용체(recipient)인 숙주 세포 또는 세포 배양물을 포함한다. 숙주 세포는 단일 숙주 세포의 자손을 포함하고, 이러한 자손은 천연적, 우발적 또는 고의적 돌연변이 및/또는 변화로 인해 원래의 어버이 세포와 반드시 완전하게 동일하지는 않을 수 있다 (형태학 또는 전체 DNA 함량 면에서). 숙주 세포는 생체 내에서 또는 시험관 내에서 본 발명의 모노클로날 항체 또는 이의 경쇄 또는 중쇄를 발현하는 하나 이상의 재조합 벡터 또는 폴리뉴클레오티드로 형질전환되었거나, 이들이 형질도입되었거나, 또는 이들로 감염된 세포를 포함한다. 본 발명의 재조합 벡터 (숙주 염색체 내로 안정적으로 혼입되었거나 또는 그렇지 않음)를 포함하는 숙주 세포는 "재조합 숙주 세포"로 또한 지칭될 수 있다. 본 발명에서 사용하기 위한 바람직한 숙주 세포는 CHO 세포, NS0 세포, HeLa, SP2/0 세포 또는 COS 세포이다. 본 발명에서 사용하기 위한 추가적인 숙주 세포에는 식물 세포, 효모 세포, 기타 포유류 세포 및 원핵생물 세포가 포함된다.
포장재 및 상기 포장재 내에 함유된 본 발명의 Fab 단편 또는 인간화 모노클로날 항체를 포함하는 제조품이 본 발명에서 구현되고, 이때 포장재는 Fab 단편 또는 인간화 모노클로날 항체가 GluR을 중화하거나 환자의 GluR 활성 수준을 감소시킨다는 것을 가리키는 포장 삽입물을 포함한다.
생물학적 분석법:
글루카곤 수용체 (
GlucR
) 막 제제
결합 연구를 위한 막 제제를 클로닝된 인간, 마우스, 사이노몰거스 원숭이 또는 래트 글루카곤 수용체를 발현하는 293HEK 세포로부터 제조한다. 각각의 클론 세포주를 먼저 현탁 배양물로서 성장시키고, 동결된 세포 펠렛을 4℃에서 25 mM 트리스(Tris), pH 7.5, 1 mM MgCl2, 컴플리트(Complete)R EDTA-프리(free) 프로티에이스 억제제 정제 (Roche Applied Science), 및 20 U/㎖ DNase I (Sigma Chemical Company)로 구성된 막 프렙(prep) 완충제에 재현탁시킨다. 세포를 25 스트로크를 사용하여 모터-구동 테플론(Teflon)-유리 포터-엘비헴(Potter-Elvehjem) 균질화기로 균질화시킨 후, 4℃에서 15분 동안 1800×g에서 원심분리한다. 상등액을 수집하고, 펠렛을 막 프렙 완충제에 재현탁시키고, 다시 균질화시키고, 원심분리한다. 제2 상등액을 제1 상등액과 합하고, 1800× g에서 15분 동안 재원심분리하여 청정화시킨다. 청정화된 상등액을 고속 튜브로 옮기고, 4℃에서 30분 동안 25000×g에서 원심분리한다. 막 펠렛 (P2)을 막 프렙 완충제 (DNAase 없음)에 재현탁시키고, 분취하고, 드라이 아이스 상에서 급속 동결시키고, 필요할 때까지 -80℃에서 보관한다.
섬광 근접 분석법 (
SPA
)에 의한 [
125
I]글루카곤 결합
경쟁적 수용체/리간드 결합 실험을 섬광 근접 분석법 (SPA) 양식으로 개조한다. 바닥이 투명한 불투명 96-웰 마이크로플레이트에서 인큐베이션을 수행한다. 화합물을 25 mM HEPES, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1％ 무지방산 BSA, 0.003％ 트윈(tween)-20 및 컴플리트(Complete)R EDTA-프리 프로티에이스 억제제 정제로 구성된 결합 완충제에서 3배 단계 희석한다. P2 막 (상기에서 제조됨)을 각각의 수용체 제제로부터 결합 완충제에 희석한 후, 희석된 화합물에 첨가하고 나서, 1％ 무지방산 BSA로 미리 차단된 0.15 ㎎의 밀 배아 응집소 (WGA) SPA 비드 (GE Healthcare), 및 0.15 nM [125I]-글루카곤 (Perkin-Elmer)을 첨가한다. 플레이트를 접착성 밀봉 테이프로 밀봉하고, 엔드-오버-엔드(end over end) 혼합하고, 실온에서 12시간 동안 인큐베이션한다. 수용체에 결합된 방사성 (WGA SPA 비드에 매우 근접함)을 PE 라이프 앤 어낼리티컬 사이언스(PE Life and Analytical Sciences)의 트릴룩스 마이크로베타(Trilux Microbeta) 플레이트 섬광 카운터 상에서 정량하고, 이는 분 당 카운트 (CPM)로 표현된다. 첨가된 화합물의 부재 하에 전체적인 결합을 결정하고, 1 uM 글루카곤 (Lilly Research Labs)을 첨가함으로써 비-특이적 결합을 결정한다. 최종 농도 1 uM의 미표지 글루카곤이 배경 수준으로 [125I]-글루카곤 결합을 완전히 억제할 수 있다.
[
125
I]글루카곤 결합 데이터 분석
비-특이적 결합을 개별적인 CPM 값으로부터 차감하고 전체 결합 신호 (비-특이적 결합에 대해 또한 수정됨)로 나눔으로써, 화합물의 농도 곡선에 대한 미처리(raw) CPM 데이터가 억제 백분율로 변환된다. 4-파라메터 (곡선 최대값, 곡선 최소값, IC50, 힐(Hill) 경사) 비-선형 회귀 루틴(routine) (XLFit 버젼 3.0: Activity Base, IDBS)을 사용하여 데이터를 분석한다. 경쟁물 억제 방사성 리간드 결합에 의해 결정되는 평형 해리 상수 Ki가 식 [Ki = IC50/(1+D/Kd)] (식중 D는 실험에서 사용된 방사성 리간드의 농도이고, Kd는 각각의 개별적인 수용체에 대한 분석법에서의 [125I] 글루카곤의 평형 결합 친화력 상수이다)를 기초로 절대 IC50 값으로부터 계산된다.
글루카곤-자극
cAMP
기능적 길항제 분석법
동일한 클론형 래트, 마우스, 사이노몰거스, 및 인간 글루카곤 수용체-293HEK 세포주를 사용하여 준-최대 용량의 글루카곤으로의 세포내 cAMP 증가의 용량-의존적 억제로부터 기능적 길항제 활성이 결정된다. 퍼킨 엘머(Perkin Elmer)로부터의 증폭형 발광 근접 균질성 분석법(Amplified Luminescent Proximity Homogeneous Assay) (Alpha Screen) (6760625R)으로 세포내 cAMP 수준을 정량한다. 간략하게, 세포 내에서 생성된 cAMP는 비오틴화 cAMP-스트렙타비딘이 코팅된 도너(Donor) 비드와 코팅된 항-cAMP 항체 어셉터(Acceptor) 비드의 결합에 대해 경쟁한다. 세포 내의 cAMP 수준이 증가하면, 어셉터 비드-비오틴화 cAMP-도너 비드 복합체의 파괴가 발생한다. 10 mM HEPES, pH 7.4 + Mg+2 및 Ca+2를 함유하는 HBSS 내의 0.25 mM IBMX에서 기능적 분석법이 수행된다. 클론형 글루카곤 수용체-293HEK 세포를 웰 당 2500개의 세포로 현탁시키고, 1 유닛/웰로 총 부피 20 ㎕의 키트로부터의 비오틴화 cAMP를 첨가한다. 세포를 30분 동안 실온에서 20 ㎕의 3배 단계 희석 화합물 또는 3배 단계 희석 cAMP (표준 곡선용)와 함께 예비-인큐베이션한다. 최대 세포내 cAMP의 90％를 생산하는데 충분한 용량인 20 ㎕의 300 pM 글루카곤 (3×)을 첨가함으로써 반응이 시작된다. 암실, 실온에서의 60분 후, 웰 당 1 유닛의 각각의 키트 도너 및 어셉터 비드를 함유하는 10 mM HEPES, pH 7.4 내의 1％ IGEPAL CA630 (Sigma) 및 0.1％ 무지방산 BSA (Gibco)로 제조된 용해 완충제 30 ㎕를 첨가함으로써 반응이 정지된다. 플레이트를 호일로 감싸서 도너 및 어셉터 비드를 빛으로부터 보호하고, 타이터텍(Titertek) 진탕기에서 중간 속도로 30초 동안 혼합한다. 실온에서 하룻밤 동안 인큐베이션한 후, 플레이트를 패커드 퓨전(Packard Fusion)™-α 기기 상에서 판독한다.
기능적
cAMP
활성에 대한 데이터 분석
알파 스크린 유닛을 cAMP 표준 곡선을 기초로 웰 당 생성된 cAMP의 pM로 전환시킨다. 화합물의 존재 하에 생산된 cAMP의 pM을 준-최대 용량의 단독 글루카곤으로의 최대 응답의 ％로 전환시킨다. 각각의 실험에서, cAMP의 pM에서의 50％ 응답을 일으키는데 필요한 글루카곤의 농도가 결정된다. 이러한 EC50 농도를 사용하여 실행들 간의 결과를 Kb로 표준화시키고, 이때 Kb = (EC50 화합물/[1+(사용된 글루카곤의 pM/글루카곤 용량 응답에 대한 EC50 (pM 단위))]이다. 4-파라메터 (곡선 최대값, 곡선 최소값, IC50, 힐 경사) 비-선형 회귀 루틴 (XLFit 버젼 3.0: Activity Base, IDBS)을 사용하여 데이터를 분석한다.
실시예
:
당업계에 공지된 바와 같이 항체 예 Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6 및 Ab-7을 제조하고 정제하였다. 적합한 숙주 세포, 예컨대 HEK 293 EBNA 또는 CHO를 경쇄 (서열 70, 72, 74, 76에 기재됨) 및 중쇄 (서열 71, 73, 75, 77, 78, 79, 80에 기재됨) 양쪽 모두를 코딩하는 단일 벡터 시스템 또는 최적의 미리 결정된 경쇄 대 중쇄 벡터 비율을 사용하는 항체를 분비시키기 위한 발현 시스템으로 일시적으로 또는 안정적으로 형질감염시켰다. 항체가 내부로 분비된 청정화된 배지를 다수의 통상적으로 사용되는 기술 중 임의의 것을 사용하여 정제하였다. 예를 들어, 상용성 완충제, 예컨대 포스페이트 완충 염수 (pH 7.4)로 평형화된 단백질 A 또는 G 세파로스 FF 칼럼에 간편하게 배지를 적용할 수 있었다. 칼럼을 세정하여 비-특이적 결합 성분을 제거하였다. 예를 들어, pH 구배 (예컨대 0.1 M 인산나트륨 완충제 pH 6.8 → 0.1 M 시트르산나트륨 완충제 pH 2.5)에 의해, 결합된 항체를 용출시켰다. 예컨대 SDS-PAGE에 의해, 항체 분획을 검출한 후, 풀링(pooling)하였다. 의도되는 용도에 따라, 추가적인 정제를 선택할 수 있었다. 통상적인 기술을 사용하여 항체를 농축 및/또는 무균성 여과할 수 있었다. 크기 배제, 소수성 상호작용, 이온 교환, 또는 하이드록시아파타이트 크로마토그래피가 포함되는 통상적인 기술에 의해, 안정적인 응집물 및 다량체를 효과적으로 제거할 수 있었다. 이러한 크로마토그래피 단계 이후의 항체의 순도는 99％를 초과하였다. 생성물을 즉각적으로 -70℃에서 동결시키거나, 또는 동결건조시킬 수 있었다.
대장균에서 Fab 발현이 달성되었고, 이때 Fab 분자가 원형질막 주위공간 내로 분비되었다. 삼투압 충격에 의해 세포벽을 파괴하고, His 태그를 함유하는 Fab를 IMAC 칼럼 상에서 정제하였다.
본 발명에 따른 항체 예들에서 사용된 CDR 조합이 표 1에 기재된다. 전장 항체 경쇄에서는 3개의 경쇄 CDR이 사이에 있는 경쇄 프레임워크 서열들이 조합된다; 프레임워크 1 (서열 23) - CDRL1 - 프레임워크 2 (서열 24) - CDRL2 - 프레임워크 3 (서열 25) - CDRL3 - 프레임워크 4 (서열 26) 및 경쇄 불변 영역 (서열 53). 중쇄 프레임워크 서열에는 3개의 중쇄 CDR이 사이에 있다: 프레임워크 5 (서열 27) - CDRH1 - 프레임워크 6 (서열 28) - CDRH2 - 프레임워크 7 (서열 29) - CDRH3 - 프레임워크 8 (서열 30) 및 중쇄 CH1 불변 영역 (서열 51). 여기에 Ab의 경우에는 Fc 도메인이 이어지고, 이는 Fab 단편에서는 존재하지 않는다 (서열 52, 식중 X10=P; X15=E; X16=A; X17=A; X79=N; X229= 부재).
항체 예 1 내지 7 및 이의 Fab 단편 모두가 상기 글루카곤 수용체 결합 분석법에서 50 nM 미만의 Ki로 인간, 마우스, 사이노몰거스 원숭이 및 래트 글루카곤 수용체에 대한 글루카곤 결합을 억제하였다.
예 4의 항체 (
Ab4
)의
시험관내
활성
이러한 분석법에서, 나노몰 농도에서 GluR에 대한 Ab4 결합이 래트 또는 인간 글루카곤 수용체 세포주의 하류 활성을 차단할 수 있고, 세포에 의한 cAMP 생산을 감소시킬 수 있음이 실연되었다.
본 분석법에서, 시험관내 글루카곤 경쟁 결합 분석법에서 Ab4가 인간, 마우스, 래트, 사이노몰거스 원숭이 기원의 글루카곤 수용체에 높은 친화력 (Ki)으로 결합하고 인간 GLP-1 수용체에는 낮은 친화력으로 결합한다는 것이 실연되었다.
예 4의 항체 (
Ab4
)의
생체내
활성
체중이 약 400 g인 약 8주령의 ZDF 래트에게 예 4의 항체 (즉, Ab4) 또는 인간 IgG (hIgG4) 대조군을 단일 피하 주사로 투약하였다. 각각의 처리군은 6마리의 동물로 구성되었다. 투약 전에, 그리고 3 또는 15 ㎎/㎏ 용량의 Ab4 또는 15 ㎎/㎏의 hIgG 대조군의 단일 피하 주입 후 13일 동안 매일 글루코스 측정을 위해 혈액 샘플을 취하였다. 투약 전 및 3 또는 15 ㎎/㎏의 Ab4 또는 15 ㎎/㎏의 hIgG 대조군의 피하 투약 후 제2일, 제4일, 제6일 및 제8일에 GLP-1 분석용 혈액 샘플을 취하였다.
1마리가 AQL로 측정되어 n=5인 1개의 값 (*)을 제외하고는 군 당 6마리의 래트가 있었다.
정량가능한 GLP-1 수준이 있는 래트로부터만 평균 및 SD가 결정되었고, n은 정량가능한 GLP-1 수준이 있는 동물의 수/군을 나타낸다. 정량가능한 GLP-1 수준이 있는 동물이 없으면, 결과가 < 6 pM으로 기입된다. N.D.는 값이 결정되지 않았음을 의미한다.
SEQUENCE LISTING
<110> Eli Lilly and Company
Millican, Rohn
Korytko, Andrew
Ondek, Brian
<120> Glucagon Receptor Antagonists
<130> X17255
<150> US 61/039,907
<151> 2008-03-27
<160> 80
<170> PatentIn version 3.3
<210> 1
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 1
<400> 1
Ser Tyr Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 2
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 1
<400> 2
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 3
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 1
<400> 3
Ser Ala Ser Ser Ser Val Ser Tyr Ile His
1 5 10
<210> 4
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 2
<400> 4
Thr Thr Ser Asn Leu Ala His
1 5
<210> 5
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 2
<400> 5
Thr Thr Ser Tyr Leu Ala His
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 3
<400> 6
Gln Gln Arg Ser Thr Leu Pro Pro Thr
1 5
<210> 7
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 3
<400> 7
Gln Trp Arg Ser Thr Leu Pro Pro Thr
1 5
<210> 8
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 3
<400> 8
Leu Gln Arg Ser Thr Leu Pro Pro Thr
1 5
<210> 9
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRL 3
<400> 9
Gln Gln Arg Ser Thr Ile Pro Pro Thr
1 5
<210> 10
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 1
<400> 10
Gly Asp Asp Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 11
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 1
<400> 11
Gly Asp Asp Ile Thr Ser Gly Tyr Trp Asp
1 5 10
<210> 12
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 1
<400> 12
Gly Asp Asp Ile Thr Ser Gly Tyr His Asp
1 5 10
<210> 13
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 1
<400> 13
Gly Asp Asp Ile Thr Ser Gly Tyr His Glu
1 5 10
<210> 14
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 14
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 15
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 15
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 16
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 16
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ile Pro Ser Leu Lys Ser
1 5 10 15
<210> 17
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 17
Tyr Ile Ser Tyr Ser Gly Ser Thr Gln Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 18
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 18
Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 19
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 2
<400> 19
Tyr Ile Ser Tyr Ser Gly Ser Thr Val Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 20
<211> 14
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 3
<400> 20
Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met Asp Tyr
1 5 10
<210> 21
<211> 14
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 3
<400> 21
Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr
1 5 10
<210> 22
<211> 14
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized CDRH 3
<400> 22
Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr
1 5 10
<210> 23
<211> 23
<212> PRT
<213> Homo sapiens
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 24
<211> 15
<212> PRT
<213> Homo sapiens
<400> 24
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 25
<211> 32
<212> PRT
<213> Homo sapiens
<400> 25
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 26
<211> 10
<212> PRT
<213> Homo sapiens
<400> 26
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 27
<211> 25
<212> PRT
<213> Homo sapiens
<400> 27
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser
20 25
<210> 28
<211> 14
<212> PRT
<213> Homo sapiens
<400> 28
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 29
<211> 32
<212> PRT
<213> Homo sapiens
<400> 29
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 30
<211> 11
<212> PRT
<213> Homo sapiens
<400> 30
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 31
<211> 451
<212> PRT
<213> Homo sapiens
<400> 31
Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp Gln
1 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys
20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala Asn
35 40 45
Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His Lys
50 55 60
Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln Trp
65 70 75 80
Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys Gln
85 90 95
Met Asp Gly Glu Glu Ile Glu Val Gln Lys Glu Val Ala Lys Met Tyr
100 105 110
Ser Ser Phe Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly
115 120 125
Ala Leu Leu Leu Ala Leu Ala Ile Leu Gly Gly Leu Ser Lys Leu His
130 135 140
Cys Thr Arg Asn Ala Ile His Ala Asn Leu Phe Ala Ser Phe Val Leu
145 150 155 160
Lys Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr
165 170 175
Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Thr Trp Leu Ser Asp
180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly
195 200 205
Ile Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu His
210 215 220
Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser Leu
225 230 235 240
Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu Phe Val Val Pro Trp
245 250 255
Ala Val Val Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn
260 265 270
Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala
275 280 285
Ile Leu Ile Asn Phe Phe Ile Phe Val Arg Ile Val Gln Leu Leu Val
290 295 300
Ala Lys Leu Arg Ala Arg Gln Met His His Thr Asp Tyr Lys Phe Arg
305 310 315 320
Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu
325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg
340 345 350
Ser Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly Leu
355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ser Glu
370 375 380
Leu Arg Arg Arg Trp His Arg Trp Arg Leu Gly Lys Val Leu Trp Glu
385 390 395 400
Glu Arg Asn Thr Ser Asn His Arg Ala Ser Ser Ser Pro Gly His Gly
405 410 415
Pro Pro Ser Lys Glu Leu Gln Phe Gly Arg Gly Gly Gly Ser Gln Asp
420 425 430
Ser Ser Ala Glu Thr Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala Glu
435 440 445
Ser Pro Phe
450
<210> 32
<211> 2034
<212> DNA
<213> Homo sapiens
<400> 32
ggatctggca gcgccgcgaa gacgagcggt caccggcgcc cgacccgagc gcgcccagag 60
gacggcgggg agccaagccg acccccgagc agcgccgcgc gggccctgag gctcaaaggg 120
gcagcttcag gggaggacac cccactggcc aggacgcccc aggctctgct gctctgccac 180
tcagctgccc tcggaggagc gtacacacac accaggactg cattgcccca gtgtgcagcc 240
cctgccagat gtgggaggca gctagctgcc cagaggcatg cccccctgcc agccacagcg 300
acccctgctg ctgttgctgc tgctgctggc ctgccagcca caggtcccct ccgctcaggt 360
gatggacttc ctgtttgaga agtggaagct ctacggtgac cagtgtcacc acaacctgag 420
cctgctgccc cctcccacgg agctggtgtg caacagaacc ttcgacaagt attcctgctg 480
gccggacacc cccgccaata ccacggccaa catctcctgc ccctggtacc tgccttggca 540
ccacaaagtg caacaccgct tcgtgttcaa gagatgcggg cccgacggtc agtgggtgcg 600
tggaccccgg gggcagcctt ggcgtgatgc ctcccagtgc cagatggatg gcgaggagat 660
tgaggtccag aaggaggtgg ccaagatgta cagcagcttc caggtgatgt acacagtggg 720
ctacagcctg tccctggggg ccctgctcct cgccttggcc atcctggggg gcctcagcaa 780
gctgcactgc acccgcaatg ccatccacgc gaatctgttt gcgtccttcg tgctgaaagc 840
cagctccgtg ctggtcattg atgggctgct caggacccgc tacagccaga aaattggcga 900
cgacctcagt gtcagcacct ggctcagtga tggagcggtg gctggctgcc gtgtggccgc 960
ggtgttcatg caatatggca tcgtggccaa ctactgctgg ctgctggtgg agggcctgta 1020
cctgcacaac ctgctgggcc tggccaccct ccccgagagg agcttcttca gcctctacct 1080
gggcatcggc tggggtgccc ccatgctgtt cgtcgtcccc tgggcagtgg tcaagtgtct 1140
gttcgagaac gtccagtgct ggaccagcaa tgacaacatg ggcttctggt ggatcctgcg 1200
gttccccgtc ttcctggcca tcctgatcaa cttcttcatc ttcgtccgca tcgttcagct 1260
gctcgtggcc aagctgcggg cacggcagat gcaccacaca gactacaagt tccggctggc 1320
caagtccacg ctgaccctca tccctctgct gggcgtccac gaagtggtct ttgccttcgt 1380
gacggacgag cacgcccagg gcaccctgcg ctccgccaag ctcttcttcg acctcttcct 1440
cagctccttc cagggcctgc tggtggctgt cctctactgc ttcctcaaca aggaggtgca 1500
gtcggagctg cggcggcgtt ggcaccgctg gcgcctgggc aaagtgctat gggaggagcg 1560
gaacaccagc aaccacaggg cctcatcttc gcccggccac ggccctccca gcaaggagct 1620
gcagtttggg aggggtggtg gcagccagga ttcatctgcg gagaccccct tggctggtgg 1680
cctccctaga ttggctgaga gccccttctg aaccctgctg ggaccccagc tagggctgga 1740
ctctggcacc cagaggcgtc gctggacaac ccagaactgg acgcccagct gaggctgggg 1800
gcgggggagc caacagcagc ccccacctac cccccacccc cagtgtggct gtctgcgaga 1860
ttgggcctcc tctccctgca cctgccttgt ccctggtgca gaggtgagca gaggagtcca 1920
gggcgggagt gggggctgtg ccgtgaactg cgtgccagtg tccccacgta tgtcggcacg 1980
tcccatgtgc atggaaatgt cctccaacaa taaagagctc aagtggtcac cgtg 2034
<210> 33
<211> 458
<212> PRT
<213> Rattus sp.
<400> 33
Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Ser Asp Gln
1 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys
20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Pro Asn
35 40 45
Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp Tyr His Lys
50 55 60
Val Gln His Arg Leu Val Phe Lys Arg Cys Gly Pro Asp Gly Gln Trp
65 70 75 80
Val Arg Gly Pro Arg Gly Gln Ser Trp Arg Asp Ala Ser Gln Cys Gln
85 90 95
Met Asp Asp Asp Glu Ile Glu Val Gln Lys Gly Val Ala Lys Met Tyr
100 105 110
Ser Ser Tyr Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly
115 120 125
Ala Leu Leu Leu Ala Leu Val Ile Leu Leu Gly Leu Arg Lys Leu His
130 135 140
Cys Thr Arg Asn Tyr Ile His Gly Asn Leu Phe Ala Ser Phe Val Leu
145 150 155 160
Lys Ala Gly Ser Val Leu Val Ile Asp Trp Leu Leu Lys Thr Arg Tyr
165 170 175
Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Val Trp Leu Ser Asp
180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Thr Val Ile Met Gln Tyr Gly
195 200 205
Ile Ile Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Val Tyr Leu Tyr
210 215 220
Ser Leu Leu Ser Ile Thr Thr Phe Ser Glu Lys Ser Phe Phe Ser Leu
225 230 235 240
Tyr Leu Cys Ile Gly Trp Gly Ser Pro Leu Leu Phe Val Ile Pro Trp
245 250 255
Val Val Val Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn
260 265 270
Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Ile Pro Val Leu Leu Ala
275 280 285
Ile Leu Ile Asn Phe Phe Ile Phe Val Arg Ile Ile His Leu Leu Val
290 295 300
Ala Lys Leu Arg Ala His Gln Met His Tyr Ala Asp Tyr Lys Phe Arg
305 310 315 320
Leu Ala Arg Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu
325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg
340 345 350
Ser Thr Lys Leu Phe Phe Asp Leu Phe Phe Ser Ser Phe Gln Gly Leu
355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ala Glu
370 375 380
Leu Leu Arg Arg Trp Arg Arg Trp Gln Glu Gly Lys Ala Leu Gln Glu
385 390 395 400
Glu Arg Met Ala Ser Ser His Gly Ser His Met Ala Pro Ala Gly Thr
405 410 415
Cys His Gly Asp Pro Cys Glu Lys Leu Gln Leu Met Ser Ala Gly Ser
420 425 430
Ser Ser Gly Thr Gly Cys Glu Pro Ser Ala Lys Thr Ser Leu Ala Ser
435 440 445
Ser Leu Pro Arg Leu Ala Asp Ser Pro Thr
450 455
<210> 34
<211> 1875
<212> DNA
<213> Rattus sp.
<400> 34
gaattcgcgg ccgccgccgg gccccagatc ccagtgcgcg aggagcccag tcctagaccc 60
agcaacctga ggagaggtgc acacaccccc aaggacccag gcacccaacc tctgccagat 120
gtgggggggt ggctacccag aggcatgctc ctcacccagc tccactgtcc ctacctgctg 180
ctgctgctgg tggtgctgtc atgtctgcca aaggcaccct ctgcccaggt aatggacttt 240
ttgtttgaga agtggaagct ctatagtgac cagtgccacc acaacctaag cctgctgccc 300
ccacctactg agctggtctg caacagaact ttcgacaagt actcctgctg gcctgacacc 360
cctcccaaca ccactgccaa catttcctgc ccctggtacc taccttggta ccacaaagtg 420
cagcaccgcc tagtgttcaa gaggtgtggg cctgatgggc agtgggttcg agggccacgg 480
gggcagtcat ggcgcgacgc ctcccaatgt cagatggatg atgacgagat cgaggtccag 540
aagggggtag ccaagatgta tagcagctac caggtgatgt acactgtggg ctacagtctg 600
tccctggggg ccttgctcct ggcgctggtc atcctgctgg gcctcaggaa gctgcactgc 660
acccggaact acatccacgg gaacctgttc gcgtccttcg tgctcaaggc tggctctgtg 720
ctggtcattg attggctgct caagacacgc tatagccaga agattggaga tgacctcagt 780
gtgagcgtct ggctcagtga tggggcggtg gctggctgca gagtggccac agtgatcatg 840
cagtacggca tcatagccaa ctactgctgg ttgctggtgg agggtgtgta cctgtacagc 900
ctgctgagca tcaccacctt ctcggagaag agcttcttct ccctctatct gtgcatcggc 960
tggggatctc ccctgctgtt tgtcatcccc tgggtggtgg tcaagtgtct gtttgagaat 1020
gtccagtgct ggaccagcaa tgacaatatg ggattctggt ggatcctgcg tatccctgta 1080
ctcctggcca tactgatcaa ttttttcatc tttgtccgca tcattcatct tcttgtggcc 1140
aagctgcgtg cccatcagat gcactatgct gattacaagt tccggctagc caggtccacg 1200
ctgaccctca ttcctctgct gggagtccac gaagtggtct ttgcctttgt gactgatgag 1260
catgcccagg gcaccctgcg ctccaccaag ctcttttttg acctgttctt cagctccttt 1320
cagggtctgc tggtggctgt tctctactgt ttcctcaaca aggaggtgca ggcagagcta 1380
ctgcggcgtt ggaggcgatg gcaagaaggc aaagctcttc aggaggaaag gatggccagc 1440
agccatggca gccacatggc cccagcaggg acttgtcatg gtgatccctg tgagaaactt 1500
cagcttatga gtgcaggcag cagcagtggg actggctgtg agccctctgc gaagacctca 1560
ttggccagta gtctcccaag gctggctgac agccccacct gaatctccac tggactccag 1620
ccaagttgga ttcagaaagg gcctcacaag acaacccaga aacagatgcc tggccaaggc 1680
tgaagaggca aagcagcaag acagcagctt gtactatcca cactccccta acctgtcctg 1740
gccgggtaca ggccacattg atggagtagg ggctggatat gatggagtag ccatgctatg 1800
aactatgggt gttcccatga gtgttgccat gttccatgca cacagatatg accttcagta 1860
aagagctccc gtagg 1875
<210> 35
<211> 458
<212> PRT
<213> Mus sp.
<400> 35
Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Ser Asp Gln
1 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys
20 25 30
Asn Arg Thr Phe Asp Asn Tyr Ser Cys Trp Pro Asp Thr Pro Pro Asn
35 40 45
Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp Cys His Lys
50 55 60
Val Gln His Arg Leu Val Phe Lys Arg Cys Gly Pro Asp Gly Gln Trp
65 70 75 80
Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asn Ala Ser Gln Cys Gln
85 90 95
Leu Asp Asp Glu Glu Ile Glu Val Gln Lys Gly Val Ala Lys Met Tyr
100 105 110
Ser Ser Gln Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly
115 120 125
Ala Leu Leu Leu Ala Leu Val Ile Leu Leu Gly Leu Arg Lys Leu His
130 135 140
Cys Thr Arg Asn Tyr Ile His Gly Asn Leu Phe Ala Ser Phe Val Leu
145 150 155 160
Lys Ala Gly Ser Val Leu Val Ile Asp Trp Leu Leu Lys Thr Arg Tyr
165 170 175
Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Val Trp Leu Ser Asp
180 185 190
Gly Ala Met Ala Gly Cys Arg Val Ala Thr Val Ile Met Gln Tyr Gly
195 200 205
Ile Ile Pro Asn Tyr Cys Trp Leu Leu Val Glu Gly Val Tyr Leu Tyr
210 215 220
Ser Leu Leu Ser Leu Ala Thr Phe Ser Glu Arg Ser Phe Phe Ser Leu
225 230 235 240
Tyr Leu Gly Ile Gly Trp Gly Ala Pro Leu Leu Phe Val Ile Pro Trp
245 250 255
Val Val Val Lys Cys Leu Phe Glu Asn Val Gln Cys Trp Thr Ser Asn
260 265 270
Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Ile Pro Val Phe Leu Ala
275 280 285
Leu Leu Ile Asn Phe Phe Ile Phe Val His Ile Ile Gln Leu Leu Val
290 295 300
Ala Lys Leu Arg Ala His Gln Met His Tyr Ala Asp Tyr Lys Phe Arg
305 310 315 320
Leu Ala Arg Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu
325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg
340 345 350
Ser Thr Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly Leu
355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ala Glu
370 375 380
Leu Met Arg Arg Trp Arg Gln Trp Gln Glu Gly Lys Ala Leu Gln Glu
385 390 395 400
Glu Arg Leu Ala Ser Ser His Gly Ser His Met Ala Pro Ala Gly Pro
405 410 415
Cys His Gly Asp Pro Cys Glu Lys Leu Gln Leu Met Ser Ala Gly Ser
420 425 430
Ser Ser Gly Thr Gly Cys Val Pro Ser Met Glu Thr Ser Leu Ala Ser
435 440 445
Ser Leu Pro Arg Leu Ala Asp Ser Pro Thr
450 455
<210> 36
<211> 1944
<212> DNA
<213> Mus sp.
<400> 36
cagggtctcc cttgcaacct gaggagaggt gcacacactc tgaggaccta ggtgtgcaac 60
ctctgccaga tgtggggcgt ggctacccag aggcatgccc ctcacccagc tccactgtcc 120
ccacctgctg ctgctgctgt tggtgctgtc atgtctgcca gaggcaccct ctgcccaggt 180
aatggacttt ttgtttgaga agtggaagct ctatagtgac caatgtcacc acaacctaag 240
cctgctgccc ccacctactg agctggtctg taacagaacc ttcgacaact actcctgctg 300
gcctgacacc cctcccaaca ccactgccaa catttcctgc ccctggtacc taccttggtg 360
ccacaaagtg cagcaccgcc tagtgttcaa gaggtgtggg cccgatgggc agtgggttcg 420
agggccacgg gggcagccgt ggcgcaacgc ctcccaatgt cagttggatg atgaagagat 480
cgaggtccag aagggggtgg ccaagatgta tagcagccag caggtgatgt acaccgtggg 540
ctacagtctg tccctggggg ccttgctcct tgcgctggtc atcctgctgg gcctcaggaa 600
gctgcactgc acccgaaact acatccatgg gaacctgttt gcgtcctttg tgctcaaggc 660
tggctctgtg ttggtcatcg attggctgct gaagacacgg tacagccaga agattggcga 720
tgacctcagt gtgagcgtct ggctcagtga cggggcgatg gccggctgca gagtggccac 780
agtgatcatg cagtacggca tcatacccaa ctattgctgg ttgctggtag agggcgtgta 840
cctgtacagc ctgctgagcc ttgccacctt ctctgagagg agcttctttt ccctctacct 900
gggcattggc tggggtgcgc ccctgctgtt tgtcatcccc tgggtggtgg tcaagtgtct 960
gtttgagaat gttcagtgct ggaccagcaa tgacaacatg ggattctggt ggatcctgcg 1020
tattcctgtc ttcctggcct tactgatcaa ttttttcatc tttgtccaca tcattcaact 1080
tcttgtggcc aagctgcgtg cccatcagat gcactatgct gattacaagt tccggctggc 1140
caggtccacg ctgaccctca tccctctgct gggggtccac gaggtggtct ttgcctttgt 1200
gactgacgag catgcccaag gcaccctgcg ctccaccaag ctcttttttg acctgttcct 1260
cagctccttc cagggtctgc tggtggctgt tctctactgt ttcctcaaca aggaggtgca 1320
ggcagagctg atgcggcgtt ggaggcaatg gcaagaaggc aaagctcttc aggaggaaag 1380
gttggccagc agccatggca gccacatggc cccagcaggg ccttgtcatg gtgatccctg 1440
tgagaaactt cagcttatga gtgcaggcag cagcagtggg actggctgtg tgccctctat 1500
ggagacctcg ctggccagta gtctcccaag gttggctgac agccccacct gaatctccac 1560
ttggagccta ggcaggttgt gttcaagaaa gggcctcaga ggacaaccca gagccagatg 1620
cccggccaag gttgaagagc caaagcagca agacagcagc ttgtactgtg cacactcccc 1680
taacctgtcc tagcctggca caggccacag tgacagagta ggggttggat atgatggaga 1740
agccatgtta tctatgaact ctgagtgttc ccatgtgtgt tgacatggtc cctgtaccca 1800
gatatgtcct tcagtaaaaa gctcgagtgg agctgctgca cagctcgtgg acagcaggct 1860
tgaagccccc agggacgggg tttgggaggc cggggatgag cagcacactc agcaggtgga 1920
gcgctagtgc aacccaggaa agaa 1944
<210> 37
<211> 451
<212> PRT
<213> Macaca fascicularis
<400> 37
Gln Val Met Asp Phe Leu Phe Glu Lys Trp Lys Leu Tyr Gly Asp Gln
1 5 10 15
Cys His His Asn Leu Ser Leu Leu Pro Pro Pro Thr Glu Leu Val Cys
20 25 30
Asn Arg Thr Phe Asp Lys Tyr Ser Cys Trp Pro Asp Thr Pro Ala Asn
35 40 45
Thr Thr Ala Asn Ile Ser Cys Pro Trp Tyr Leu Pro Trp His His Lys
50 55 60
Val Gln His Arg Phe Val Phe Lys Arg Cys Gly Pro Asp Gly Gln Trp
65 70 75 80
Val Arg Gly Pro Arg Gly Gln Pro Trp Arg Asp Ala Ser Gln Cys Gln
85 90 95
Met Asp Gly Glu Glu Leu Glu Val Gln Lys Glu Val Ala Lys Met Tyr
100 105 110
Ser Ser Phe Gln Val Met Tyr Thr Val Gly Tyr Ser Leu Ser Leu Gly
115 120 125
Ala Leu Leu Leu Ala Leu Ala Val Leu Gly Gly Ile Ser Lys Leu His
130 135 140
Cys Thr Arg Asn Ala Ile His Ala Asn Leu Phe Val Ser Phe Val Leu
145 150 155 160
Lys Ala Ser Ser Val Leu Val Ile Asp Gly Leu Leu Arg Thr Arg Tyr
165 170 175
Ser Gln Lys Ile Gly Asp Asp Leu Ser Val Ser Ile Trp Leu Ser Asp
180 185 190
Gly Ala Val Ala Gly Cys Arg Val Ala Ala Val Phe Met Gln Tyr Gly
195 200 205
Val Val Ala Asn Tyr Cys Trp Leu Leu Val Glu Gly Leu Tyr Leu His
210 215 220
Asn Leu Leu Gly Leu Ala Thr Leu Pro Glu Arg Ser Phe Phe Ser Leu
225 230 235 240
Tyr Leu Gly Ile Gly Trp Gly Ala Pro Met Leu Phe Ile Ile Pro Trp
245 250 255
Val Val Val Arg Cys Leu Phe Glu Asn Ile Gln Cys Trp Thr Ser Asn
260 265 270
Asp Asn Met Gly Phe Trp Trp Ile Leu Arg Phe Pro Val Phe Leu Ala
275 280 285
Ile Leu Ile Asn Phe Phe Ile Phe Ile Arg Ile Val His Leu Leu Val
290 295 300
Ala Lys Leu Arg Ala Arg Glu Met His His Thr Asp Tyr Lys Phe Arg
305 310 315 320
Leu Ala Lys Ser Thr Leu Thr Leu Ile Pro Leu Leu Gly Val His Glu
325 330 335
Val Val Phe Ala Phe Val Thr Asp Glu His Ala Gln Gly Thr Leu Arg
340 345 350
Phe Ala Lys Leu Phe Phe Asp Leu Phe Leu Ser Ser Phe Gln Gly Leu
355 360 365
Leu Val Ala Val Leu Tyr Cys Phe Leu Asn Lys Glu Val Gln Ser Glu
370 375 380
Leu Arg Arg His Trp His Arg Trp Arg Leu Gly Lys Val Leu Gln Glu
385 390 395 400
Glu Arg Gly Thr Ser Asn His Lys Ala Pro Ser Ala Pro Gly Gln Gly
405 410 415
Leu Pro Gly Lys Lys Leu Gln Ser Gly Arg Asp Gly Gly Ser Gln Asp
420 425 430
Ser Ser Ala Glu Ile Pro Leu Ala Gly Gly Leu Pro Arg Leu Ala Glu
435 440 445
Ser Pro Phe
450
<210> 38
<211> 1434
<212> DNA
<213> Macaca fascicularis
<400> 38
atgccgccgt gccagccgcg ccgcccgctg ctgctgctgc tgctgctgct ggcgtgccag 60
ccgcaggcgc cgagcgcgca ggtgatggat tttctgtttg aaaaatggaa actgtatggc 120
gatcagtgcc atcataacct gagcctgctg ccgccgccga ccgaactggt gtgcaaccgc 180
acctttgata aatatagctg ctggccggat accccggcga acaccaccgc gaacattagc 240
tgcccgtggt atctgccgtg gcatcataaa gtgcagcatc gctttgtgtt taaacgctgc 300
ggcccggatg gccagtgggt gcgcggcccg cgcggccagc cgtggcgcga tgcgagccag 360
tgccagatgg atggcgaaga actggaagtg cagaaagaag tggcgaaaat gtatagcagc 420
tttcaggtga tgtataccgt gggctatagc ctgagcctgg gcgcgctgct gctggcgctg 480
gcggtgctgg gcggcattag caaactgcat tgcacccgca acgcgattca tgcgaacctg 540
tttgtgagct ttgtgctgaa agcgagcagc gtgctggtga ttgatggcct gctgcgcacc 600
cgctatagcc agaaaattgg cgatgatctg agcgtgagca tttggctgag cgatggcgcg 660
gtggcgggct gccgcgtggc ggcggtgttt atgcagtatg gcgtggtggc gaactattgc 720
tggctgctgg tggaaggcct gtatctgcat aacctgctgg gcctggcgac cctgccggaa 780
cgcagctttt ttagcctgta tctgggcatt ggctggggcg cgccgatgct gtttattatt 840
ccgtgggtgg tggtgcgctg cctgtttgaa aacattcagt gctggaccag caacgataac 900
atgggctttt ggtggattct gcgctttccg gtgtttctgg cgattctgat taactttttt 960
atttttattc gcattgtgca tctgctggtg gcgaaactgc gcgcgcgcga aatgcatcat 1020
accgattata aatttcgcct ggcgaaaagc accctgaccc tgattccgct gctgggcgtg 1080
catgaagtgg tgtttgcgtt tgtgaccgat gaacatgcgc agggcaccct gcgctttgcg 1140
aaactgtttt ttgatctgtt tctgagcagc tttcagggcc tgctggtggc ggtgctgtat 1200
tgctttctga acaaagaagt gcagagcgaa ctgcgccgcc attggcatcg ctggcgcctg 1260
ggcaaagtgc tgcaggaaga acgcggcacc agcaaccata aagcgccgag cgcgccgggc 1320
cagggcctgc cgggcaaaaa actgcagagc ggccgcgatg gcggcagcca ggatagcagc 1380
gcggaaattc cgctggcggg cggcctgccg cgcctggcgg aaagcccgtt ttaa 1434
<210> 39
<211> 106
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable light chain
<400> 39
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Trp Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 40
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 40
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 41
<211> 106
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable light chain
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Tyr Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 42
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ile Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 43
<211> 106
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable light chain
<400> 43
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 44
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 45
<211> 106
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable light chain
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 46
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 47
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Gln Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 48
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 49
<211> 122
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized variable heavy chain
<400> 49
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Glu Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 107
<212> PRT
<213> Homo sapiens
<400> 50
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 51
<211> 98
<212> PRT
<213> Homo sapiens
<400> 51
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val
<210> 52
<211> 229
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Modified human IgG4 Fc sequence
<220>
<221> VARIANT
<222> (10)..(10)
<223> Xaa is Ser or Pro
<220>
<221> VARIANT
<222> (15)..(15)
<223> Xaa is Pro or Glu
<220>
<221> VARIANT
<222> (16)..(16)
<223> Xaa is Ala or Val or Phe
<220>
<221> VARIANT
<222> (17)..(17)
<223> Xaa is Ala or Glu or Leu
<220>
<221> VARIANT
<222> (79)..(79)
<223> Xaa is Ala or Asn
<220>
<221> VARIANT
<222> (229)..(229)
<223> Xaa is Lys or deleted
<400> 52
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Xaa Cys Pro Ala Pro Xaa Xaa
1 5 10 15
Xaa Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Xaa Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Xaa
225
<210> 53
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Light chain CDR1
<220>
<221> VARIANT
<222> (2)..(2)
<223> Xaa is Tyr or Ala
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is Met or Ile
<400> 53
Ser Xaa Ser Ser Ser Val Ser Tyr Xaa His
1 5 10
<210> 54
<211> 7
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Light chain CDR2
<220>
<221> VARIANT
<222> (4)..(4)
<223> Xaa is Asn or Tyr
<400> 54
Thr Thr Ser Xaa Leu Ala His
1 5
<210> 55
<211> 9
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Light chain CDR3
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa is Gln or Leu
<220>
<221> VARIANT
<222> (2)..(2)
<223> Xaa is Gln or Trp
<220>
<221> VARIANT
<222> (6)..(6)
<223> Xaa is Leu or Ile
<400> 55
Xaa Xaa Arg Ser Thr Xaa Pro Pro Thr
1 5
<210> 56
<211> 10
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Heavy chain CDR1
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is Trp or His
<220>
<221> VARIANT
<222> (10)..(10)
<223> Xaa is Asn, Asp or Glu
<400> 56
Gly Asp Asp Ile Thr Ser Gly Tyr Xaa Xaa
1 5 10
<210> 57
<211> 16
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Heavy chain CDR2
<220>
<221> VARIANT
<222> (9)..(9)
<223> Xaa is Tyr, Gln, Ser or Val
<220>
<221> VARIANT
<222> (11)..(11)
<223> Xaa is Asn, Ser or Ile
<400> 57
Tyr Ile Ser Tyr Ser Gly Ser Thr Xaa Tyr Xaa Pro Ser Leu Lys Ser
1 5 10 15
<210> 58
<211> 14
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Heavy chain CDR3
<220>
<221> VARIANT
<222> (3)..(3)
<223> Xaa is Gly or Ala
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa is Met or Leu
<400> 58
Pro Pro Xaa Tyr Tyr Gly Phe Gly Pro Tyr Ala Xaa Asp Tyr
1 5 10
<210> 59
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody light chain
<400> 59
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Trp Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 60
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 60
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 61
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody light chain
<400> 61
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Tyr Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Asn Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 62
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 62
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ile Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 63
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody light chain
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 64
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 64
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr Trp Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 65
<211> 213
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody light chain
<400> 65
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Thr Thr Ser Tyr Leu Ala His Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Leu Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 66
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 66
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 67
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 67
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Gln Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Gly Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 68
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 68
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Asp Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 69
<211> 448
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic sequence: Humanized monoclonal antibody heavy chain
<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Asp Ile Thr Ser Gly
20 25 30
Tyr His Glu Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Ser Tyr Ser Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Pro Pro Ala Tyr Tyr Gly Phe Gly Pro Tyr Ala Leu Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 70
<211> 639
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody light chain of SEQ ID NO: 59
<400> 70
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca gcgcgagcag cagcgtgagc tatatgcatt ggtatcagca gaaaccgggc 120
aaagcgccga aactgctgat ttataccacc agcaacctgg cgcatggcgt gccgagccgc 180
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240
gattttgcga cctattattg ccagtggcgc agcaccctgc cgccgacctt tggcggcggc 300
accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360
gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420
cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480
agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540
agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600
agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639
<210> 71
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 60
<400> 71
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatt gggattggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 72
<211> 639
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody light chain of SEQ ID NO: 61
<400> 72
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca gctatagcag cagcgtgagc tatatgcatt ggtatcagca gaaaccgggc 120
aaagcgccga aactgctgat ttataccacc agcaacctgg cgcatggcgt gccgagccgc 180
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240
gattttgcga cctattattg ccagcagcgc agcaccctgc cgccgacctt tggcggcggc 300
accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360
gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420
cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480
agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540
agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600
agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639
<210> 73
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 62
<400> 73
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatt ggaactggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatatt 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300
tattatggct ttggcccgta tgcgatggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 74
<211> 639
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody light chain of SEQ ID NO: 63
<400> 74
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca gcgcgagcag cagcgtgagc tatattcatt ggtatcagca gaaaccgggc 120
aaagcgccga aactgctgat ttataccacc agctatctgg cgcatggcgt gccgagccgc 180
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240
gattttgcga cctattattg cctgcagcgc agcaccctgc cgccgacctt tggcggcggc 300
accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360
gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420
cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480
agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540
agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600
agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639
<210> 75
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 64
<400> 75
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatt gggattggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 76
<211> 639
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody light chain of SEQ ID NO: 65
<400> 76
gatattcaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca gcgcgagcag cagcgtgagc tatattcatt ggtatcagca gaaaccgggc 120
aaagcgccga aactgctgat ttataccacc agctatctgg cgcatggcgt gccgagccgc 180
tttagcggca gcggcagcgg caccgatttt accctgacca ttagcagcct gcagccggaa 240
gattttgcga cctattattg ccagcagcgc agcaccctgc cgccgacctt tggcggcggc 300
accaaagtgg aaattaaacg caccgtggcg gcgccgagcg tgtttatttt tccgccgagc 360
gatgaacagc tgaaaagcgg caccgcgagc gtggtgtgcc tgctgaacaa cttttatccg 420
cgcgaagcga aagtgcagtg gaaagtggat aacgcgctgc agagcggcaa cagccaggaa 480
agcgtgaccg aacaggatag caaagatagc acctatagcc tgagcagcac cctgaccctg 540
agcaaagcgg attatgaaaa acataaagtg tatgcgtgcg aagtgaccca tcagggcctg 600
agcagcccgg tgaccaaaag ctttaaccgc ggcgaatgc 639
<210> 77
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 66
<400> 77
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 78
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 67
<400> 78
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ccagtatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccgggc 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 79
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 68
<400> 79
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatc atgattggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac ctattatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccggcg 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
<210> 80
<211> 1344
<212> DNA
<213> Artificial sequence
<220>
<223> Synthetic sequence: DNA sequence encoding the humanized
monoclonal antibody heavy chain of SEQ ID NO: 69
<400> 80
caggtgcagc tgcaggaaag cggcccgggc ctggtgaaac cgagcgaaac cctgagcctg 60
acctgcaccg tgagcggcga tgatattacc agcggctatc atgaatggat tcgccagccg 120
ccgggcaaag gcctggaatg gattggctat attagctata gcggcagcac cagctatagc 180
ccgagcctga aaagccgcgt gaccattagc gtggatacca gcaaaaacca gtttagcctg 240
aaactgagca gcgtgaccgc ggcggatacc gcggtgtatt attgcgcgcg cccgccggcg 300
tattatggct ttggcccgta tgcgctggat tattggggcc agggcaccct ggtgaccgtg 360
agcagcgcga gcaccaaagg cccgagcgtg tttccgctgg cgccgtgcag ccgcagcacc 420
agcgaaagca ccgcggcgct gggctgcctg gtgaaagatt attttccgga accggtgacc 480
gtgagctgga acagcggcgc gctgaccagc ggcgtgcata cctttccggc ggtgctgcag 540
agcagcggcc tgtatagcct gagcagcgtg gtgaccgtgc cgagcagcag cctgggcacc 600
aaaacctata cctgcaacgt ggatcataaa ccgagcaaca ccaaagtgga taaacgcgtg 660
gaaagcaaat atggcccgcc gtgcccgccg tgcccggcgc cggaagcggc gggcggcccg 720
agcgtgtttc tgtttccgcc gaaaccgaaa gataccctga tgattagccg caccccggaa 780
gtgacctgcg tggtggtgga tgtgagccag gaagatccgg aagtgcagtt taactggtat 840
gtggatggcg tggaagtgca taacgcgaaa accaaaccgc gcgaagaaca gtttaacagc 900
acctatcgcg tggtgagcgt gctgaccgtg ctgcatcagg attggctgaa cggcaaagaa 960
tataaatgca aagtgagcaa caaaggcctg ccgagcagca ttgaaaaaac cattagcaaa 1020
gcgaaaggcc agccgcgcga accgcaggtg tataccctgc cgccgagcca ggaagaaatg 1080
accaaaaacc aggtgagcct gacctgcctg gtgaaaggct tttatccgag cgatattgcg 1140
gtggaatggg aaagcaacgg ccagccggaa aacaactata aaaccacccc gccggtgctg 1200
gatagcgatg gcagcttttt tctgtatagc cgcctgaccg tggataaaag ccgctggcag 1260
gaaggcaacg tgtttagctg cagcgtgatg catgaagcgc tgcataacca ttatacccag 1320
aaaagcctga gcctgagcct gggc 1344
Claims (18)
- (i) CDRL1: S A S S S V S Y I H (서열 3);
CDRL2: T T S Y L A H (서열 5); 및
CDRL3: Q Q R S T L P P T (서열 6)
를 포함하는 경쇄; 및
(ii) CDRH1: G D D I T S G Y H D (서열 12);
CDRH2: Y I S Y S G S T X8 Y X9 P S L K S (서열 57); 및
CDRH3: P P G Y Y G F G P Y A L D Y (서열 21)
를 포함하는 중쇄
를 포함하고, 여기서, X8은 Y 또는 Q이고, X9는 S인, 글루카곤 수용체에 대한 글루카곤 결합을 억제하는 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체. - 제1항에 있어서, (i) 경쇄가 서열 3의 CDRL1, 서열 5의 CDRL2 및 서열 6의 CDRL3을 포함하고, (ii) 중쇄가 서열 12의 CDRH1, 서열 17의 CDRH2 및 서열 21의 CDRH3을 포함하는 인간화 모노클로날 항체.
- 제1항 또는 제2항에 있어서, 상기 경쇄가 서열 45의 가변 영역 서열을 포함하고, 상기 중쇄가 서열 47의 가변 영역 서열을 포함하는 인간화 모노클로날 항체.
- 제1항 또는 제2항에 있어서, 서열 65의 경쇄 2개 및 서열 67의 중쇄 2개를 포함하는 인간화 모노클로날 항체.
- 유효량의 제1항 또는 제2항에 따른 Fab 단편 또는 상기 Fab 단편을 포함하는 인간화 모노클로날 항체 및 제약상 허용가능한 부형제를 포함하는, 인간에서 제1형 또는 제2형 당뇨병을 치료하거나 체중 감소를 달성하기 위한 제약 조성물.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3990708P | 2008-03-27 | 2008-03-27 | |
| US61/039,907 | 2008-03-27 | ||
| PCT/US2009/037349 WO2009120530A1 (en) | 2008-03-27 | 2009-03-17 | Glucagon receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20100117130A KR20100117130A (ko) | 2010-11-02 |
| KR101235934B1 true KR101235934B1 (ko) | 2013-02-21 |
Family
ID=40794248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020107021297A KR101235934B1 (ko) | 2008-03-27 | 2009-03-17 | 글루카곤 수용체 길항제 |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US7968686B2 (ko) |
| EP (1) | EP2268670A1 (ko) |
| JP (1) | JP5438095B2 (ko) |
| KR (1) | KR101235934B1 (ko) |
| CN (1) | CN101983208A (ko) |
| AR (1) | AR070844A1 (ko) |
| AU (1) | AU2009228866A1 (ko) |
| BR (1) | BRPI0910118A2 (ko) |
| CA (1) | CA2719761A1 (ko) |
| CL (1) | CL2009000586A1 (ko) |
| EA (1) | EA201071126A1 (ko) |
| MX (1) | MX2010010517A (ko) |
| PE (1) | PE20091674A1 (ko) |
| TW (1) | TW201000126A (ko) |
| WO (1) | WO2009120530A1 (ko) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2475683A4 (en) * | 2009-09-08 | 2013-04-24 | Neopharm Co Ltd | GLUCAGONIC RECEPTOR ANTIBODY YOUR USE |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
| TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
| US8771696B2 (en) | 2010-11-23 | 2014-07-08 | Regeneron Pharmaceuticals, Inc. | Method of reducing the severity of stress hyperglycemia with human antibodies to the glucagon receptor |
| JO3756B1 (ar) * | 2010-11-23 | 2021-01-31 | Regeneron Pharma | اجسام مضادة بشرية لمستقبلات الجلوكاجون |
| WO2012097313A2 (en) | 2011-01-14 | 2012-07-19 | The Regents Of The University Of California | Therapeutic antibodies against ror-1 protein and methods for use of same |
| WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
| WO2013059531A1 (en) * | 2011-10-20 | 2013-04-25 | Genentech, Inc. | Anti-gcgr antibodies and uses thereof |
| WO2013081993A1 (en) | 2011-12-02 | 2013-06-06 | Eli Lilly And Company | Anti-glucagon antibodies and uses thereof |
| MX2015015339A (es) * | 2013-05-07 | 2016-07-15 | Rinat Neuroscience Corp | Anticuerpos de receptor anti-glucagon y metodos de uso de los mismos. |
| CN108025060A (zh) * | 2014-06-08 | 2018-05-11 | 瑞美德生物医药科技有限公司 | 使用胰高血糖素受体拮抗性抗体治疗1型糖尿病的方法 |
| SG10201913074WA (en) | 2016-08-30 | 2020-03-30 | Regeneron Pharma | Methods of treating severe insulin resistance by interfering with glucagon receptor signaling |
| EP3529278A1 (en) | 2016-10-20 | 2019-08-28 | Regeneron Pharmaceuticals, Inc. | Methods of lowering blood glucose levels |
| KR102627311B1 (ko) | 2017-01-27 | 2024-01-22 | 엔지엠 바이오파마슈티컬스, 아이엔씨. | 글루카곤 수용체 결합 단백질 및 이의 사용 방법 |
| CA3071387A1 (en) | 2017-08-22 | 2019-02-28 | Regeneron Pharmaceuticals, Inc. | Methods of treating urea cycle disorders by interfering with glucagon receptor signaling |
| CN110357959B (zh) | 2018-04-10 | 2023-02-28 | 鸿运华宁（杭州）生物医药有限公司 | Gcgr抗体及其与glp-1的融合蛋白质，以及其药物组合物和应用 |
| EP3829636A1 (en) | 2018-07-27 | 2021-06-09 | NGM Biopharmaceuticals, Inc. | Use of glucagon receptor antagonists with immunotherapeutic agent |
| AU2019410643A1 (en) | 2018-12-21 | 2021-08-12 | Jiangsu Hengrui Medicine Co., Ltd. | Bispecific protein |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69333726T8 (de) | 1992-08-28 | 2006-04-27 | Novo Nordisk A/S | Glucagonrezeptoren |
| US5776725A (en) | 1992-08-28 | 1998-07-07 | Zymogenetics, Inc. | Recombinant production of glucagon receptors |
| WO2002045494A2 (en) | 2000-12-06 | 2002-06-13 | Deltagen, Inc. | Transgenic mice containing glucagon receptor gene disruptions |
| AR036711A1 (es) | 2001-10-05 | 2004-09-29 | Bayer Corp | Peptidos que actuan como agonistas del receptor del glp-1 y como antagonistas del receptor del glucagon y sus metodos de uso farmacologico |
| US7399853B2 (en) | 2003-04-28 | 2008-07-15 | Isis Pharmaceuticals | Modulation of glucagon receptor expression |
| WO2006005469A2 (en) | 2004-07-15 | 2006-01-19 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with glucagon receptor (gcgr) |
| EP2034916A1 (en) | 2006-07-04 | 2009-03-18 | Bracco Imaging S.p.A | Device for localized thermal ablation of biological tissue, particularly tumoral tissues or the like |
| CL2007002668A1 (es) | 2006-09-20 | 2008-05-09 | Amgen Inc | Proteina de union a antigeno que se une al receptor de glucagon humano; acido nucleico que la codifica; metodo de produccion; composicion farmaceutica que la comprende; y su uso para tratar o prevenir la diabetes tipo 2. |
-
2009
- 2009-03-12 PE PE2009000369A patent/PE20091674A1/es not_active Application Discontinuation
- 2009-03-12 AR ARP090100889A patent/AR070844A1/es unknown
- 2009-03-12 CL CL2009000586A patent/CL2009000586A1/es unknown
- 2009-03-13 TW TW098108296A patent/TW201000126A/zh unknown
- 2009-03-17 JP JP2011501904A patent/JP5438095B2/ja not_active Expired - Fee Related
- 2009-03-17 EP EP09726006A patent/EP2268670A1/en not_active Withdrawn
- 2009-03-17 BR BRPI0910118A patent/BRPI0910118A2/pt not_active IP Right Cessation
- 2009-03-17 CA CA2719761A patent/CA2719761A1/en not_active Abandoned
- 2009-03-17 WO PCT/US2009/037349 patent/WO2009120530A1/en active Application Filing
- 2009-03-17 MX MX2010010517A patent/MX2010010517A/es not_active Application Discontinuation
- 2009-03-17 EA EA201071126A patent/EA201071126A1/ru unknown
- 2009-03-17 CN CN2009801107130A patent/CN101983208A/zh active Pending
- 2009-03-17 AU AU2009228866A patent/AU2009228866A1/en not_active Abandoned
- 2009-03-17 US US12/405,458 patent/US7968686B2/en not_active Expired - Fee Related
- 2009-03-17 KR KR1020107021297A patent/KR101235934B1/ko not_active IP Right Cessation
-
2011
- 2011-05-16 US US13/108,073 patent/US20110212092A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| Acta Crystallographica Section D Biological Crystallography. 2000, D56, pp.573-580 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201000126A (en) | 2010-01-01 |
| EP2268670A1 (en) | 2011-01-05 |
| CN101983208A (zh) | 2011-03-02 |
| JP2011518125A (ja) | 2011-06-23 |
| US20090252727A1 (en) | 2009-10-08 |
| AR070844A1 (es) | 2010-05-05 |
| MX2010010517A (es) | 2010-12-20 |
| BRPI0910118A2 (pt) | 2015-12-29 |
| CA2719761A1 (en) | 2009-10-01 |
| US7968686B2 (en) | 2011-06-28 |
| EA201071126A1 (ru) | 2011-04-29 |
| WO2009120530A1 (en) | 2009-10-01 |
| JP5438095B2 (ja) | 2014-03-12 |
| CL2009000586A1 (es) | 2010-06-04 |
| US20110212092A1 (en) | 2011-09-01 |
| PE20091674A1 (es) | 2009-11-04 |
| KR20100117130A (ko) | 2010-11-02 |
| AU2009228866A1 (en) | 2009-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101235934B1 (ko) | 글루카곤 수용체 길항제 | |
| US10882916B2 (en) | Anti-C5a receptor antibodies | |
| US20220204615A1 (en) | Caninized Antibodies | |
| CN102971342B (zh) | 亲和力降低的新抗体和制备所述抗体的方法 | |
| US9447182B2 (en) | Antibodies directed against the alpha chain of IL7 receptor—their use for the preparation of drug candidates | |
| CN113248618B (zh) | 抗pd-l1/抗lag3双特异性抗体及其用途 | |
| TW202041537A (zh) | 針對lag-3之工程化抗體及自其製備之雙特異性pd-1/lag-3結合蛋白 | |
| CN109721656A (zh) | 靶向rankl的治疗性抗体 | |
| EP2336188A1 (en) | Novel antagonist antibodies and their Fab fragments against GPVI and uses thereof | |
| KR20240021162A (ko) | Alpha 5 베타 1 인테그린 결합제 및 이의 용도 | |
| EP2397495A1 (en) | Novel antagonist antibodies and their Fab fragments against GPVI and uses thereof | |
| EP2402371A1 (en) | Novel antagonist antibodies and their Fab fragments against GPVI and uses thereof | |
| TR201816428T4 (tr) | Terapötik antikorlar. | |
| MX2013013911A (es) | Anticuerpos terapeuticos. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| LAPS | Lapse due to unpaid annual fee |