CN117858721A - 用于治疗α-突触核蛋白病的抗体 - Google Patents
用于治疗α-突触核蛋白病的抗体 Download PDFInfo
- Publication number
- CN117858721A CN117858721A CN202280034495.2A CN202280034495A CN117858721A CN 117858721 A CN117858721 A CN 117858721A CN 202280034495 A CN202280034495 A CN 202280034495A CN 117858721 A CN117858721 A CN 117858721A
- Authority
- CN
- China
- Prior art keywords
- ser
- gly
- val
- leu
- thr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000032859 Synucleinopathies Diseases 0.000 title claims abstract description 23
- 230000027455 binding Effects 0.000 claims abstract description 185
- 239000000427 antigen Substances 0.000 claims abstract description 92
- 102000036639 antigens Human genes 0.000 claims abstract description 92
- 108091007433 antigens Proteins 0.000 claims abstract description 92
- 239000012634 fragment Substances 0.000 claims abstract description 89
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 21
- 102000003802 alpha-Synuclein Human genes 0.000 claims abstract description 15
- 108090000185 alpha-Synuclein Proteins 0.000 claims abstract description 15
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 claims abstract description 3
- 241000282414 Homo sapiens Species 0.000 claims description 82
- 210000004027 cell Anatomy 0.000 claims description 67
- 230000035772 mutation Effects 0.000 claims description 53
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 claims description 30
- 239000004570 mortar (masonry) Substances 0.000 claims description 29
- 108090000623 proteins and genes Proteins 0.000 claims description 27
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 24
- 208000018737 Parkinson disease Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 11
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 10
- 108020004707 nucleic acids Proteins 0.000 claims description 10
- 150000007523 nucleic acids Chemical class 0.000 claims description 10
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims description 8
- 238000004113 cell culture Methods 0.000 claims description 7
- 239000002773 nucleotide Substances 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 201000002832 Lewy body dementia Diseases 0.000 claims description 5
- 208000001089 Multiple system atrophy Diseases 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 2
- 210000004962 mammalian cell Anatomy 0.000 claims description 2
- 108091008324 binding proteins Proteins 0.000 abstract description 44
- 102000023732 binding proteins Human genes 0.000 abstract 3
- 230000015572 biosynthetic process Effects 0.000 description 73
- 238000003786 synthesis reaction Methods 0.000 description 73
- 102000014914 Carrier Proteins Human genes 0.000 description 41
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 36
- 210000004556 brain Anatomy 0.000 description 35
- 108090000765 processed proteins & peptides Proteins 0.000 description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 28
- 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 25
- 241000699666 Mus <mouse, genus> Species 0.000 description 25
- 201000010099 disease Diseases 0.000 description 24
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 24
- 108010089804 glycyl-threonine Proteins 0.000 description 24
- 239000002953 phosphate buffered saline Substances 0.000 description 24
- 206010057249 Phagocytosis Diseases 0.000 description 22
- 230000008782 phagocytosis Effects 0.000 description 22
- 108020004414 DNA Proteins 0.000 description 20
- 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 20
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 19
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 19
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 18
- 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 18
- 108010047857 aspartylglycine Proteins 0.000 description 18
- 108010031719 prolyl-serine Proteins 0.000 description 18
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 17
- 108010050848 glycylleucine Proteins 0.000 description 17
- 108010051242 phenylalanylserine Proteins 0.000 description 17
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 16
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 16
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 16
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 15
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 15
- 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 15
- 241000699670 Mus sp. Species 0.000 description 15
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 15
- 108010077112 prolyl-proline Proteins 0.000 description 15
- 241000880493 Leptailurus serval Species 0.000 description 14
- 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 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
- 238000004458 analytical method Methods 0.000 description 14
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 14
- 239000000178 monomer Substances 0.000 description 14
- GKKUBLFXKRDMFC-BQBZGAKWSA-N Asn-Pro-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O GKKUBLFXKRDMFC-BQBZGAKWSA-N 0.000 description 13
- SKQTXVZTCGSRJS-SRVKXCTJSA-N Asn-Tyr-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O SKQTXVZTCGSRJS-SRVKXCTJSA-N 0.000 description 13
- 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 13
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 13
- 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 13
- 108010079364 N-glycylalanine Proteins 0.000 description 13
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 13
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 13
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 13
- 108010092854 aspartyllysine Proteins 0.000 description 13
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 13
- 230000001737 promoting effect Effects 0.000 description 13
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 13
- 108010038745 tryptophylglycine Proteins 0.000 description 13
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 12
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 12
- 238000002965 ELISA Methods 0.000 description 12
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 12
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 12
- HGFGEMSVBMCFKK-MNXVOIDGSA-N Leu-Ile-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O HGFGEMSVBMCFKK-MNXVOIDGSA-N 0.000 description 12
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 12
- 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 12
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 12
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 12
- SJPDTIQHLBQPFO-VLCNGCBASA-N Thr-Tyr-Trp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O SJPDTIQHLBQPFO-VLCNGCBASA-N 0.000 description 12
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 12
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 12
- 108010037850 glycylvaline Proteins 0.000 description 12
- 108010057821 leucylproline Proteins 0.000 description 12
- 108010038320 lysylphenylalanine Proteins 0.000 description 12
- 108010070643 prolylglutamic acid Proteins 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108010073969 valyllysine Proteins 0.000 description 12
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 11
- 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 11
- 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 11
- 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 11
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 11
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 11
- 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 11
- 108010049041 glutamylalanine Proteins 0.000 description 11
- 210000001320 hippocampus Anatomy 0.000 description 11
- 108010000761 leucylarginine Proteins 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 10
- 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 10
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 10
- 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 10
- 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 10
- 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 10
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 10
- 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 10
- 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 10
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 10
- 108010081404 acein-2 Proteins 0.000 description 10
- 108010087924 alanylproline Proteins 0.000 description 10
- 210000001218 blood-brain barrier Anatomy 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 9
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 9
- DXVMJJNAOVECBA-WHFBIAKZSA-N Asn-Gly-Asn Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O DXVMJJNAOVECBA-WHFBIAKZSA-N 0.000 description 9
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 9
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 9
- 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 9
- 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 9
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 9
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 9
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 9
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 9
- 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 9
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 9
- YUPVPKZBKCLFLT-QTKMDUPCSA-N Thr-His-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N)O YUPVPKZBKCLFLT-QTKMDUPCSA-N 0.000 description 9
- 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 9
- 150000001413 amino acids Chemical group 0.000 description 9
- 230000008499 blood brain barrier function Effects 0.000 description 9
- 238000010494 dissociation reaction Methods 0.000 description 9
- 230000005593 dissociations Effects 0.000 description 9
- 108010078144 glutaminyl-glycine Proteins 0.000 description 9
- 108010015792 glycyllysine Proteins 0.000 description 9
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 9
- 108010073472 leucyl-prolyl-proline Proteins 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
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 8
- 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
- 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 8
- 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 8
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 8
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-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
- 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 8
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 8
- 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 8
- 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 8
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 8
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 8
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 8
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 8
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 8
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 8
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 8
- 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 8
- 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 8
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 8
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 8
- 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 8
- 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 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
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 8
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 8
- 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 8
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 8
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 8
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 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
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 8
- 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 8
- 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 8
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 8
- 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 8
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 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
- 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
- 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 8
- 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 8
- 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 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
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 8
- 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 8
- 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 8
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 8
- 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 8
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 8
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 8
- 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 8
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 8
- 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 8
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 8
- 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 8
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 8
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-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
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 8
- 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 8
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 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
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-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
- 108010008355 arginyl-glutamine Proteins 0.000 description 8
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 8
- 108010010147 glycylglutamine Proteins 0.000 description 8
- 108010018006 histidylserine Proteins 0.000 description 8
- 108010091871 leucylmethionine Proteins 0.000 description 8
- 108010003700 lysyl aspartic acid Proteins 0.000 description 8
- 108010064235 lysylglycine Proteins 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 8
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 8
- 238000003118 sandwich ELISA Methods 0.000 description 8
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 8
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-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
- ZGERHCJBLPQPGV-ACZMJKKPSA-N Cys-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N ZGERHCJBLPQPGV-ACZMJKKPSA-N 0.000 description 7
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 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
- 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 7
- LMDVGHQPPPLYAR-IHRRRGAJSA-N Leu-Val-His Chemical compound N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O LMDVGHQPPPLYAR-IHRRRGAJSA-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
- 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 7
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 7
- 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 7
- 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 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
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 7
- 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 7
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 7
- 108010038633 aspartylglutamate Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 210000005064 dopaminergic neuron Anatomy 0.000 description 7
- 238000011156 evaluation Methods 0.000 description 7
- 210000004602 germ cell Anatomy 0.000 description 7
- 108010017391 lysylvaline Proteins 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 210000003523 substantia nigra Anatomy 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- 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 6
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 6
- 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 6
- 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 6
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 6
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 6
- FNAJNWPDTIXYJN-CIUDSAMLSA-N Gln-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(N)=O FNAJNWPDTIXYJN-CIUDSAMLSA-N 0.000 description 6
- XUMFMAVDHQDATI-DCAQKATOSA-N Gln-Pro-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUMFMAVDHQDATI-DCAQKATOSA-N 0.000 description 6
- 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 6
- 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 6
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 6
- 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 6
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 6
- UIQGJYUEQDOODF-KWQFWETISA-N Gly-Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 UIQGJYUEQDOODF-KWQFWETISA-N 0.000 description 6
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- JOSAKOKSPXROGQ-BJDJZHNGSA-N Lys-Ser-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JOSAKOKSPXROGQ-BJDJZHNGSA-N 0.000 description 6
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 6
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 6
- 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 6
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 6
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 6
- 230000005540 biological transmission Effects 0.000 description 6
- 210000005013 brain tissue Anatomy 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 108010060199 cysteinylproline Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 6
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 6
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 6
- 230000005847 immunogenicity Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 108010073101 phenylalanylleucine Proteins 0.000 description 6
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 6
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 6
- AKEBUSZTMQLNIX-UWJYBYFXSA-N Asn-Ala-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N AKEBUSZTMQLNIX-UWJYBYFXSA-N 0.000 description 5
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 5
- ZUNMTUPRQMWMHX-LSJOCFKGSA-N Asp-Val-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O ZUNMTUPRQMWMHX-LSJOCFKGSA-N 0.000 description 5
- RRIJEABIXPKSGP-FXQIFTODSA-N Cys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CS RRIJEABIXPKSGP-FXQIFTODSA-N 0.000 description 5
- NSTUFLGQJCOCDL-UWVGGRQHSA-N Gly-Leu-Arg Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NSTUFLGQJCOCDL-UWVGGRQHSA-N 0.000 description 5
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 5
- DTPGSUQHUMELQB-GVARAGBVSA-N Ile-Tyr-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 DTPGSUQHUMELQB-GVARAGBVSA-N 0.000 description 5
- KXODZBLFVFSLAI-AVGNSLFASA-N Leu-His-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 KXODZBLFVFSLAI-AVGNSLFASA-N 0.000 description 5
- VKVDRTGWLVZJOM-DCAQKATOSA-N Leu-Val-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O VKVDRTGWLVZJOM-DCAQKATOSA-N 0.000 description 5
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 5
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 5
- GSCVDSBEYVGMJQ-SRVKXCTJSA-N Ser-Tyr-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)O GSCVDSBEYVGMJQ-SRVKXCTJSA-N 0.000 description 5
- NQQMWWVVGIXUOX-SVSWQMSJSA-N Thr-Ser-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NQQMWWVVGIXUOX-SVSWQMSJSA-N 0.000 description 5
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 5
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 5
- 210000004727 amygdala Anatomy 0.000 description 5
- 108010068265 aspartyltyrosine Proteins 0.000 description 5
- 210000003710 cerebral cortex Anatomy 0.000 description 5
- 210000001947 dentate gyrus Anatomy 0.000 description 5
- 230000016784 immunoglobulin production Effects 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 230000002025 microglial effect Effects 0.000 description 5
- 108010029020 prolylglycine Proteins 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000013207 serial dilution Methods 0.000 description 5
- 108010003137 tyrosyltyrosine Proteins 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XUCIJNAGGSZNQT-JHSLDZJXSA-N (R)-amygdalin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O[C@@H](C#N)C=2C=CC=CC=2)O1 XUCIJNAGGSZNQT-JHSLDZJXSA-N 0.000 description 4
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 4
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 4
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 4
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 4
- WZZSKAJIHTUUSG-ACZMJKKPSA-N Glu-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O WZZSKAJIHTUUSG-ACZMJKKPSA-N 0.000 description 4
- IALQAMYQJBZNSK-WHFBIAKZSA-N Gly-Ser-Asn Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O IALQAMYQJBZNSK-WHFBIAKZSA-N 0.000 description 4
- 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 4
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 4
- 108010065920 Insulin Lispro Proteins 0.000 description 4
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 4
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 4
- ISHNZELVUVPCHY-ZETCQYMHSA-N Lys-Gly-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O ISHNZELVUVPCHY-ZETCQYMHSA-N 0.000 description 4
- QWTGQXGNNMIUCW-BPUTZDHNSA-N Met-Asn-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QWTGQXGNNMIUCW-BPUTZDHNSA-N 0.000 description 4
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 4
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 4
- 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 4
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 4
- 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 4
- 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 4
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 4
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 4
- 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 4
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 4
- 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 4
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 4
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 4
- 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 4
- 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 4
- BABINGWMZBWXIX-BPUTZDHNSA-N Trp-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N BABINGWMZBWXIX-BPUTZDHNSA-N 0.000 description 4
- 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 4
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 4
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 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 4
- 229940089837 amygdalin Drugs 0.000 description 4
- YZLOSXFCSIDECK-UHFFFAOYSA-N amygdalin Natural products OCC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC(C#N)c3ccccc3 YZLOSXFCSIDECK-UHFFFAOYSA-N 0.000 description 4
- 108010062796 arginyllysine Proteins 0.000 description 4
- 108010060035 arginylproline Proteins 0.000 description 4
- 108010077245 asparaginyl-proline Proteins 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- YGHHWSRCTPQFFC-UHFFFAOYSA-N eucalyptosin A Natural products OC1C(O)C(O)C(CO)OC1OC1C(OC(C#N)C=2C=CC=CC=2)OC(CO)C(O)C1O YGHHWSRCTPQFFC-UHFFFAOYSA-N 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- XWTNPSHCJMZAHQ-QMMMGPOBSA-N 2-[[2-[[2-[[(2s)-2-amino-4-methylpentanoyl]amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(=O)NCC(O)=O XWTNPSHCJMZAHQ-QMMMGPOBSA-N 0.000 description 3
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-N 0.000 description 3
- GORKKVHIBWAQHM-GCJQMDKQSA-N Ala-Asn-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GORKKVHIBWAQHM-GCJQMDKQSA-N 0.000 description 3
- 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 3
- NBTGEURICRTMGL-WHFBIAKZSA-N Ala-Gly-Ser Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O NBTGEURICRTMGL-WHFBIAKZSA-N 0.000 description 3
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 3
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 3
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 3
- 108700028369 Alleles Proteins 0.000 description 3
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 3
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 3
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 3
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 3
- KNMRXHIAVXHCLW-ZLUOBGJFSA-N Asp-Asn-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O KNMRXHIAVXHCLW-ZLUOBGJFSA-N 0.000 description 3
- DCJNIJAWIRPPBB-CIUDSAMLSA-N Cys-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N DCJNIJAWIRPPBB-CIUDSAMLSA-N 0.000 description 3
- XLLSMEFANRROJE-GUBZILKMSA-N Cys-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N XLLSMEFANRROJE-GUBZILKMSA-N 0.000 description 3
- 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 3
- 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 3
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 3
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 3
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 3
- 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 3
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 3
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 3
- 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 3
- WSWWTQYHFCBKBT-DVJZZOLTSA-N Gly-Thr-Trp Chemical compound C[C@@H](O)[C@H](NC(=O)CN)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O WSWWTQYHFCBKBT-DVJZZOLTSA-N 0.000 description 3
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 3
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 3
- LBRCLQMZAHRTLV-ZKWXMUAHSA-N Ile-Gly-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LBRCLQMZAHRTLV-ZKWXMUAHSA-N 0.000 description 3
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 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 3
- 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 3
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 3
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 3
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 3
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 3
- MNGBICITWAPGAS-BPUTZDHNSA-N Met-Ser-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MNGBICITWAPGAS-BPUTZDHNSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 3
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 3
- 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 3
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 3
- 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 3
- YMEXHZTVKDAKIY-GHCJXIJMSA-N Ser-Asn-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(O)=O YMEXHZTVKDAKIY-GHCJXIJMSA-N 0.000 description 3
- GVIGVIOEYBOTCB-XIRDDKMYSA-N Ser-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC(C)C)C(O)=O)=CNC2=C1 GVIGVIOEYBOTCB-XIRDDKMYSA-N 0.000 description 3
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 3
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 3
- 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 3
- 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 3
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 3
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 3
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 3
- FBQHKSPOIAFUEI-OWLDWWDNSA-N Thr-Trp-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O FBQHKSPOIAFUEI-OWLDWWDNSA-N 0.000 description 3
- 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 3
- FQNUWOHNGJWNLM-QWRGUYRKSA-N Tyr-Cys-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FQNUWOHNGJWNLM-QWRGUYRKSA-N 0.000 description 3
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 3
- AGKDVLSDNSTLFA-UMNHJUIQSA-N Val-Gln-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N AGKDVLSDNSTLFA-UMNHJUIQSA-N 0.000 description 3
- 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 3
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 3
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 3
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 108010016616 cysteinylglycine Proteins 0.000 description 3
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 3
- 102000045648 human IGF1R Human genes 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 108010073093 leucyl-glycyl-glycyl-glycine Proteins 0.000 description 3
- 210000004558 lewy body Anatomy 0.000 description 3
- 210000000274 microglia Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- HMRWQTHUDVXMGH-GUBZILKMSA-N Ala-Glu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN HMRWQTHUDVXMGH-GUBZILKMSA-N 0.000 description 2
- 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 2
- OZNSCVPYWZRQPY-CIUDSAMLSA-N Arg-Asp-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OZNSCVPYWZRQPY-CIUDSAMLSA-N 0.000 description 2
- ATABBWFGOHKROJ-GUBZILKMSA-N Arg-Pro-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O ATABBWFGOHKROJ-GUBZILKMSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 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 2
- OXOQBEVULIBOSH-ZDLURKLDSA-N Cys-Gly-Thr Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O OXOQBEVULIBOSH-ZDLURKLDSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 2
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 2
- ZBKUIQNCRIYVGH-SDDRHHMPSA-N Gln-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZBKUIQNCRIYVGH-SDDRHHMPSA-N 0.000 description 2
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 2
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 2
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- HILMIYALTUQTRC-XVKPBYJWSA-N Glu-Gly-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HILMIYALTUQTRC-XVKPBYJWSA-N 0.000 description 2
- NTHIHAUEXVTXQG-KKUMJFAQSA-N Glu-Tyr-Arg Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O NTHIHAUEXVTXQG-KKUMJFAQSA-N 0.000 description 2
- JBRBACJPBZNFMF-YUMQZZPRSA-N Gly-Ala-Lys Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN JBRBACJPBZNFMF-YUMQZZPRSA-N 0.000 description 2
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 2
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 2
- VDCRBJACQKOSMS-JSGCOSHPSA-N Gly-Phe-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O VDCRBJACQKOSMS-JSGCOSHPSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- 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 2
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 2
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 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 2
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- KUIDCYNIEJBZBU-AJNGGQMLSA-N Leu-Ile-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O KUIDCYNIEJBZBU-AJNGGQMLSA-N 0.000 description 2
- 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 2
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 2
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 2
- 208000009829 Lewy Body Disease Diseases 0.000 description 2
- 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 2
- 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 2
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 2
- KSIPKXNIQOWMIC-RCWTZXSCSA-N Met-Thr-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KSIPKXNIQOWMIC-RCWTZXSCSA-N 0.000 description 2
- 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 2
- LRBSWBVUCLLRLU-BZSNNMDCSA-N Phe-Leu-Lys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(O)=O LRBSWBVUCLLRLU-BZSNNMDCSA-N 0.000 description 2
- 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 2
- 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 2
- ZOGICTVLQDWPER-UFYCRDLUSA-N Phe-Tyr-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O ZOGICTVLQDWPER-UFYCRDLUSA-N 0.000 description 2
- VCYJKOLZYPYGJV-AVGNSLFASA-N Pro-Arg-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VCYJKOLZYPYGJV-AVGNSLFASA-N 0.000 description 2
- ICTZKEXYDDZZFP-SRVKXCTJSA-N Pro-Arg-Pro Chemical compound N([C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(O)=O)C(=O)[C@@H]1CCCN1 ICTZKEXYDDZZFP-SRVKXCTJSA-N 0.000 description 2
- XROLYVMNVIKVEM-BQBZGAKWSA-N Pro-Asn-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O XROLYVMNVIKVEM-BQBZGAKWSA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 2
- 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 2
- 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 2
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 2
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 2
- 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 2
- 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 2
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 2
- 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 2
- 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 2
- DANHCMVVXDXOHN-SRVKXCTJSA-N Tyr-Asp-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DANHCMVVXDXOHN-SRVKXCTJSA-N 0.000 description 2
- 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 2
- 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 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 2
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 2
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 2
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 2
- 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 2
- 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 2
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 2
- 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 2
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 2
- YQYFYUSYEDNLSD-YEPSODPASA-N Val-Thr-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O YQYFYUSYEDNLSD-YEPSODPASA-N 0.000 description 2
- 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 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 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 2
- 238000011534 incubation Methods 0.000 description 2
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 2
- 108010053037 kyotorphin Proteins 0.000 description 2
- 108010012058 leucyltyrosine Proteins 0.000 description 2
- 108010009298 lysylglutamic acid Proteins 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 210000002241 neurite Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000007331 pathological accumulation Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 2
- 108010020532 tyrosyl-proline Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- KUHSEZKIEJYEHN-BXRBKJIMSA-N (2s)-2-amino-3-hydroxypropanoic acid;(2s)-2-aminopropanoic acid Chemical compound C[C@H](N)C(O)=O.OC[C@H](N)C(O)=O KUHSEZKIEJYEHN-BXRBKJIMSA-N 0.000 description 1
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- DKJPOZOEBONHFS-ZLUOBGJFSA-N Ala-Ala-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O DKJPOZOEBONHFS-ZLUOBGJFSA-N 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 1
- JAMAWBXXKFGFGX-KZVJFYERSA-N Ala-Arg-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JAMAWBXXKFGFGX-KZVJFYERSA-N 0.000 description 1
- ZIBWKCRKNFYTPT-ZKWXMUAHSA-N Ala-Asn-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O ZIBWKCRKNFYTPT-ZKWXMUAHSA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- WJRXVTCKASUIFF-FXQIFTODSA-N Ala-Cys-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WJRXVTCKASUIFF-FXQIFTODSA-N 0.000 description 1
- VIGKUFXFTPWYER-BIIVOSGPSA-N Ala-Cys-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N VIGKUFXFTPWYER-BIIVOSGPSA-N 0.000 description 1
- MIPWEZAIMPYQST-FXQIFTODSA-N Ala-Cys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O MIPWEZAIMPYQST-FXQIFTODSA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- BLIMFWGRQKRCGT-YUMQZZPRSA-N Ala-Gly-Lys Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN BLIMFWGRQKRCGT-YUMQZZPRSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- RZZMZYZXNJRPOJ-BJDJZHNGSA-N Ala-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C)N RZZMZYZXNJRPOJ-BJDJZHNGSA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- CJQAEJMHBAOQHA-DLOVCJGASA-N Ala-Phe-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CJQAEJMHBAOQHA-DLOVCJGASA-N 0.000 description 1
- FQNILRVJOJBFFC-FXQIFTODSA-N Ala-Pro-Asp Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N FQNILRVJOJBFFC-FXQIFTODSA-N 0.000 description 1
- OLVCTPPSXNRGKV-GUBZILKMSA-N Ala-Pro-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OLVCTPPSXNRGKV-GUBZILKMSA-N 0.000 description 1
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 1
- OMCKWYSDUQBYCN-FXQIFTODSA-N Ala-Ser-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O OMCKWYSDUQBYCN-FXQIFTODSA-N 0.000 description 1
- 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 1
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 1
- XKXAZPSREVUCRT-BPNCWPANSA-N Ala-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=C(O)C=C1 XKXAZPSREVUCRT-BPNCWPANSA-N 0.000 description 1
- 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 1
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 1
- XEPSCVXTCUUHDT-AVGNSLFASA-N Arg-Arg-Leu Natural products CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N XEPSCVXTCUUHDT-AVGNSLFASA-N 0.000 description 1
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 1
- TTXYKSADPSNOIF-IHRRRGAJSA-N Arg-Asp-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O TTXYKSADPSNOIF-IHRRRGAJSA-N 0.000 description 1
- VXXHDZKEQNGXNU-QXEWZRGKSA-N Arg-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N VXXHDZKEQNGXNU-QXEWZRGKSA-N 0.000 description 1
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 1
- BEXGZLUHRXTZCC-CIUDSAMLSA-N Arg-Gln-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N BEXGZLUHRXTZCC-CIUDSAMLSA-N 0.000 description 1
- QAODJPUKWNNNRP-DCAQKATOSA-N Arg-Glu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QAODJPUKWNNNRP-DCAQKATOSA-N 0.000 description 1
- NYZGVTGOMPHSJW-CIUDSAMLSA-N Arg-Glu-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N NYZGVTGOMPHSJW-CIUDSAMLSA-N 0.000 description 1
- OGUPCHKBOKJFMA-SRVKXCTJSA-N Arg-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N OGUPCHKBOKJFMA-SRVKXCTJSA-N 0.000 description 1
- CRCCTGPNZUCAHE-DCAQKATOSA-N Arg-His-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CN=CN1 CRCCTGPNZUCAHE-DCAQKATOSA-N 0.000 description 1
- YQGZIRIYGHNSQO-ZPFDUUQYSA-N Arg-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](CCCN=C(N)N)N YQGZIRIYGHNSQO-ZPFDUUQYSA-N 0.000 description 1
- FSNVAJOPUDVQAR-AVGNSLFASA-N Arg-Lys-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FSNVAJOPUDVQAR-AVGNSLFASA-N 0.000 description 1
- PSOPJDUQUVFSLS-GUBZILKMSA-N Arg-Met-Cys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N PSOPJDUQUVFSLS-GUBZILKMSA-N 0.000 description 1
- VIINVRPKMUZYOI-DCAQKATOSA-N Arg-Met-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O VIINVRPKMUZYOI-DCAQKATOSA-N 0.000 description 1
- 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 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- YFHATWYGAAXQCF-JYJNAYRXSA-N Arg-Pro-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YFHATWYGAAXQCF-JYJNAYRXSA-N 0.000 description 1
- 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 1
- VENMDXUVHSKEIN-GUBZILKMSA-N Arg-Ser-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VENMDXUVHSKEIN-GUBZILKMSA-N 0.000 description 1
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 1
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 1
- SYFHFLGAROUHNT-VEVYYDQMSA-N Arg-Thr-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SYFHFLGAROUHNT-VEVYYDQMSA-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
- BXLDDWZOTGGNOJ-SZMVWBNQSA-N Arg-Trp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N BXLDDWZOTGGNOJ-SZMVWBNQSA-N 0.000 description 1
- SWLOHUMCUDRTCL-ZLUOBGJFSA-N Asn-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N SWLOHUMCUDRTCL-ZLUOBGJFSA-N 0.000 description 1
- YJRORCOAFUZVKA-FXQIFTODSA-N Asn-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N YJRORCOAFUZVKA-FXQIFTODSA-N 0.000 description 1
- MEFGKQUUYZOLHM-GMOBBJLQSA-N Asn-Arg-Ile 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)CC)C(O)=O MEFGKQUUYZOLHM-GMOBBJLQSA-N 0.000 description 1
- JJGRJMKUOYXZRA-LPEHRKFASA-N Asn-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)C(=O)O JJGRJMKUOYXZRA-LPEHRKFASA-N 0.000 description 1
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 1
- XQQVCUIBGYFKDC-OLHMAJIHSA-N Asn-Asp-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XQQVCUIBGYFKDC-OLHMAJIHSA-N 0.000 description 1
- IYVSIZAXNLOKFQ-BYULHYEWSA-N Asn-Asp-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IYVSIZAXNLOKFQ-BYULHYEWSA-N 0.000 description 1
- ULRPXVNMIIYDDJ-ACZMJKKPSA-N Asn-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N ULRPXVNMIIYDDJ-ACZMJKKPSA-N 0.000 description 1
- MECFLTFREHAZLH-ACZMJKKPSA-N Asn-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N MECFLTFREHAZLH-ACZMJKKPSA-N 0.000 description 1
- BZMWJLLUAKSIMH-FXQIFTODSA-N Asn-Glu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BZMWJLLUAKSIMH-FXQIFTODSA-N 0.000 description 1
- JZDZLBJVYWIIQU-AVGNSLFASA-N Asn-Glu-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JZDZLBJVYWIIQU-AVGNSLFASA-N 0.000 description 1
- GJFYPBDMUGGLFR-NKWVEPMBSA-N Asn-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC(=O)N)N)C(=O)O GJFYPBDMUGGLFR-NKWVEPMBSA-N 0.000 description 1
- FTCGGKNCJZOPNB-WHFBIAKZSA-N Asn-Gly-Ser Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FTCGGKNCJZOPNB-WHFBIAKZSA-N 0.000 description 1
- QEQVUHQQYDZUEN-GUBZILKMSA-N Asn-His-Glu Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N QEQVUHQQYDZUEN-GUBZILKMSA-N 0.000 description 1
- NKLRWRRVYGQNIH-GHCJXIJMSA-N Asn-Ile-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O NKLRWRRVYGQNIH-GHCJXIJMSA-N 0.000 description 1
- NLRJGXZWTKXRHP-DCAQKATOSA-N Asn-Leu-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NLRJGXZWTKXRHP-DCAQKATOSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 1
- MVXJBVVLACEGCG-PCBIJLKTSA-N Asn-Phe-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVXJBVVLACEGCG-PCBIJLKTSA-N 0.000 description 1
- HZZIFFOVHLWGCS-KKUMJFAQSA-N Asn-Phe-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O HZZIFFOVHLWGCS-KKUMJFAQSA-N 0.000 description 1
- YUOXLJYVSZYPBJ-CIUDSAMLSA-N Asn-Pro-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O YUOXLJYVSZYPBJ-CIUDSAMLSA-N 0.000 description 1
- AWXDRZJQCVHCIT-DCAQKATOSA-N Asn-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(N)=O AWXDRZJQCVHCIT-DCAQKATOSA-N 0.000 description 1
- OOXUBGLNDRGOKT-FXQIFTODSA-N Asn-Ser-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OOXUBGLNDRGOKT-FXQIFTODSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- UXHYOWXTJLBEPG-GSSVUCPTSA-N Asn-Thr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UXHYOWXTJLBEPG-GSSVUCPTSA-N 0.000 description 1
- CPYHLXSGDBDULY-IHPCNDPISA-N Asn-Trp-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CPYHLXSGDBDULY-IHPCNDPISA-N 0.000 description 1
- QIRJQYQOIKBPBZ-IHRRRGAJSA-N Asn-Tyr-Arg 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](CCCNC(N)=N)C(O)=O QIRJQYQOIKBPBZ-IHRRRGAJSA-N 0.000 description 1
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 1
- 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 1
- DATSKXOXPUAOLK-KKUMJFAQSA-N Asn-Tyr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O DATSKXOXPUAOLK-KKUMJFAQSA-N 0.000 description 1
- DPWDPEVGACCWTC-SRVKXCTJSA-N Asn-Tyr-Ser 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](CO)C(O)=O DPWDPEVGACCWTC-SRVKXCTJSA-N 0.000 description 1
- XEGZSHSPQNDNRH-JRQIVUDYSA-N Asn-Tyr-Thr 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)O)C(O)=O XEGZSHSPQNDNRH-JRQIVUDYSA-N 0.000 description 1
- ZAESWDKAMDVHLL-RCOVLWMOSA-N Asn-Val-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O ZAESWDKAMDVHLL-RCOVLWMOSA-N 0.000 description 1
- MFMJRYHVLLEMQM-DCAQKATOSA-N Asp-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](CC(=O)O)N MFMJRYHVLLEMQM-DCAQKATOSA-N 0.000 description 1
- BFOYULZBKYOKAN-OLHMAJIHSA-N Asp-Asp-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BFOYULZBKYOKAN-OLHMAJIHSA-N 0.000 description 1
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 1
- ZEDBMCPXPIYJLW-XHNCKOQMSA-N Asp-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O ZEDBMCPXPIYJLW-XHNCKOQMSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- KQBVNNAPIURMPD-PEFMBERDSA-N Asp-Ile-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KQBVNNAPIURMPD-PEFMBERDSA-N 0.000 description 1
- SPKCGKRUYKMDHP-GUDRVLHUSA-N Asp-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N SPKCGKRUYKMDHP-GUDRVLHUSA-N 0.000 description 1
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 1
- AITKTFCQOBRJTG-CIUDSAMLSA-N Asp-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N AITKTFCQOBRJTG-CIUDSAMLSA-N 0.000 description 1
- DWOGMPWRQQWPPF-GUBZILKMSA-N Asp-Leu-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O DWOGMPWRQQWPPF-GUBZILKMSA-N 0.000 description 1
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 1
- RQHLMGCXCZUOGT-ZPFDUUQYSA-N Asp-Leu-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RQHLMGCXCZUOGT-ZPFDUUQYSA-N 0.000 description 1
- HJCGDIGVVWETRO-ZPFDUUQYSA-N Asp-Lys-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O)C(O)=O HJCGDIGVVWETRO-ZPFDUUQYSA-N 0.000 description 1
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 1
- IOXWDLNHXZOXQP-FXQIFTODSA-N Asp-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N IOXWDLNHXZOXQP-FXQIFTODSA-N 0.000 description 1
- QJHOOKBAHRJPPX-QWRGUYRKSA-N Asp-Phe-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 QJHOOKBAHRJPPX-QWRGUYRKSA-N 0.000 description 1
- KESWRFKUZRUTAH-FXQIFTODSA-N Asp-Pro-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O KESWRFKUZRUTAH-FXQIFTODSA-N 0.000 description 1
- FAUPLTGRUBTXNU-FXQIFTODSA-N Asp-Pro-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O FAUPLTGRUBTXNU-FXQIFTODSA-N 0.000 description 1
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 1
- BRRPVTUFESPTCP-ACZMJKKPSA-N Asp-Ser-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O BRRPVTUFESPTCP-ACZMJKKPSA-N 0.000 description 1
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 1
- 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
- JDDYEZGPYBBPBN-JRQIVUDYSA-N Asp-Thr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JDDYEZGPYBBPBN-JRQIVUDYSA-N 0.000 description 1
- DKQCWCQRAMAFLN-UBHSHLNASA-N Asp-Trp-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(O)=O)C(O)=O DKQCWCQRAMAFLN-UBHSHLNASA-N 0.000 description 1
- HCOQNGIHSXICCB-IHRRRGAJSA-N Asp-Tyr-Arg Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)O HCOQNGIHSXICCB-IHRRRGAJSA-N 0.000 description 1
- OYSYWMMZGJSQRB-AVGNSLFASA-N Asp-Tyr-Gln 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](CCC(N)=O)C(O)=O OYSYWMMZGJSQRB-AVGNSLFASA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu 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](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- XMKXONRMGJXCJV-LAEOZQHASA-N Asp-Val-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XMKXONRMGJXCJV-LAEOZQHASA-N 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 241001573498 Compacta Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- PLBJMUUEGBBHRH-ZLUOBGJFSA-N Cys-Ala-Asn Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O PLBJMUUEGBBHRH-ZLUOBGJFSA-N 0.000 description 1
- HYKFOHGZGLOCAY-ZLUOBGJFSA-N Cys-Cys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O HYKFOHGZGLOCAY-ZLUOBGJFSA-N 0.000 description 1
- UXUSHQYYQCZWET-WDSKDSINSA-N Cys-Glu-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O UXUSHQYYQCZWET-WDSKDSINSA-N 0.000 description 1
- DZLQXIFVQFTFJY-BYPYZUCNSA-N Cys-Gly-Gly Chemical compound SC[C@H](N)C(=O)NCC(=O)NCC(O)=O DZLQXIFVQFTFJY-BYPYZUCNSA-N 0.000 description 1
- 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 1
- WTNLLMQAFPOCTJ-GARJFASQSA-N Cys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CS)N)C(=O)O WTNLLMQAFPOCTJ-GARJFASQSA-N 0.000 description 1
- ODDOYXKAHLKKQY-MMWGEVLESA-N Cys-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CS)N ODDOYXKAHLKKQY-MMWGEVLESA-N 0.000 description 1
- KJJASVYBTKRYSN-FXQIFTODSA-N Cys-Pro-Asp Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CC(=O)O)C(=O)O KJJASVYBTKRYSN-FXQIFTODSA-N 0.000 description 1
- HMWBPUDETPKSSS-DCAQKATOSA-N Cys-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CCCCN)C(=O)O HMWBPUDETPKSSS-DCAQKATOSA-N 0.000 description 1
- SWJYSDXMTPMBHO-FXQIFTODSA-N Cys-Pro-Ser Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SWJYSDXMTPMBHO-FXQIFTODSA-N 0.000 description 1
- WZJLBUPPZRZNTO-CIUDSAMLSA-N Cys-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N WZJLBUPPZRZNTO-CIUDSAMLSA-N 0.000 description 1
- JAHCWGSVNZXHRR-SVSWQMSJSA-N Cys-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)N JAHCWGSVNZXHRR-SVSWQMSJSA-N 0.000 description 1
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 1
- KARBMKZDLYMMOW-JYBASQMISA-N Cys-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CS)N)O KARBMKZDLYMMOW-JYBASQMISA-N 0.000 description 1
- DGQJGBDBFVGLGL-ZKWXMUAHSA-N Cys-Val-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N DGQJGBDBFVGLGL-ZKWXMUAHSA-N 0.000 description 1
- QQAYIVHVRFJICE-AEJSXWLSSA-N Cys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CS)N QQAYIVHVRFJICE-AEJSXWLSSA-N 0.000 description 1
- LPBUBIHAVKXUOT-FXQIFTODSA-N Cys-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N LPBUBIHAVKXUOT-FXQIFTODSA-N 0.000 description 1
- 108010090461 DFG peptide Proteins 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 description 1
- 101710163305 Fibril protein Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010072062 GEKG peptide Proteins 0.000 description 1
- MLZRSFQRBDNJON-GUBZILKMSA-N Gln-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MLZRSFQRBDNJON-GUBZILKMSA-N 0.000 description 1
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 1
- CYTSBCIIEHUPDU-ACZMJKKPSA-N Gln-Asp-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O CYTSBCIIEHUPDU-ACZMJKKPSA-N 0.000 description 1
- WQWMZOIPXWSZNE-WDSKDSINSA-N Gln-Asp-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O WQWMZOIPXWSZNE-WDSKDSINSA-N 0.000 description 1
- KVXVVDFOZNYYKZ-DCAQKATOSA-N Gln-Gln-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O KVXVVDFOZNYYKZ-DCAQKATOSA-N 0.000 description 1
- DDNIZQDYXDENIT-FXQIFTODSA-N Gln-Glu-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N DDNIZQDYXDENIT-FXQIFTODSA-N 0.000 description 1
- 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 1
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 1
- ORYMMTRPKVTGSJ-XVKPBYJWSA-N Gln-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O ORYMMTRPKVTGSJ-XVKPBYJWSA-N 0.000 description 1
- QKCZZAZNMMVICF-DCAQKATOSA-N Gln-Leu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O QKCZZAZNMMVICF-DCAQKATOSA-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
- WEAVZFWWIPIANL-SRVKXCTJSA-N Gln-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N WEAVZFWWIPIANL-SRVKXCTJSA-N 0.000 description 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- IRDASPPCLZIERZ-XHNCKOQMSA-N Glu-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N IRDASPPCLZIERZ-XHNCKOQMSA-N 0.000 description 1
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 1
- RCCDHXSRMWCOOY-GUBZILKMSA-N Glu-Arg-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCCDHXSRMWCOOY-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- SBYVDRJAXWSXQL-AVGNSLFASA-N Glu-Asn-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SBYVDRJAXWSXQL-AVGNSLFASA-N 0.000 description 1
- LXAUHIRMWXQRKI-XHNCKOQMSA-N Glu-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O LXAUHIRMWXQRKI-XHNCKOQMSA-N 0.000 description 1
- RDDSZZJOKDVPAE-ACZMJKKPSA-N Glu-Asn-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDDSZZJOKDVPAE-ACZMJKKPSA-N 0.000 description 1
- VAIWPXWHWAPYDF-FXQIFTODSA-N Glu-Asp-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O VAIWPXWHWAPYDF-FXQIFTODSA-N 0.000 description 1
- CYHBMLHCQXXCCT-AVGNSLFASA-N Glu-Asp-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CYHBMLHCQXXCCT-AVGNSLFASA-N 0.000 description 1
- ZZIFPJZQHRJERU-WDSKDSINSA-N Glu-Cys-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O ZZIFPJZQHRJERU-WDSKDSINSA-N 0.000 description 1
- RQNYYRHRKSVKAB-GUBZILKMSA-N Glu-Cys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O RQNYYRHRKSVKAB-GUBZILKMSA-N 0.000 description 1
- WLIPTFCZLHCNFD-LPEHRKFASA-N Glu-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O WLIPTFCZLHCNFD-LPEHRKFASA-N 0.000 description 1
- HTTSBEBKVNEDFE-AUTRQRHGSA-N Glu-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N HTTSBEBKVNEDFE-AUTRQRHGSA-N 0.000 description 1
- CGOHAEBMDSEKFB-FXQIFTODSA-N Glu-Glu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O CGOHAEBMDSEKFB-FXQIFTODSA-N 0.000 description 1
- BUZMZDDKFCSKOT-CIUDSAMLSA-N Glu-Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BUZMZDDKFCSKOT-CIUDSAMLSA-N 0.000 description 1
- AIGROOHQXCACHL-WDSKDSINSA-N Glu-Gly-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O AIGROOHQXCACHL-WDSKDSINSA-N 0.000 description 1
- ZWABFSSWTSAMQN-KBIXCLLPSA-N Glu-Ile-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O ZWABFSSWTSAMQN-KBIXCLLPSA-N 0.000 description 1
- ZCOJVESMNGBGLF-GRLWGSQLSA-N Glu-Ile-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZCOJVESMNGBGLF-GRLWGSQLSA-N 0.000 description 1
- KRRFFAHEAOCBCQ-SIUGBPQLSA-N Glu-Ile-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KRRFFAHEAOCBCQ-SIUGBPQLSA-N 0.000 description 1
- DWBBKNPKDHXIAC-SRVKXCTJSA-N Glu-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(O)=O DWBBKNPKDHXIAC-SRVKXCTJSA-N 0.000 description 1
- 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 1
- UJMNFCAHLYKWOZ-DCAQKATOSA-N Glu-Lys-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O UJMNFCAHLYKWOZ-DCAQKATOSA-N 0.000 description 1
- MFNUFCFRAZPJFW-JYJNAYRXSA-N Glu-Lys-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFNUFCFRAZPJFW-JYJNAYRXSA-N 0.000 description 1
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 1
- VNCNWQPIQYAMAK-ACZMJKKPSA-N Glu-Ser-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O VNCNWQPIQYAMAK-ACZMJKKPSA-N 0.000 description 1
- TWYSSILQABLLME-HJGDQZAQSA-N Glu-Thr-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYSSILQABLLME-HJGDQZAQSA-N 0.000 description 1
- BDISFWMLMNBTGP-NUMRIWBASA-N Glu-Thr-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O BDISFWMLMNBTGP-NUMRIWBASA-N 0.000 description 1
- QCMVGXDELYMZET-GLLZPBPUSA-N Glu-Thr-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QCMVGXDELYMZET-GLLZPBPUSA-N 0.000 description 1
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 1
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 1
- QXUPRMQJDWJDFR-NRPADANISA-N Glu-Val-Ser Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXUPRMQJDWJDFR-NRPADANISA-N 0.000 description 1
- SOYWRINXUSUWEQ-DLOVCJGASA-N Glu-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O SOYWRINXUSUWEQ-DLOVCJGASA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- 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 1
- 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 1
- LURCIJSJAKFCRO-QWRGUYRKSA-N Gly-Asn-Tyr Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LURCIJSJAKFCRO-QWRGUYRKSA-N 0.000 description 1
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 1
- UTYGDAHJBBDPBA-BYULHYEWSA-N Gly-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)CN UTYGDAHJBBDPBA-BYULHYEWSA-N 0.000 description 1
- LLZXNUUIBOALNY-QWRGUYRKSA-N Gly-Leu-Lys Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN LLZXNUUIBOALNY-QWRGUYRKSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- VLIJYPMATZSOLL-YUMQZZPRSA-N Gly-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN VLIJYPMATZSOLL-YUMQZZPRSA-N 0.000 description 1
- FXLVSYVJDPCIHH-STQMWFEESA-N Gly-Phe-Arg Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FXLVSYVJDPCIHH-STQMWFEESA-N 0.000 description 1
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 1
- BMWFDYIYBAFROD-WPRPVWTQSA-N Gly-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN BMWFDYIYBAFROD-WPRPVWTQSA-N 0.000 description 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
- HUFUVTYGPOUCBN-MBLNEYKQSA-N Gly-Thr-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HUFUVTYGPOUCBN-MBLNEYKQSA-N 0.000 description 1
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 1
- FXTUGWXZTFMTIV-GJZGRUSLSA-N Gly-Trp-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)CN FXTUGWXZTFMTIV-GJZGRUSLSA-N 0.000 description 1
- NWOSHVVPKDQKKT-RYUDHWBXSA-N Gly-Tyr-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O NWOSHVVPKDQKKT-RYUDHWBXSA-N 0.000 description 1
- UVTSZKIATYSKIR-RYUDHWBXSA-N Gly-Tyr-Glu Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O UVTSZKIATYSKIR-RYUDHWBXSA-N 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- 102100040482 HLA class II histocompatibility antigen, DR beta 3 chain Human genes 0.000 description 1
- 108010061311 HLA-DRB3 Chains Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- VSLXGYMEHVAJBH-DLOVCJGASA-N His-Ala-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O VSLXGYMEHVAJBH-DLOVCJGASA-N 0.000 description 1
- CIWILNZNBPIHEU-DCAQKATOSA-N His-Arg-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O CIWILNZNBPIHEU-DCAQKATOSA-N 0.000 description 1
- HRGGKHFHRSFSDE-CIUDSAMLSA-N His-Asn-Ser Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N HRGGKHFHRSFSDE-CIUDSAMLSA-N 0.000 description 1
- VOKCBYNCZVSILJ-KKUMJFAQSA-N His-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CN=CN2)N)O VOKCBYNCZVSILJ-KKUMJFAQSA-N 0.000 description 1
- ORZGPQXISSXQGW-IHRRRGAJSA-N His-His-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(O)=O ORZGPQXISSXQGW-IHRRRGAJSA-N 0.000 description 1
- JJHWJUYYTWYXPL-PYJNHQTQSA-N His-Ile-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CN=CN1 JJHWJUYYTWYXPL-PYJNHQTQSA-N 0.000 description 1
- BXOLYFJYQQRQDJ-MXAVVETBSA-N His-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CN=CN1)N BXOLYFJYQQRQDJ-MXAVVETBSA-N 0.000 description 1
- WKEABZIITNXXQZ-CIUDSAMLSA-N His-Ser-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N WKEABZIITNXXQZ-CIUDSAMLSA-N 0.000 description 1
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 1
- KECFCPNPPYCGBL-PMVMPFDFSA-N His-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CN=CN4)N KECFCPNPPYCGBL-PMVMPFDFSA-N 0.000 description 1
- HIJIJPFILYPTFR-ACRUOGEOSA-N His-Tyr-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HIJIJPFILYPTFR-ACRUOGEOSA-N 0.000 description 1
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 1
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 1
- 101000968028 Homo sapiens HLA class II histocompatibility antigen, DRB1 beta chain Proteins 0.000 description 1
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 1
- 101001092197 Homo sapiens RNA binding protein fox-1 homolog 3 Proteins 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- VAXBXNPRXPHGHG-BJDJZHNGSA-N Ile-Ala-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O)N VAXBXNPRXPHGHG-BJDJZHNGSA-N 0.000 description 1
- BOTVMTSMOUSDRW-GMOBBJLQSA-N Ile-Arg-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O BOTVMTSMOUSDRW-GMOBBJLQSA-N 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- YPQDTQJBOFOTJQ-SXTJYALSSA-N Ile-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N YPQDTQJBOFOTJQ-SXTJYALSSA-N 0.000 description 1
- UKTUOMWSJPXODT-GUDRVLHUSA-N Ile-Asn-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N UKTUOMWSJPXODT-GUDRVLHUSA-N 0.000 description 1
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 1
- BGZIJZJBXRVBGJ-SXTJYALSSA-N Ile-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N BGZIJZJBXRVBGJ-SXTJYALSSA-N 0.000 description 1
- MTFVYKQRLXYAQN-LAEOZQHASA-N Ile-Glu-Gly Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O MTFVYKQRLXYAQN-LAEOZQHASA-N 0.000 description 1
- FUOYNOXRWPJPAN-QEWYBTABSA-N Ile-Glu-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N FUOYNOXRWPJPAN-QEWYBTABSA-N 0.000 description 1
- WUKLZPHVWAMZQV-UKJIMTQDSA-N Ile-Glu-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N WUKLZPHVWAMZQV-UKJIMTQDSA-N 0.000 description 1
- UQXADIGYEYBJEI-DJFWLOJKSA-N Ile-His-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N UQXADIGYEYBJEI-DJFWLOJKSA-N 0.000 description 1
- AXNGDPAKKCEKGY-QPHKQPEJSA-N Ile-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N AXNGDPAKKCEKGY-QPHKQPEJSA-N 0.000 description 1
- HPCFRQWLTRDGHT-AJNGGQMLSA-N Ile-Leu-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O HPCFRQWLTRDGHT-AJNGGQMLSA-N 0.000 description 1
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 1
- RCMNUBZKIIJCOI-ZPFDUUQYSA-N Ile-Met-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N RCMNUBZKIIJCOI-ZPFDUUQYSA-N 0.000 description 1
- 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 1
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 1
- WLRJHVNFGAOYPS-HJPIBITLSA-N Ile-Ser-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N WLRJHVNFGAOYPS-HJPIBITLSA-N 0.000 description 1
- JJQQGCMKLOEGAV-OSUNSFLBSA-N Ile-Thr-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)O)N JJQQGCMKLOEGAV-OSUNSFLBSA-N 0.000 description 1
- NJGXXYLPDMMFJB-XUXIUFHCSA-N Ile-Val-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N NJGXXYLPDMMFJB-XUXIUFHCSA-N 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- WUFYAPWIHCUMLL-CIUDSAMLSA-N Leu-Asn-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O WUFYAPWIHCUMLL-CIUDSAMLSA-N 0.000 description 1
- IGUOAYLTQJLPPD-DCAQKATOSA-N Leu-Asn-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IGUOAYLTQJLPPD-DCAQKATOSA-N 0.000 description 1
- KKXDHFKZWKLYGB-GUBZILKMSA-N Leu-Asn-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KKXDHFKZWKLYGB-GUBZILKMSA-N 0.000 description 1
- BPANDPNDMJHFEV-CIUDSAMLSA-N Leu-Asp-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O BPANDPNDMJHFEV-CIUDSAMLSA-N 0.000 description 1
- ZURHXHNAEJJRNU-CIUDSAMLSA-N Leu-Asp-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ZURHXHNAEJJRNU-CIUDSAMLSA-N 0.000 description 1
- QCSFMCFHVGTLFF-NHCYSSNCSA-N Leu-Asp-Val Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O QCSFMCFHVGTLFF-NHCYSSNCSA-N 0.000 description 1
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 1
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 1
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 1
- HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 description 1
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 1
- FMEICTQWUKNAGC-YUMQZZPRSA-N Leu-Gly-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O FMEICTQWUKNAGC-YUMQZZPRSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- FIYMBBHGYNQFOP-IUCAKERBSA-N Leu-Gly-Gln Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N FIYMBBHGYNQFOP-IUCAKERBSA-N 0.000 description 1
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 1
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 1
- XBCWOTOCBXXJDG-BZSNNMDCSA-N Leu-His-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 XBCWOTOCBXXJDG-BZSNNMDCSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- KYIIALJHAOIAHF-KKUMJFAQSA-N Leu-Leu-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 KYIIALJHAOIAHF-KKUMJFAQSA-N 0.000 description 1
- ARRIJPQRBWRNLT-DCAQKATOSA-N Leu-Met-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ARRIJPQRBWRNLT-DCAQKATOSA-N 0.000 description 1
- JVTYXRRFZCEPPK-RHYQMDGZSA-N Leu-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)N)O JVTYXRRFZCEPPK-RHYQMDGZSA-N 0.000 description 1
- DRWMRVFCKKXHCH-BZSNNMDCSA-N Leu-Phe-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=CC=C1 DRWMRVFCKKXHCH-BZSNNMDCSA-N 0.000 description 1
- XWEVVRRSIOBJOO-SRVKXCTJSA-N Leu-Pro-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O XWEVVRRSIOBJOO-SRVKXCTJSA-N 0.000 description 1
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 1
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- IDGZVZJLYFTXSL-DCAQKATOSA-N Leu-Ser-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IDGZVZJLYFTXSL-DCAQKATOSA-N 0.000 description 1
- KZZCOWMDDXDKSS-CIUDSAMLSA-N Leu-Ser-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KZZCOWMDDXDKSS-CIUDSAMLSA-N 0.000 description 1
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 1
- RGUXWMDNCPMQFB-YUMQZZPRSA-N Leu-Ser-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RGUXWMDNCPMQFB-YUMQZZPRSA-N 0.000 description 1
- SQUFDMCWMFOEBA-KKUMJFAQSA-N Leu-Ser-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SQUFDMCWMFOEBA-KKUMJFAQSA-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
- GZRABTMNWJXFMH-UVOCVTCTSA-N Leu-Thr-Thr 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)O)C(O)=O GZRABTMNWJXFMH-UVOCVTCTSA-N 0.000 description 1
- HOMFINRJHIIZNJ-HOCLYGCPSA-N Leu-Trp-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)NCC(O)=O HOMFINRJHIIZNJ-HOCLYGCPSA-N 0.000 description 1
- UCRJTSIIAYHOHE-ULQDDVLXSA-N Leu-Tyr-Arg Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N UCRJTSIIAYHOHE-ULQDDVLXSA-N 0.000 description 1
- ARNIBBOXIAWUOP-MGHWNKPDSA-N Leu-Tyr-Ile 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]([C@@H](C)CC)C(O)=O ARNIBBOXIAWUOP-MGHWNKPDSA-N 0.000 description 1
- 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 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- PNPYKQFJGRFYJE-GUBZILKMSA-N Lys-Ala-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNPYKQFJGRFYJE-GUBZILKMSA-N 0.000 description 1
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 1
- WXJKFRMKJORORD-DCAQKATOSA-N Lys-Arg-Ala Chemical compound NC(=N)NCCC[C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CCCCN WXJKFRMKJORORD-DCAQKATOSA-N 0.000 description 1
- ALSRJRIWBNENFY-DCAQKATOSA-N Lys-Arg-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O ALSRJRIWBNENFY-DCAQKATOSA-N 0.000 description 1
- QYOXSYXPHUHOJR-GUBZILKMSA-N Lys-Asn-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYOXSYXPHUHOJR-GUBZILKMSA-N 0.000 description 1
- HIIZIQUUHIXUJY-GUBZILKMSA-N Lys-Asp-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HIIZIQUUHIXUJY-GUBZILKMSA-N 0.000 description 1
- WGCKDDHUFPQSMZ-ZPFDUUQYSA-N Lys-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)CCCCN WGCKDDHUFPQSMZ-ZPFDUUQYSA-N 0.000 description 1
- SSYOBDBNBQBSQE-SRVKXCTJSA-N Lys-Cys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O SSYOBDBNBQBSQE-SRVKXCTJSA-N 0.000 description 1
- DRCILAJNUJKAHC-SRVKXCTJSA-N Lys-Glu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DRCILAJNUJKAHC-SRVKXCTJSA-N 0.000 description 1
- PBIPLDMFHAICIP-DCAQKATOSA-N Lys-Glu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PBIPLDMFHAICIP-DCAQKATOSA-N 0.000 description 1
- GCMWRRQAKQXDED-IUCAKERBSA-N Lys-Glu-Gly Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)N[C@@H](CCC([O-])=O)C(=O)NCC([O-])=O GCMWRRQAKQXDED-IUCAKERBSA-N 0.000 description 1
- GPJGFSFYBJGYRX-YUMQZZPRSA-N Lys-Gly-Asp Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O GPJGFSFYBJGYRX-YUMQZZPRSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- HAUUXTXKJNVIFY-ONGXEEELSA-N Lys-Gly-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HAUUXTXKJNVIFY-ONGXEEELSA-N 0.000 description 1
- IVFUVMSKSFSFBT-NHCYSSNCSA-N Lys-Ile-Gly Chemical compound OC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN IVFUVMSKSFSFBT-NHCYSSNCSA-N 0.000 description 1
- WWEWGPOLIJXGNX-XUXIUFHCSA-N Lys-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)N WWEWGPOLIJXGNX-XUXIUFHCSA-N 0.000 description 1
- MTBBHUKKPWKXBT-ULQDDVLXSA-N Lys-Met-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MTBBHUKKPWKXBT-ULQDDVLXSA-N 0.000 description 1
- CRIODIGWCUPXKU-AVGNSLFASA-N Lys-Pro-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O CRIODIGWCUPXKU-AVGNSLFASA-N 0.000 description 1
- UQJOKDAYFULYIX-AVGNSLFASA-N Lys-Pro-Pro Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 UQJOKDAYFULYIX-AVGNSLFASA-N 0.000 description 1
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 1
- QFSYGUMEANRNJE-DCAQKATOSA-N Lys-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N QFSYGUMEANRNJE-DCAQKATOSA-N 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- ZAJNRWKGHWGPDQ-SDDRHHMPSA-N Met-Arg-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N ZAJNRWKGHWGPDQ-SDDRHHMPSA-N 0.000 description 1
- ACYHZNZHIZWLQF-BQBZGAKWSA-N Met-Asn-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ACYHZNZHIZWLQF-BQBZGAKWSA-N 0.000 description 1
- CAODKDAPYGUMLK-FXQIFTODSA-N Met-Asn-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CAODKDAPYGUMLK-FXQIFTODSA-N 0.000 description 1
- FVKRQMQQFGBXHV-QXEWZRGKSA-N Met-Asp-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O FVKRQMQQFGBXHV-QXEWZRGKSA-N 0.000 description 1
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 1
- PHWSCIFNNLLUFJ-NHCYSSNCSA-N Met-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N PHWSCIFNNLLUFJ-NHCYSSNCSA-N 0.000 description 1
- GPAHWYRSHCKICP-GUBZILKMSA-N Met-Glu-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O GPAHWYRSHCKICP-GUBZILKMSA-N 0.000 description 1
- OGAZPKJHHZPYFK-GARJFASQSA-N Met-Glu-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGAZPKJHHZPYFK-GARJFASQSA-N 0.000 description 1
- HLQWFLJOJRFXHO-CIUDSAMLSA-N Met-Glu-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O HLQWFLJOJRFXHO-CIUDSAMLSA-N 0.000 description 1
- MYAPQOBHGWJZOM-UWVGGRQHSA-N Met-Gly-Leu Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C MYAPQOBHGWJZOM-UWVGGRQHSA-N 0.000 description 1
- ZIIMORLEZLVRIP-SRVKXCTJSA-N Met-Leu-Gln Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZIIMORLEZLVRIP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- WPTHAGXMYDRPFD-SRVKXCTJSA-N Met-Lys-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O WPTHAGXMYDRPFD-SRVKXCTJSA-N 0.000 description 1
- CGUYGMFQZCYJSG-DCAQKATOSA-N Met-Lys-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O CGUYGMFQZCYJSG-DCAQKATOSA-N 0.000 description 1
- VQILILSLEFDECU-GUBZILKMSA-N Met-Pro-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O VQILILSLEFDECU-GUBZILKMSA-N 0.000 description 1
- BJPQKNHZHUCQNQ-SRVKXCTJSA-N Met-Pro-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N BJPQKNHZHUCQNQ-SRVKXCTJSA-N 0.000 description 1
- OVTOTTGZBWXLFU-QXEWZRGKSA-N Met-Val-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O OVTOTTGZBWXLFU-QXEWZRGKSA-N 0.000 description 1
- PVSPJQWHEIQTEH-JYJNAYRXSA-N Met-Val-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PVSPJQWHEIQTEH-JYJNAYRXSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- UUWCIPUVJJIEEP-SRVKXCTJSA-N Phe-Asn-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N UUWCIPUVJJIEEP-SRVKXCTJSA-N 0.000 description 1
- XXAOSEUPEMQJOF-KKUMJFAQSA-N Phe-Glu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 XXAOSEUPEMQJOF-KKUMJFAQSA-N 0.000 description 1
- JWQWPTLEOFNCGX-AVGNSLFASA-N Phe-Glu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 JWQWPTLEOFNCGX-AVGNSLFASA-N 0.000 description 1
- MMYUOSCXBJFUNV-QWRGUYRKSA-N Phe-Gly-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N MMYUOSCXBJFUNV-QWRGUYRKSA-N 0.000 description 1
- HNFUGJUZJRYUHN-JSGCOSHPSA-N Phe-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 HNFUGJUZJRYUHN-JSGCOSHPSA-N 0.000 description 1
- FXPZZKBHNOMLGA-HJWJTTGWSA-N Phe-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FXPZZKBHNOMLGA-HJWJTTGWSA-N 0.000 description 1
- RMKGXGPQIPLTFC-KKUMJFAQSA-N Phe-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RMKGXGPQIPLTFC-KKUMJFAQSA-N 0.000 description 1
- AUJWXNGCAQWLEI-KBPBESRZSA-N Phe-Lys-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AUJWXNGCAQWLEI-KBPBESRZSA-N 0.000 description 1
- FUAIIFPQELBNJF-ULQDDVLXSA-N Phe-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FUAIIFPQELBNJF-ULQDDVLXSA-N 0.000 description 1
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- RVEVENLSADZUMS-IHRRRGAJSA-N Phe-Pro-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RVEVENLSADZUMS-IHRRRGAJSA-N 0.000 description 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- YFXXRYFWJFQAFW-JHYOHUSXSA-N Phe-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N)O YFXXRYFWJFQAFW-JHYOHUSXSA-N 0.000 description 1
- MSSXKZBDKZAHCX-UNQGMJICSA-N Phe-Thr-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O MSSXKZBDKZAHCX-UNQGMJICSA-N 0.000 description 1
- KIQUCMUULDXTAZ-HJOGWXRNSA-N Phe-Tyr-Tyr Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O KIQUCMUULDXTAZ-HJOGWXRNSA-N 0.000 description 1
- VDTYRPWRWRCROL-UFYCRDLUSA-N Phe-Val-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VDTYRPWRWRCROL-UFYCRDLUSA-N 0.000 description 1
- LNLNHXIQPGKRJQ-SRVKXCTJSA-N Pro-Arg-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1 LNLNHXIQPGKRJQ-SRVKXCTJSA-N 0.000 description 1
- SWXSLPHTJVAWDF-VEVYYDQMSA-N Pro-Asn-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWXSLPHTJVAWDF-VEVYYDQMSA-N 0.000 description 1
- CJZTUKSFZUSNCC-FXQIFTODSA-N Pro-Asp-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 CJZTUKSFZUSNCC-FXQIFTODSA-N 0.000 description 1
- VJLJGKQAOQJXJG-CIUDSAMLSA-N Pro-Asp-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VJLJGKQAOQJXJG-CIUDSAMLSA-N 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- 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 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- FEPSEIDIPBMIOS-QXEWZRGKSA-N Pro-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 FEPSEIDIPBMIOS-QXEWZRGKSA-N 0.000 description 1
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 1
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 1
- SOACYAXADBWDDT-CYDGBPFRSA-N Pro-Ile-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SOACYAXADBWDDT-CYDGBPFRSA-N 0.000 description 1
- MCWHYUWXVNRXFV-RWMBFGLXSA-N Pro-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 MCWHYUWXVNRXFV-RWMBFGLXSA-N 0.000 description 1
- GFHOSBYCLACKEK-GUBZILKMSA-N Pro-Pro-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O GFHOSBYCLACKEK-GUBZILKMSA-N 0.000 description 1
- 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 1
- RMJZWERKFFNNNS-XGEHTFHBSA-N Pro-Thr-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMJZWERKFFNNNS-XGEHTFHBSA-N 0.000 description 1
- VBZXFFYOBDLLFE-HSHDSVGOSA-N Pro-Trp-Thr Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H]([C@H](O)C)C(O)=O)C(=O)[C@@H]1CCCN1 VBZXFFYOBDLLFE-HSHDSVGOSA-N 0.000 description 1
- 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 1
- XDKKMRPRRCOELJ-GUBZILKMSA-N Pro-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 XDKKMRPRRCOELJ-GUBZILKMSA-N 0.000 description 1
- VDHGTOHMHHQSKG-JYJNAYRXSA-N Pro-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O VDHGTOHMHHQSKG-JYJNAYRXSA-N 0.000 description 1
- 102100035530 RNA binding protein fox-1 homolog 3 Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 1
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 1
- QWZIOCFPXMAXET-CIUDSAMLSA-N Ser-Arg-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QWZIOCFPXMAXET-CIUDSAMLSA-N 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 1
- BYIROAKULFFTEK-CIUDSAMLSA-N Ser-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO BYIROAKULFFTEK-CIUDSAMLSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- WTPKKLMBNBCCNL-ACZMJKKPSA-N Ser-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N WTPKKLMBNBCCNL-ACZMJKKPSA-N 0.000 description 1
- MPPHJZYXDVDGOF-BWBBJGPYSA-N Ser-Cys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CO MPPHJZYXDVDGOF-BWBBJGPYSA-N 0.000 description 1
- OJPHFSOMBZKQKQ-GUBZILKMSA-N Ser-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO OJPHFSOMBZKQKQ-GUBZILKMSA-N 0.000 description 1
- HVKMTOIAYDOJPL-NRPADANISA-N Ser-Gln-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVKMTOIAYDOJPL-NRPADANISA-N 0.000 description 1
- BRGQQXQKPUCUJQ-KBIXCLLPSA-N Ser-Glu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRGQQXQKPUCUJQ-KBIXCLLPSA-N 0.000 description 1
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 1
- MIJWOJAXARLEHA-WDSKDSINSA-N Ser-Gly-Glu Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O MIJWOJAXARLEHA-WDSKDSINSA-N 0.000 description 1
- IXCHOHLPHNGFTJ-YUMQZZPRSA-N Ser-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CO)N IXCHOHLPHNGFTJ-YUMQZZPRSA-N 0.000 description 1
- SFTZTYBXIXLRGQ-JBDRJPRFSA-N Ser-Ile-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SFTZTYBXIXLRGQ-JBDRJPRFSA-N 0.000 description 1
- MOINZPRHJGTCHZ-MMWGEVLESA-N Ser-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N MOINZPRHJGTCHZ-MMWGEVLESA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- 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 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
- 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 1
- LRZLZIUXQBIWTB-KATARQTJSA-N Ser-Lys-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LRZLZIUXQBIWTB-KATARQTJSA-N 0.000 description 1
- AXOHAHIUJHCLQR-IHRRRGAJSA-N Ser-Met-Tyr Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CO)N AXOHAHIUJHCLQR-IHRRRGAJSA-N 0.000 description 1
- UGTZYIPOBYXWRW-SRVKXCTJSA-N Ser-Phe-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O UGTZYIPOBYXWRW-SRVKXCTJSA-N 0.000 description 1
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 1
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 1
- FBLNYDYPCLFTSP-IXOXFDKPSA-N Ser-Phe-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FBLNYDYPCLFTSP-IXOXFDKPSA-N 0.000 description 1
- BSXKBOUZDAZXHE-CIUDSAMLSA-N Ser-Pro-Glu Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O BSXKBOUZDAZXHE-CIUDSAMLSA-N 0.000 description 1
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- VLMIUSLQONKLDV-HEIBUPTGSA-N Ser-Thr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VLMIUSLQONKLDV-HEIBUPTGSA-N 0.000 description 1
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 1
- HAUVENOGHPECML-BPUTZDHNSA-N Ser-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CO)=CNC2=C1 HAUVENOGHPECML-BPUTZDHNSA-N 0.000 description 1
- ANOQEBQWIAYIMV-AEJSXWLSSA-N Ser-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N ANOQEBQWIAYIMV-AEJSXWLSSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- JXKMXEBNZCKSDY-JIOCBJNQSA-N Thr-Asp-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O JXKMXEBNZCKSDY-JIOCBJNQSA-N 0.000 description 1
- LYGKYFKSZTUXGZ-ZDLURKLDSA-N Thr-Cys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)NCC(O)=O LYGKYFKSZTUXGZ-ZDLURKLDSA-N 0.000 description 1
- VGYBYGQXZJDZJU-XQXXSGGOSA-N Thr-Glu-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VGYBYGQXZJDZJU-XQXXSGGOSA-N 0.000 description 1
- CQNFRKAKGDSJFR-NUMRIWBASA-N Thr-Glu-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O CQNFRKAKGDSJFR-NUMRIWBASA-N 0.000 description 1
- BNGDYRRHRGOPHX-IFFSRLJSSA-N Thr-Glu-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O BNGDYRRHRGOPHX-IFFSRLJSSA-N 0.000 description 1
- JQAWYCUUFIMTHE-WLTAIBSBSA-N Thr-Gly-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JQAWYCUUFIMTHE-WLTAIBSBSA-N 0.000 description 1
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 1
- CRZNCABIJLRFKZ-IUKAMOBKSA-N Thr-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@@H](C)O)N CRZNCABIJLRFKZ-IUKAMOBKSA-N 0.000 description 1
- BVOVIGCHYNFJBZ-JXUBOQSCSA-N Thr-Leu-Ala 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(O)=O BVOVIGCHYNFJBZ-JXUBOQSCSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 1
- SCSVNSNWUTYSFO-WDCWCFNPSA-N Thr-Lys-Glu Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O SCSVNSNWUTYSFO-WDCWCFNPSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- WRUWXBBEFUTJOU-XGEHTFHBSA-N Thr-Met-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N)O WRUWXBBEFUTJOU-XGEHTFHBSA-N 0.000 description 1
- IVDFVBVIVLJJHR-LKXGYXEUSA-N Thr-Ser-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IVDFVBVIVLJJHR-LKXGYXEUSA-N 0.000 description 1
- IQPWNQRRAJHOKV-KATARQTJSA-N Thr-Ser-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN IQPWNQRRAJHOKV-KATARQTJSA-N 0.000 description 1
- XGUAUKUYQHBUNY-SWRJLBSHSA-N Thr-Trp-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O XGUAUKUYQHBUNY-SWRJLBSHSA-N 0.000 description 1
- 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 1
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- ILUOMMDDGREELW-OSUNSFLBSA-N Thr-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O ILUOMMDDGREELW-OSUNSFLBSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- QNTBGBCOEYNAPV-CWRNSKLLSA-N Trp-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)O QNTBGBCOEYNAPV-CWRNSKLLSA-N 0.000 description 1
- ZJKZLNAECPIUTL-JBACZVJFSA-N Trp-Gln-Tyr Chemical compound C([C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=C(O)C=C1 ZJKZLNAECPIUTL-JBACZVJFSA-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
- 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 1
- GQEXFCQNAJHJTI-IHPCNDPISA-N Trp-Phe-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N GQEXFCQNAJHJTI-IHPCNDPISA-N 0.000 description 1
- IVBJBFSWJDNQFW-XIRDDKMYSA-N Trp-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IVBJBFSWJDNQFW-XIRDDKMYSA-N 0.000 description 1
- IKUMWSDCGQVGHC-UMPQAUOISA-N Trp-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC2=CNC3=CC=CC=C32)N)O IKUMWSDCGQVGHC-UMPQAUOISA-N 0.000 description 1
- DDHFMBDACJYSKW-AQZXSJQPSA-N Trp-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O DDHFMBDACJYSKW-AQZXSJQPSA-N 0.000 description 1
- LGEYOIQBBIPHQN-UWJYBYFXSA-N Tyr-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 LGEYOIQBBIPHQN-UWJYBYFXSA-N 0.000 description 1
- XHALUUQSNXSPLP-UFYCRDLUSA-N Tyr-Arg-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 XHALUUQSNXSPLP-UFYCRDLUSA-N 0.000 description 1
- MTEQZJFSEMXXRK-CFMVVWHZSA-N Tyr-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N MTEQZJFSEMXXRK-CFMVVWHZSA-N 0.000 description 1
- NSTPFWRAIDTNGH-BZSNNMDCSA-N Tyr-Asn-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NSTPFWRAIDTNGH-BZSNNMDCSA-N 0.000 description 1
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 1
- YRBHLWWGSSQICE-IHRRRGAJSA-N Tyr-Asp-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O YRBHLWWGSSQICE-IHRRRGAJSA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- RYSNTWVRSLCAJZ-RYUDHWBXSA-N Tyr-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RYSNTWVRSLCAJZ-RYUDHWBXSA-N 0.000 description 1
- IMXAAEFAIBRCQF-SIUGBPQLSA-N Tyr-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N IMXAAEFAIBRCQF-SIUGBPQLSA-N 0.000 description 1
- FMOSEWZYZPMJAL-KKUMJFAQSA-N Tyr-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N FMOSEWZYZPMJAL-KKUMJFAQSA-N 0.000 description 1
- FJBCEFPCVPHPPM-STECZYCISA-N Tyr-Ile-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O FJBCEFPCVPHPPM-STECZYCISA-N 0.000 description 1
- YKCXQOBTISTQJD-BZSNNMDCSA-N Tyr-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N YKCXQOBTISTQJD-BZSNNMDCSA-N 0.000 description 1
- NVZVJIUDICCMHZ-BZSNNMDCSA-N Tyr-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O NVZVJIUDICCMHZ-BZSNNMDCSA-N 0.000 description 1
- RCMWNNJFKNDKQR-UFYCRDLUSA-N Tyr-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 RCMWNNJFKNDKQR-UFYCRDLUSA-N 0.000 description 1
- 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 1
- GPLTZEMVOCZVAV-UFYCRDLUSA-N Tyr-Tyr-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 GPLTZEMVOCZVAV-UFYCRDLUSA-N 0.000 description 1
- NWEGIYMHTZXVBP-JSGCOSHPSA-N Tyr-Val-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O NWEGIYMHTZXVBP-JSGCOSHPSA-N 0.000 description 1
- IZFVRRYRMQFVGX-NRPADANISA-N Val-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N IZFVRRYRMQFVGX-NRPADANISA-N 0.000 description 1
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 1
- 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 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- JYVKKBDANPZIAW-AVGNSLFASA-N Val-Arg-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N JYVKKBDANPZIAW-AVGNSLFASA-N 0.000 description 1
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 1
- UDLYXGYWTVOIKU-QXEWZRGKSA-N Val-Asn-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N UDLYXGYWTVOIKU-QXEWZRGKSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- TZVUSFMQWPWHON-NHCYSSNCSA-N Val-Asp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N TZVUSFMQWPWHON-NHCYSSNCSA-N 0.000 description 1
- NXRAUQGGHPCJIB-RCOVLWMOSA-N Val-Gly-Asn Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O NXRAUQGGHPCJIB-RCOVLWMOSA-N 0.000 description 1
- PTFPUAXGIKTVNN-ONGXEEELSA-N Val-His-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)NCC(=O)O)N PTFPUAXGIKTVNN-ONGXEEELSA-N 0.000 description 1
- BZMIYHIJVVJPCK-QSFUFRPTSA-N Val-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N BZMIYHIJVVJPCK-QSFUFRPTSA-N 0.000 description 1
- OTJMMKPMLUNTQT-AVGNSLFASA-N Val-Leu-Arg Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N OTJMMKPMLUNTQT-AVGNSLFASA-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
- 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
- RFKJNTRMXGCKFE-FHWLQOOXSA-N Val-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC(C)C)C(O)=O)=CNC2=C1 RFKJNTRMXGCKFE-FHWLQOOXSA-N 0.000 description 1
- QRVPEKJBBRYISE-XUXIUFHCSA-N Val-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N QRVPEKJBBRYISE-XUXIUFHCSA-N 0.000 description 1
- YLRAFVVWZRSZQC-DZKIICNBSA-N Val-Phe-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N YLRAFVVWZRSZQC-DZKIICNBSA-N 0.000 description 1
- NHXZRXLFOBFMDM-AVGNSLFASA-N Val-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C NHXZRXLFOBFMDM-AVGNSLFASA-N 0.000 description 1
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 1
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-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
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-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
- SVLAAUGFIHSJPK-JYJNAYRXSA-N Val-Trp-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CO)C(=O)O)N SVLAAUGFIHSJPK-JYJNAYRXSA-N 0.000 description 1
- ZNGPROMGGGFOAA-JYJNAYRXSA-N Val-Tyr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=C(O)C=C1 ZNGPROMGGGFOAA-JYJNAYRXSA-N 0.000 description 1
- 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 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 108010070783 alanyltyrosine Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 1
- 108010043240 arginyl-leucyl-glycine Proteins 0.000 description 1
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 108091092328 cellular RNA Proteins 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 108010004073 cysteinylcysteine Proteins 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution 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
- 108010054812 diprotin A Proteins 0.000 description 1
- 108010054813 diprotin B Proteins 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 1
- 108010079547 glutamylmethionine Proteins 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 108010077515 glycylproline Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 239000012561 harvest cell culture fluid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 102000054751 human RUNX1T1 Human genes 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 239000012516 mab select resin Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 108700023046 methionyl-leucyl-phenylalanine Proteins 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007171 neuropathology Effects 0.000 description 1
- 210000004179 neuropil Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 108010012581 phenylalanylglutamate Proteins 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108010079317 prolyl-tyrosine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 239000012557 regeneration buffer Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000002864 sequence alignment 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
- 108010026333 seryl-proline Proteins 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 1
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 108010000998 wheylin-2 peptide Proteins 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/35—Valency
-
- 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
- C07K2317/50—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
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Psychology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本公开文本提供了靶向α‑突触核蛋白的分离的结合蛋白,诸如人源化抗体及其抗原结合片段,包括靶向α‑突触核蛋白和胰岛素样生长因子1受体两者的多特异性分离的结合蛋白。还提供了使用所述结合蛋白治疗α‑突触核蛋白病的方法。
Description
相关申请的交叉引用
本申请要求2021年5月12日提交的韩国申请号10-2021-0061407的优先权,将其公开内容通过引用以其整体并入本文。
序列表
本申请含有已经以ASCII格式电子提交并且通过引用以其整体特此并入的序列表。创建于2022年5月11日的所述ASCII副本被命名为122548_WO015_SL.txt,并且大小为87,684字节。
背景技术
α-突触核蛋白(α-syn)是一种参与囊泡运输、脑中突触传递和DNA修复的神经元蛋白。α-突触核蛋白病(也称为突触核蛋白病)是以不溶性α-syn在脑中异常积累为特征的神经变性疾病。这些α-突触核蛋白病包括帕金森病、路易体痴呆、多系统萎缩和杏仁体路易体阿尔茨海默病。α-突触核蛋白病很普遍,并且是人类痛苦和死亡的重要原因。例如,全世界大约有1000万人患有帕金森病。α-syn病理性积累的逐渐增加已经与疾病严重程度的进展相关(Henderson等人,Neurosci Lett.(2019)709:134316)。治疗α-突触核蛋白病的一个治疗目标是减少α-syn在脑中的异常积累。
防止或减少α-syn病理性积累的一种方法是开发通常基于免疫球蛋白G(IgG)的α-syn靶向性抗体。尽管已经开发出此类抗体,但它们有显著的临床局限性(Vaikath等人,JNeurochem.(2019)150:612-25)。一个关键问题是治疗性抗体穿过血脑屏障(BBB)(一种限制血液中分子进入脑中的内皮细胞屏障)的效率低。此外,先前开发的α-syn靶向性抗体不能区分生理性单体形式的α-syn和疾病相关的寡聚体或原纤维形式的α-syn(Lashuel等人,Nat Rev Neurosci.(2013)14(1):38-48;Vaikath,同上)。事实上,单体形式的α-syn的减少已经牵涉在一些形式的神经病理中(Gorbatyuk等人,Mol Ther.(2010)18(8):1450-7)。因此,仍然需要改进α-突触核蛋白病的治疗。
发明内容
本文描述了可用于治疗α-突触核蛋白病的重组α-syn结合蛋白,诸如抗α-syn抗体及其抗原结合片段。在一个方面,本公开文本提供了一种与人α-突触核蛋白结合的人源化抗体或其抗原结合片段,其中所述抗体或所述抗原结合片段包含:重链可变区(VH),所述重链可变区包含(i)分别在SEQ ID NO:33-35中示出的重链互补决定区(CDR)1-3,和(ii)源自人VH1-02基因的重链框架区(FR)1、2和/或3;以及轻链可变区(VL),所述轻链可变区包含分别在SEQ ID NO:36-38中示出的轻链CDR1-3。源自所述VH1-02基因的FR1、FR2或FR3相对于由所述人VH1-02基因编码的相应FR可以含有不超过六个(例如,6、5、4、3、2、1或0个)突变(例如,取代)。在一些实施方案中,所述抗体或抗原结合片段包含源自人JH1、JH4或JH5基因的重链FR4。
在一个方面,本公开文本提供了一种与人α-突触核蛋白结合的人源化抗体或其抗原结合片段,其中所述抗体或所述抗原结合片段包含:重链可变区(VH),所述重链可变区包含分别在SEQ ID NO:64-66中示出的重链互补决定区(CDR)1-3;和/或轻链可变区(VL),所述轻链可变区包含分别在SEQ ID NO:67-69中示出的轻链CDR1-3。
在一些实施方案中,本文的抗体或抗原结合片段具有包含SEQ ID NO:1至9中任一个的VH,以及包含SEQ ID NO:11至15中任一个的VL。在另外的实施方案中,所述VH和所述VL分别包含:SEQ ID NO:1和11、SEQ ID NO:2和12、SEQ ID NO:3和12、SEQ ID NO:4和12、SEQID NO:7和12、SEQ ID NO:5和13、SEQ ID NO:5和15、SEQ ID NO:6和13、SEQ ID NO:6和14、SEQ ID NO:5和14、SEQ ID NO:8和14或SEQ ID NO:9和14。在某些实施方案中,所述VH包含SEQ ID NO:1,或者所述VL包含SEQ ID NO:11。在某些实施方案中,所述VH包含SEQ ID NO:1,并且所述VL包含SEQ ID NO:11。
在一些实施方案中,本文的抗体或抗原结合片段包含人κ轻链恒定区(例如,SEQID NO:43)。
在一些实施方案中,本文的抗原结合片段是单链可变片段(scFv)。
在一些实施方案中,所述抗体或抗原结合片段是双特异性的。所述双特异性抗体或抗原结合片段可以包含结合胰岛素样生长因子1受体(IGF1R)的部分。在一些实施方案中,所述IGF1R结合部分包含VH和VL,其中所述VH包含分别在SEQ ID NO:51-53中示出的重链CDR1-3,并且所述VL包含分别在SEQ ID NO:46-48中示出的轻链CDR1-3。在另外的实施方案中,所述IGF1R结合部分的VH和VL分别包含SEQ ID NO:50和45。在某些实施方案中,所述IGF1R结合部分是scFv(例如,SEQ ID NO:54)。
在一些实施方案中,所述IGF1R结合部分与所述抗体的两条重链的C末端融合。
在一些实施方案中,所述IGF1R结合部分与所述抗体的仅一条重链的C末端融合。
在一些实施方案中,本公开文本的抗α-syn抗体包含人IgG1恒定区。此恒定区相对于野生型人IgG1序列可以任选地包含突变。例如,所述抗体的一条重链可以包含一个或多个杵(knob)突变(例如,T366W),而所述抗体的另一条重链可以包含一个或多个臼(hole)突变(例如,T366S、L368A和Y407V)(全部为Eu编号)。在另外的实施方案中,所述杵重链包含SEQ ID NO:39,和/或所述臼重链包含SEQ ID NO:40。在一些实施方案中,所述抗体的重链进一步包含M428L突变(Eu编号)。因此,在一些实施方案中,所述杵重链可以包含SEQ IDNO:41,并且所述臼重链可以包含SEQ ID NO:42。
在一些实施方案中,本文的双特异性抗体包含在所述杵重链的C末端处融合的IGF1R结合部分。例如,所述IGF1R结合部分位于所述臼重链的C末端处,任选地其中所述臼重链包含SEQ ID NO:55或56。
在某些实施方案中,本发明的双特异性抗体包含含有SEQ ID NO:57的重链和含有SEQ ID NO:58的重链;以及各自含有SEQ ID NO:59的两条轻链。
本公开文本的单特异性或多特异性(例如,双特异性)抗体或抗原结合片段可以任选地以不超过200pM、100pM、50pM、30pM、20pM或10pM的KD与聚集或寡聚体α-突触核蛋白结合,并且任选地不与单体α-突触核蛋白特异性结合。
在另一个方面,本公开文本提供了一种药物组合物,所述药物组合物包含本文的单特异性或多特异性(例如,双特异性)抗α-syn抗体或抗原结合片段以及药学上可接受的载体。
在另一个方面,本公开文本提供了编码本发明的抗体或抗原结合片段的一种或多种核酸分子,诸如表达构建体。在一些实施方案中,所述一种或多种核酸分子包含选自SEQID NO:17-25的核苷酸序列和选自SEQ ID NO:27-31的核苷酸序列。还提供了包含这些核酸分子的宿主细胞(例如,哺乳动物宿主细胞);以及通过在允许所述抗体或抗原结合片段表达的条件下培养所述宿主细胞以及从所述细胞培养物中分离所述抗体或抗原结合片段来产生所述抗体或抗原结合片段的方法。
在另一个方面,本公开文本提供了一种治疗有需要的人类受试者的α-突触核蛋白病(例如,帕金森病、路易体痴呆、多系统萎缩或杏仁体路易体阿尔茨海默病)的方法,所述方法包括将治疗有效量的本文的抗体或抗原结合片段施用给所述受试者。还提供了用于在这些方法中使用的抗体或抗原结合片段或药物组合物;以及所述抗体或抗原结合片段在制造用于在此类治疗方法中使用的药物中的用途。
附图说明
图1是示出在ELISA中所指示的单特异性嵌合1E4抗体(ch1E4)或单特异性人源化1E4抗体(hu1E4;具体地hu1E4(V1_VL1)、hu1E4(V2_VL2)、hu1E4(V3_VL2)、hu1E4(V7_VL2)和hu1E4(V4_VL2))在所指示的抗体浓度(nM)下对α-突触核蛋白(α-syn)预形成原纤维(PFF)的结合的图。平均值:在450nm波长处的平均光密度,指示结合。
图2是示出在ELISA中单特异性嵌合抗体ch1E4和单特异性hu1E4抗体(hu1E4(V8_VL4)和hu1E4(V9_VL4))对α-syn PFF的结合的图。“hIgG1”:作为阴性对照的无关人IgG1。
图3是示出在ELISA中单特异性ch1E4抗体和基于Grabody B(一种抗IGF1RscFv)的双特异性hu1E4抗体在所指示的抗体浓度下对α-syn PFF的结合的图。双特异性抗体(BsAb)是hu1E4(V1_VL1)x Grabody B;hu1E4(V2_VL2)x Grabody B;hu1E4(V3_VL2)x Grabody B;hu1E4(V4_VL2)x Grabody B;以及hu1E4(V7_VL2)x Grabody B。
图4是示出在ELISA中ch1E4抗体和基于Grabody B的双特异性hu1E4抗体在所指示的抗体浓度下对α-syn PFF的结合的图。BsAb是hu1E4(V5_VL3)x Grabody B;hu1E4(V5_VL5)x Grabody B;hu1E4(V6_VL3)x Grabody B抗体;hu1E4(V6_VL4)x Grabody B;以及hu1E4(V5_VL4)x Grabody B。
图5是示出在ELISA中重组小鼠1E4、ch1E4和hu1E4(V1_VL1)在所指示的浓度下对α-syn PFF的结合的图。
图6是示出在ELISA中BsAb hu11F11(ver.2)x Grabody和BsAb hu1E4(V1_VL1)xGrabody B在所指示的抗体浓度下对α-syn PFF的结合的图。
图7是示出在ELISA中本发明的抗体和先前已知的抗体对寡聚体α-syn的结合的图。抗体是hu11F11(ver.2);嵌合9E4抗体(ch9E4,又名普尼珠单抗(prasinezumab);Roche/Prothena);hu1E4(V1_VL1);hu1E4(V1_VL1)x Grabody B;NI-202(Biogen);以及小鼠杂交瘤1E4(hy1E4)。
图8是示出在ELISA中BsAb hu11F11(ver.2)x Grabody B和hu1E4(V1_VL1)xGrabody B对寡聚体α-syn的结合的图。
图9是示出如通过表面等离子共振(SPR)所测量的BsAb hu11F11(ver.2)xGrabodyB和hu1E4(V1_VL1)x Grabody B对α-syn PFF的结合的一组曲线图。每个曲线图示出了跨时间(秒)的共振单位(RU)。使用数据来计算α-syn PFF/抗体结合的定量特性,诸如缔合速率常数(ka)、解离速率常数(kd)和平衡解离常数(KD)。
图10是示出如通过SPR所测量的hu1E4(V1_VL1)x Grabody B和市售(单特异性)抗α-syn抗体(BA149(BioArctic)、ch9E4和NI-202)对α-syn PFF的结合的一组曲线图。
图11是示出如通过SPR所测量的hu1E4(V1_VL1)x Grabody B、ch9E4和hIgG1(阴性对照)对单体α-syn的结合的一组曲线图。
图12是示出在ch1E4、ch9E4或hIgG1(阴性对照)存在下BV-2细胞(小胶质细胞)对细胞外α-syn PFF的吞噬的图。“gMFI”:几何平均荧光强度,如使用荧光激活细胞分选(FACS)分析测量的。
图13是示出在ch1E4 x Grabody B或hIgG1(阴性对照)存在下THP-1细胞(单核细胞)对细胞外α-syn PFF的吞噬的图。
图14是示出在不同浓度的hu1E4(V1_VL1)x Grabody B、hu1E4(V7_VL2)xGrabodyB抗体、hu1E4(V5_VL5)x Grabody B或hIgG1存在下BV2细胞对细胞外α-syn PFF的吞噬的直方图。
图15是示出在不同浓度的ch1E4(单特异性)、hu1E4(V1_VL1)x Grabody B或hIgG1存在下BV2细胞对细胞外α-syn PFF的吞噬的图。
图16是示出在不同浓度的hu1E4(V1_VL1)x Grabody B、ch9E4或hIgG1存在下BV2细胞对细胞外α-syn PFF的吞噬的图。
图17是示出在不同浓度的hu1E4(V1_VL1)x Grabody B、hu11F11(ver.2)xGrabodyB或hIgG1存在下BV2细胞对细胞外α-syn PFF的吞噬的图。
图18是示出包含大脑皮层、纹状体和黑质(SN)(包括黑质致密部(SNpc)和黑质网状部(SNpr))的小鼠脑切片中α-syn的免疫组织化学的一组图像。脑切片来自过表达人α-syn的mThy-1小鼠,并且将其用ch1E4、hu11F11、NI-202、ch9E4或BA149抗体染色。
图19是示出包含杏仁体、海马体的海马角(CA3)和海马体的齿状回(DG)(包括齿状回颗粒细胞层(GrDG)和齿状回多形层(PoDG))的小鼠脑切片中α-syn的免疫组织化学的一组图像。将脑切片用ch1E4、hu11F11、NI-202、ch9E4和BA149染色。脑组织来自过表达人α-syn的mThy-1小鼠。
图20是示出来自被诊断患有帕金森病的人类患者的死后脑组织中磷酸化α-syn的免疫组织化学的一组图像。在相邻切片中比较ch1E4和市售Syn303抗体(BioLegend)的磷酸化α-syn结合能力。
图21是示出ch1E4和ch1E4 x Grabody B在mThy-1小鼠的大脑皮层、海马体的CA3和黑质中的分布的一组图像。在右侧的条形图中示出了抗α-syn抗体的量(如通过人IgG1的水平所量化的,因为单特异性和双特异性ch1E4两者都含有人IgG1恒定区)。
图22是示出在体内施用ch1E4或ch1E4 x Grabody B后mThy-1小鼠中磷酸化α-syn的免疫组织化学的一组图像。图像示出了大脑皮层、杏仁体和海马体的齿状回。在右侧的条形图中示出了磷酸化α-syn的量化。
图23是示出在体内施用hu11F11 x Grabody B、hu1E4(V1_VL1)x Grabody B和阴性对照IgG(IgG)后mThy-1小鼠中磷酸化α-syn的免疫组织化学的一组图像和条形图。野生型(WT)小鼠没有过表达人α-syn。
图24是示出源自来自帕金森病患者的诱导多能干细胞(iPSC)的多巴胺能神经元中α-syn传播的改善的一组图和图像。用剂量为1μg/ml、3μg/ml和5μg/ml的单特异性hu1E4(V1_VL1)和hu11F11抗体处理细胞。使用DAPI(蓝色)标记细胞,并且通过针对酪氨酸羟化酶(TH;绿色)染色定位多巴胺能神经元;α-syn显示为红色。
具体实施方式
本公开文本提供了结合α-突触核蛋白的分离的结合蛋白,诸如抗体及其抗原结合片段。这些结合蛋白包含含有特异性抗原结合序列的人源化抗体重链可变区(VH)和轻链可变区(VL)。
这些结合蛋白(诸如抗体和抗原结合片段)作为α-突触核蛋白病的治疗剂是有利的,因为与单体α-syn对照,它们优先与疾病相关的聚集、寡聚体和/或磷酸化形式的α-syn结合。α-syn单体大量存在于健康人的脑和血液中,并且它们在调节神经递质释放方面发挥着重要作用。但是在α-突触核蛋白病患者的脑中通常只发现微量的疾病相关的α-syn聚集体。当抗α-syn抗体与α-syn单体和聚集体两者都很好地结合时,大量的抗体会与体内的单体结合,因为单体的存在量要大得多。因此,抗体对去除致病聚集体几乎没有作用。此外,如果治疗性抗α-syn抗体与单体形式结合的程度显著,则α-syn的正常生理功能可能会受到负面影响。因此,本发明的α-syn结合蛋白优先结合疾病相关形式在治疗α-syn相关的疾病方面很重要。
此外,诸位发明人已经惊奇地发现,本发明的结合蛋白(诸如人源化抗体)以比它们来源的亲本小鼠抗体更高的亲和力与疾病相关形式的α-syn结合。这些人源化抗体也有望在人类患者中具有低免疫原性,因为在人源化过程期间不需要或只需要很少的回复突变就能维持工程化抗体的抗原结合亲和力。
本公开文本还提供了与α-syn和IGF1R两者都结合的多特异性(例如,双特异性)结合蛋白(诸如抗体),其中结合蛋白的IGF1R结合部分显著提高了蛋白质穿过脑血屏障的能力,从而改善了患者在疾病部位对结合蛋白的暴露。
本发明的结合蛋白在显示与聚集和寡聚体α-syn高亲和力结合方面优于先前已知的抗α-syn抗体。这种优势在抗α-syn/IGF1R双特异性形式中得以保留。
除非另外指示,否则本文的α-突触核蛋白是指人α-突触核蛋白。人α-突触核蛋白多肽序列可在UniProt登录号Q6QBS3(SEQ ID NO:60)下获得。除非另外指示,否则本文的IGF1R是指人IGF1R。人IGF1R多肽序列可在UniProt登录号P08069(SEQ ID NO:77)下获得。
I.α-syn结合蛋白
本文的α-syn结合蛋白包括具有鼠源抗原结合结构域的嵌合或人源化抗α-syn抗体。本文的术语“抗体”包括单特异性和多特异性(例如,双特异性)抗体。如本文所用,术语“抗体”(Ab)或“免疫球蛋白”(Ig)可以指代包含通过二硫键互连的两条重(H)链和两条轻(L)链的四聚体。每条重链由重链可变区或结构域(VH)和重链恒定区(CH)组成。每条轻链由轻链可变区或结构域(VL)和轻链恒定区(CL)构成。VH和VL结构域可以进一步细分为具有高变性的区域,称为“互补决定区”(CDR),散布有更保守的区域,称为“框架区”(FR)。每个VH和VL由三个CDR(本文的HCDR表示来自重链的CDR;并且本文的LCDR表示来自轻链的CDR)和四个FR构成,从氨基末端到羧基末端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。
给定CDR或FR的精确氨基酸序列边界可以由几个众所周知的系统定义,所述系统包括由以下文献描述的那些系统:Kabat等人,第5版,Public Health Service,NationalInstitutes of Health,Bethesda,MD(1991)(“Kabat”系统);Al-Lazikani等人,J MolBiol.(1997)273:927-48(“Chothia”系统);MacCallum等人,J Mol Biol.(1996)262:732-45(“contact”系统);Lefranc等人,Dev Comp Immunol.(2003)27(1):55-77(“IMGT”系统);Honegger和Plückthun,J Mol Biol.(2001)309(3):657-70(“Aho”系统);以及Whitelegg和Rees,Protein Eng.(2000)13(12):819-24(“AbM”系统)。给定CDR或FR的边界可能根据所使用的系统而变化。例如,Kabat系统基于序列比对,而Chothia系统基于结构信息。Kabat和Chothia系统两者的编号都基于最常见的抗体区序列长度,其中通过插入字母(例如,“30a”)提供插入。这两种系统将某些插入和缺失(“插入缺失(indel)”)放置在不同的位置,从而产生不同的编号。contact系统基于对复杂晶体结构的分析,并且在许多方面与Chothia系统类似。在某些实施方案中,本文所述的抗体的CDR可以由选自Kabat、Chothia、IMGT、Aho、AbM或其组合的系统定义。
本文提供的抗体可以属于任何免疫球蛋白同种型,诸如IgG(例如,IgG1、IgG2、IgG3或IgG4)。本文的抗体优选地包含人IgG(例如,IgG1)恒定区。在一些实施方案中,IgG恒定区可以包含提高抗体治疗潜力的突变,诸如降低或消除抗体效应子功能的突变(参见例如,Wang等人,Protein Cell(2018)9(1):63-73)。例如,本文的单特异性或多特异性抗体可以包含具有突变L235E、“LALA”突变(L234A/L235A)或“LALAGA”突变(L234A/L235A/G237A)(Eu编号)的人IgG1恒定区。IgG恒定区可以包含提高抗体血清半衰期的突变,诸如M428L突变(Eu编号)。IgG恒定区可以包含改善抗体制造和产量的突变;参见例如以下关于双特异性抗体的杵臼结构(knob-in-hole)突变的描述。此类突变的人恒定区在本文中仍被认为是“人”恒定区。
在优选的实施方案中,本公开文本的结合蛋白是人源化抗体,例如人源化IgG1或IgG4抗体。“人源化”抗体是这样的抗体,其中所有或基本上所有CDR氨基酸残基源自非人CDR(例如,小鼠)并且所有或基本上所有FR氨基酸残基源自人FR(即,受体)。人源化抗体还可以包括源自人抗体的抗体重链和/或轻链恒定区的至少一部分。与人源化抗体来源的非人亲本抗体相比,人源化抗体对人的免疫原性降低。为了保留亲本抗体的特异性和亲和力,人受体中的一些FR残基可以被来自非人亲本抗体的相应残基取代(回复突变)。
在一些实施方案中,本文的结合蛋白是全(四聚体)抗体的抗原结合片段。本文的术语“抗原结合片段”或“抗原结合部分”涵盖不具有常规全长四聚体结构的基因工程化和/或以其他方式修饰的形式的免疫球蛋白。所述术语涵盖胞内抗体、肽体(peptibody)、双链抗体(diabody)、三链抗体(triabody)、四链抗体(tetrabody)、Fv、Fab、Fab’、Fab’-SH、F(ab’)2、单链抗体分子(例如,scFv或sFv)、串联二scFv和串联三scFv。
本公开文本的α-syn结合蛋白源自小鼠单克隆抗体1E4。小鼠1E4亲本抗体的人源化形式在本文中称为hu1E4抗体。在一些实施方案中,结合蛋白(诸如hu1E4抗体或其抗原结合片段)包含以下人源化VH序列中的一个的HCDR中的一个或多个(例如,两个或三个)。下面将这些序列与用作人源化受体的人种系基因VH1-02进行比对。Kabat定义的HCDR是斜体的;相对于人种系序列的突变是粗体且加下划线的。
在以上序列中,人VH1-02 FR1、FR2和FR3序列分别被指定为SEQ ID NO:61-63。VHhu1E4_ver.1至ver.9(也称为hu1E4V1至V9)的序列分别被指定为SEQ ID NO:1-9,如每个序列末尾括号中的数字所指示的。Kabat定义的HCDR1-3序列分别被指定为SEQ ID NO:33-35。
在一些实施方案中,本文的α-syn结合蛋白(诸如hu1E4抗体或抗原结合片段)包含在SEQ ID NO:33-35中示出的HCDR1-3序列。在另外的实施方案中,人源化抗体或抗原结合片段包含在SEQ ID NO:33-35中示出的HCDR1-3序列以及源自人VH1-02的一个或多个(例如,两个或三个)FR1-3。在某些实施方案中,抗体或片段包含相对于由人种系VH1-02基因编码的相应FR具有不超过六个突变(例如,0、1、2、3、4、5或6个突变)的重链FR。在某些实施方案中,本文的抗体或抗原结合片段包含相对于由人种系VH1-02基因编码的相应FR具有不超过两个突变的重链FR1、具有不超过两个突变的重链FR2和/或具有不超过六个突变的重链FR3。在一些实施方案中,人源化抗体或抗原结合片段包含源自人JH1、JH4或JH5基因的FR4。
在一些实施方案中,本文的人源化1E4抗体或抗原结合片段包含hu1E4V1的IMGT定义的HCDR1-3。IMGT定义的CDR在下面的VH序列中是斜体且加下划线的:
IMGT定义的HCDR1-3序列分别被指定为SEQ ID NO:64-66。
在一些实施方案中,α-syn结合蛋白(诸如人源化抗体或其抗原结合片段)包含以下人源化VL序列中的一个的LCDR中的一个或多个(例如,两个或三个)。Kabat定义的LCDR是斜体的;与LCHu1E4_VL1的不同之处是粗体且加下划线的。
LChu1E4_V1至V5(也称为hu1E4_VL1至VL5)的序列分别被指定为SEQ ID NO:11-15,如每个序列末尾括号中的数字所指示的。Kabat定义的LCDR1-3序列分别被指定为SEQID NO:36-38。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含hu1E4_VL1的IMGT定义的LCDR1-3。IMGT定义的CDR在下面的VL1序列中是斜体且加下划线的:
IMGT定义的LCDR1-3序列被指定为SEQ ID NO:67-69。可以将亲本小鼠1E7 CDR(例如,IMGT或Kabat定义的)掺入受体人κ或λ轻链中。在一些实施方案中,受体轻链源自人κV2-29(*02或*03)基因。
在一些实施方案中,本文的α-syn结合蛋白(诸如人源化抗体或抗原结合片段)包含VH和VL,其中分别地,VH包含在SEQ ID NO:33-35中示出的HCDR1-3和源自人VH1-02基因的FR1-3(相对于相应种系FR序列,每个FR具有不超过六个突变),并且VL包含在SEQ ID NO:36-38中示出的LCDR1-3。
在一些实施方案中,本文的α-syn结合蛋白(诸如人源化抗体或抗原结合片段)包含分别在SEQ ID NO:64-69中示出的HCDR1-3和LCDR1-3。
在一些实施方案中,本文的α-syn结合蛋白(诸如人源化抗体或抗原结合片段)包含选自SEQ ID NO:1-9的VH和选自SEQ ID NO:11-15的VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:1和11中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:2和12中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:3和12中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:4和12中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:7和12中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:5和13中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:5和15中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:6和13中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:6和14中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:5和14中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:8和14中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含分别在SEQ ID NO:9和14中示出的VH和VL。
在一些实施方案中,本文的人源化抗体或抗原结合片段包含VH和VL,其中分别地,VH包含在SEQ ID NO:33-35中示出的HCDR1-3和源自人VH1-02基因的FR1-3(相对于相应种系FR序列,每个FR具有不超过六个突变),并且VL包含在SEQ ID NO:36-38中示出的LCDR1-3;并且其中VH与SEQ ID NO:1-9中的一个至少90%(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)同源或相同,和/或VL与SEQ ID NO:11-15中的一个至少90%(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)同源或相同。
在一些实施方案中,本文的α-syn结合蛋白(诸如人源化抗体或抗原结合片段)包含分别在SEQ ID NO:64-69中示出的HCDR1-3和LCDR1-3;并且其中VH与SEQ ID NO:1-9中的一个至少90%(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)同源或相同,和/或VL与SEQ ID NO:11-15中的一个至少90%(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)同源或相同。
相对于参考多肽序列的序列同一性或同源性百分比(%)是在将候选序列和参考多肽序列进行比对并引入空位(如果需要)以实现最大序列同一性百分比并且不将任何保守取代视为序列同一性的一部分后,候选序列中与参考多肽序列中的氨基酸残基相同的氨基酸残基的百分比。可以使用可用的计算机软件以各种方式实现比对以用于确定氨基酸序列同一性百分比的目的。能够确定用于比对序列的适当参数,包括在所比较序列的全长上实现最大比对所需的算法。在一些实施方案中,查询序列具有参考序列长度的至少70%(例如,至少75%、80%、85%、90%或95%)。出于本文的目的,可以通过BLAST(一种可在美国国家生物技术信息中心的服务器获得的生物信息学程序)使用默认参数来鉴定序列同源性或同一性。
本公开文本的α-syn结合蛋白(包括单特异性和双特异性hu1E4抗体)以高亲和力与疾病相关形式的α-syn(例如,聚集形式、原纤维(protofibril)形式、预形成原纤维(fibril)(PFF)形式或寡聚体形式)特异性结合。结合蛋白还可以与疾病相关的磷酸化α-syn(例如,在氨基酸残基129处磷酸化的α-syn(p-129α-syn))特异性结合。在本公开文本中“特异性”结合意指结合的平衡解离常数(KD)不超过100nM、50nM、40nM、30nM、20nM、10nM、5nM、2nM、1nM、0.5nM、0.1nM、0.05nM或0.01nM。KD可以通过任何合适的测定来测量。在某些实施方案中,KD可以使用表面等离子共振(SPR)测定(例如,使用或/>设备)来测量。抗体的特异性结合也可以通过酶联免疫吸附测定(ELISA)使用同种型对照抗体来证明。
在一些实施方案中,结合蛋白(诸如hu1E4抗体或相关片段)以不超过200pM、100pM、50pM、30pM、20pM或10pM的KD结合疾病相关形式的α-syn,并且任选地不与单体α-突触核蛋白结合。在某些实施方案中,本文的单特异性或双特异性抗体以50pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以20pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以10pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以5pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以4pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以3pM或更小的KD结合聚集或寡聚体α-syn。在某些实施方案中,单特异性或双特异性抗体以2pM的KD结合聚集或寡聚体α-syn。用于确定结合KD的测定可以是如以下实施例6中详细描述进行的SPR测定。
此外,结合蛋白在促进小胶质细胞和/或单核细胞/巨噬细胞吞噬聚集或寡聚体α-syn、促进清除疾病相关形式(例如,聚集、寡聚体和磷酸化形式)的α-syn和/或抑制神经元(例如,多巴胺能神经元)之间病态形式的α-syn的传播方面可能非常有效。
II.双特异性结合蛋白
本公开文本还提供了多特异性(例如,双特异性)的α-syn结合蛋白,诸如hu1E4抗体。这些多特异性或双特异性结合蛋白对α-syn和IGF1R两者都具有特异性。IGF1R结合部分允许结合蛋白有效结合IGF1R并使结合蛋白穿梭穿过血脑屏障(BBB),而α-syn结合部分允许结合并从脑中清除聚集或寡聚体α-syn。因此,此类多特异性(例如,双特异性)结合蛋白(例如,抗体)对于治疗α-突触核蛋白病特别有用。
在某些实施方案中,本文的双特异性hu1E4抗体以比单特异性hu1E4抗体或嵌合1E4抗体或先前的抗α-syn抗体高至少2倍、3倍、4倍、5倍或6倍的速率穿过BBB。在一些实施方案中,双特异性hu1E4抗体以比单特异性hu1E4抗体或嵌合1E4抗体或先前的抗α-syn抗体高至少2倍、3倍、4倍、5倍或6倍的速率到达大脑皮层、海马体和/或黑质。
IGF1R结合部分可以通过肽接头与hu1E4抗体融合。IGF1R结合部分可以例如通过肽接头与hu1E4抗体的一条或两条重链和/或hu1E4抗体的一条或两条轻链的N末端和/或C末端融合。在一些实施方案中,肽接头可以主要包括以下氨基酸残基:Gly、Ser、Ala或Thr。肽接头的长度可以足以以这样的方式连接两个分子,使得它们相对于彼此呈现正确的构象,从而它们保持它们各自所需的活性。在一些实施方案中,接头的长度为1至50个(例如,1至30个或1至20个)氨基酸。有用的接头包括甘氨酸-丝氨酸聚合物,包括例如(GS)n、(GSGGS)n(SEQ ID NO:70)、(GGGGS)n(SEQ ID NO:71)和(GGGS)n(SEQ ID NO:72),其中n是至少为1的整数;甘氨酸-丙氨酸聚合物;丙氨酸-丝氨酸聚合物;XTEN接头;以及其他柔性接头。用于连接抗体片段或单链可变片段的其他示例性接头可以包括AAEPKSS(SEQ ID NO:73)、AAEPKSSDKTHTCPPCP(SEQ ID NO:74)、GGGG(SEQ ID NO:75)或GGGGDKTHTCPPCP(SEQ IDNO:76)。
在一些实施方案中,IGF1R结合部分包含抗体或其抗原结合片段,所述抗体或其抗原结合片段包含分别在SEQ ID NO:51-53中示出的HCDR1-3以及分别在SEQ ID NO:46-48中示出的LCDR1-3。
在另外的实施方案中,IGF1R结合部分包含抗IGF1R scFv,所述抗IGF1R scFv包含分别在SEQ ID NO:51-53中示出的HCDR1-3以及分别在SEQ ID NO:46-48中示出的LCDR1-3。
在一些实施方案中,IGF1R结合部分包含抗体或其抗原结合片段,所述抗体或其抗原结合片段包含通过肽接头(诸如如上所述的肽接头)连接的分别在SEQ ID NO:50和45中示出的VH和VL。在一些实施方案中,肽接头包含SEQ ID NO:49。在某些实施方案中,所述部分包含SEQ ID NO:54。在某些实施方案中,所述部分包含与SEQ ID NO:50至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的VH和/或与SEQ IDNO:45至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的VL。
在另外的实施方案中,IGF1R结合部分包含抗IGF1R scFv,所述抗IGF1R scFv包含通过肽接头(诸如如上所述的肽接头)连接的分别在SEQ ID NO:50和45中示出的VH和VL。在一些实施方案中,肽接头包含SEQ ID NO:49。在某些实施方案中,scFv包含SEQ ID NO:54。在某些实施方案中,scFv包含与SEQ ID NO:50至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的VH和/或与SEQ ID NO:45至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的VL。在某些实施方案中,scFv包含与SEQ ID NO:54至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列。
在另外的实施方案中,多特异性结合蛋白是双特异性hu1E4抗体,其中上述抗IGF1R scFv任选地通过肽接头与其两条重链的C末端融合。
在另外的实施方案中,多特异性结合蛋白是双特异性hu1E4抗体,其中上述抗IGF1R scFv任选地通过肽接头与其仅一条重链的C末端融合。在这些实施方案中,双特异性抗体具有两条不同的重链(一条具有抗IGF1R scFv,而另一条没有)。因此,为了在制造期间促进两条不同重链的异二聚化,可以将突变引入重链中以物理地(例如,空间位阻、杵臼结构(“knobs”into“holes”))或生化地(例如,静电相互作用)阻止相同类型的重链偶联。例如,可以引入杵臼结构(KIH)突变以产生优先相互配对的“杵”重链和“臼”重链。示例性KIH突变包括一条重链中的T366W和另一条重链中的T366S/L368A/Y407V(全部为Eu编号)。还参见WO 2009/089004和美国专利8,642,745;以及Brinkmann和Kontermann,MAbs.(2017)9(2):182-212。
在一些实施方案中,hu1E4抗体属于人IgG1同种型并且含有KIH突变,例如具有包含SEQ ID NO:55(包括抗IGF1R scFv序列)的臼重链恒定区和包含SEQ ID NO:39的杵重链恒定区。
在一些实施方案中,hu1E4抗体属于人IgG1同种型并且含有KIH突变和M428L突变,例如具有包含SEQ ID NO:56(包括抗IGF1R scFv序列)的臼重链恒定区和包含SEQ ID NO:41的杵重链恒定区。
在特定实施方案中,hu1E4抗体属于人IgG1同种型,并且包含含有SEQ ID NO:57的臼重链和含有SEQ ID NO:58的杵重链,以及各自含有SED ID NO:59的两条轻链。
在特定实施方案中,hu1E4抗体属于人IgG1同种型,并且包含含有与SEQ ID NO:57至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列的臼重链和含有与SEQ ID NO:58至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列的杵重链,以及各自含有与SEQ ID NO:59至少90%同源或相同(例如,至少91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列的两条轻链。
III.α-syn结合蛋白的制备
可以使用分离的核酸分子(诸如编码蛋白质每条链的表达构建体)重组产生结合蛋白。在本文中称为“分离”或“纯化”的生物分子(例如,核酸或多肽分子)是(1)已经与它们的来源的生物分子(例如,基因组DNA或细胞RNA的核酸,或多肽)分开和/或(2)在自然界中不存在的那些生物分子。可以将每条多肽链的编码序列克隆到单个载体中或克隆到单独的载体中。
产生蛋白质(诸如抗体)的方法是众所周知的。可以使用适当的表达构建体在例如哺乳动物宿主细胞中产生本发明的结合蛋白,诸如抗体。可用作表达宿主的哺乳动物细胞系包括可从美国典型培养物保藏中心(ATCC)获得的许多永生化细胞系。这些细胞系尤其包括中国仓鼠卵巢(CHO)细胞、NS0细胞、SP2细胞、HEK-293T细胞、293Freestyle细胞(Invitrogen)、NIH-3T3细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、非洲绿猴肾细胞(COS)、人肝细胞癌细胞(例如,Hep G2)、A549细胞和许多其他细胞系。可以使用的其他细胞系是昆虫细胞系(诸如Sf9或Sf21细胞)以及酵母细胞系。细胞系可以基于它们的表达水平来选择。可以使用众所周知的方法从宿主细胞培养物中分离和纯化结合蛋白,所述方法诸如离心,超速离心,蛋白A、蛋白G、蛋白A/G或蛋白L纯化,和/或离子交换色谱法。
IV.药物组合物和用途
本公开文本还提供了包含本文的单特异性和多特异性结合蛋白的药物组合物。药物组合物可以包含一种或多种药学上可接受的赋形剂、载体或稀释剂。如本文所用,关于“载体”、“赋形剂”或“稀释剂”的“药学上可接受的”包括适当的溶剂、分散介质、抗细菌剂和抗真菌剂、等渗剂等。在一些实施方案中,药物组合物是无菌水溶液,并且可以包含缓冲剂;表面活性剂;多元醇;抗氧化剂;和/或螯合剂。在一些实施方案中,药物组合物以冻干形式提供,并且在施用前重构。在某些实施方案中,冻干抗体制剂可以包含填充剂。
药物组合物可以通过肠胃外施用(例如,通过注射或输注)施用给患者。例如,药物组合物可以通过静脉内、大脑内、颅内或脊髓途径施用。
本文的包含结合蛋白的药物组合物可用于治疗患有α-突触核蛋白病(诸如帕金森病、路易体痴呆(DLB)、多系统萎缩(MSA)和某些形式的阿尔茨海默病(例如,杏仁体路易体阿尔茨海默病))或有患上所述α-突触核蛋白病风险的人类患者。如本文所用,术语“治疗(treat)”、“治疗(treatment)”和“治疗(treating)”是指对生理疾病状态进行故意干预,使得降低疾病或病症的严重程度;减少疾病或病症的持续时间;改善或消除与疾病或病症相关的一种或多种症状;或者为患有疾病或病症的受试者提供有益效果。治疗不要求治愈潜在的疾病或病症。
可以按由医疗保健提供者视情况而定确定的剂量强度和频率将药物组合物提供给患者。治疗有效量是足以改善与待治疗的疾病或痛苦相关的一种或多种症状的那些量。“治疗有效量”、“有效剂量”、“有效量”或“治疗有效剂量”的本文的结合蛋白保护受试者免于疾病发作或者促进疾病消退或稳定,如疾病症状的严重程度降低、无疾病症状期的频率和持续时间增加或者因疾病痛苦引起的损伤或残疾(例如,认知能力或行动能力)得到预防或延迟所证明的。
实施例
为了可以更好地理解本发明,阐述了以下实施例。这些实施例仅用于说明目的,并不被解释为以任何方式限制本发明的范围。
实施例1:嵌合抗α-syn抗体的制备
基于WO 2018/128454中公开的小鼠抗α-syn抗体1E4克隆制备嵌合1E4(ch1E4)抗体。用作抗原以获得1E4抗体的全长人α-syn的氨基酸序列在SEQ ID NO:60中示出。小鼠1E4的重链CDR1(HCDR1)、CDR2(HCDR2)和CDR3(HCDR3)分别在SEQ ID NO:33至35(Kabat定义)中示出,并且小鼠1E4的轻链CDR1(LCDR1)、CDR2(LCDR2)和CDR3(LCDR3)分别在SEQ ID NO:36至38中示出。
为了制备ch1E4,将小鼠1E4的VH和VL以及人IgG1和κ恒定区克隆到哺乳动物表达载体(pcDNA3.4)中。以gBlock(M.Biotech)形式合成每个可变区的编码序列,所述形式是CHO密码子优化的短核苷酸片段。将gBlock合成为与载体片段重叠大约20bp,并且使用Gibson组装方法进行克隆。
接下来,使用ExpiFectamineTM CHO转染试剂盒(Thermo Fisher)用表达构建体转染ExpiCHOTM细胞。用200μg DNA/200mL ExpiCHOTM细胞/1L锥形瓶进行转染。然后,将细胞孵育12天以扩大抗体产量。将所得细胞培养物离心,并且通过使用0.2μm孔径过滤器过滤上清液以去除悬浮物。
使用HiTrapTMMabSelect SuReTM(GE Healthcare,#11-0034-94)纯化过滤的上清液。必要时,通过将纯化的级分通过26/600/>200柱(Cytiva)进行二次纯化。使用质谱来确认纯化的嵌合抗体的氨基酸序列。
ch1E4是一种IgG型单价抗体,其包含具有在SEQ ID NO:10中示出的氨基酸序列的VH(ch1E4-VH)和具有在SEQ ID NO:16中示出的氨基酸序列的VL(ch1E4-VL)。
实施例2:人源化抗α-syn抗体的制备
还制备小鼠1E4的人源化形式。首先,基于小鼠1E4的VH和VL的基因序列进行基于同源性的分子建模。根据此建模,选择与小鼠框架具有高度同源性的人框架作为受体。将小鼠CDR移植到所选的人框架中以制备人源化抗体文库。
为了防止在人源化过程期间丧失抗原结合亲和力,可以在人框架中进行回复突变,以在被认为对于抗原结合亲和力很重要的某些位置处引入小鼠序列。此类回复突变可以降低人源化抗体的“人源性”。为了评价所产生的人源化VH和VL的人源性,基于人种系序列计算IMGT(%)得分,并且IMGT得分越高意味着人源性越高。人源化1E4 VH的九种形式(ver.1至ver.9)(SEQ ID NO:1-9)和人源化1E4 VL的五种形式(VL1至VL5)(SEQ ID NO:11-15)的结果分别在表1和表2中示出(BM:回复突变)。
表1.人源化VH的人源性的计算机分析
表2.人源化VL的人源性的计算机分析
基于计算机分析,认为Ver.1(HC)和VL1(LC)的框架区是最人源化的,因为需要的回复突变少且IMGT得分高。
然后,将人源化VH和VL的各种组合分别与人IgG1和κ恒定区融合,从而产生十二种人源化1E4(hu1E4)抗体克隆,称为“hu1E4(V#_VL#)”(或称为“hu1E4(Ver.#_VL#)”)。
表3列出了这十二种人源化1E4抗体,其中VH和VL的SEQ ID NO在括号中示出。将人源化抗体格式化为人IgG1抗体。
表3.人源化1E4抗体
克隆名称 | VH(SEQ ID NO) | VL(SEQ ID NO) |
hu1E4(V1_VL1) | Ver.1(1) | VL1(11) |
hu1E4(V2_VL2) | Ver.2(2) | VL2(12) |
hu1E4(V3_VL2) | Ver.3(3) | VL2(12) |
hu1E4(V4_VL2) | Ver.4(4) | VL2(12) |
hu1E4(V7_VL2) | Ver.7(7) | VL2(12) |
hu1E4(V5_VL3) | Ver.5(5) | VL3(13) |
hu1E4(V5_VL5) | Ver.5(5) | VL5(15) |
hu1E4(V6_VL3) | Ver.6(6) | VL3(13) |
hu1E4(V6_VL4) | Ver.6(6) | VL4(14) |
hu1E4(V5_VL4) | Ver.5(5) | VL4(14) |
hu1E4(V8_VL4) | Ver.8(8) | VL4(14) |
hu1E4(V9_VL4) | Ver.9(9) | VL4(14) |
实施例3:抗α-syn/IGF1R双特异性抗体的制备
接下来,产生抗α-syn和IGF1R的双特异性抗体。IGF1R结合部分促进通过血脑屏障进行的受体介导的胞吞转运,并且可以与抗α-syn抗体的一条或两条重链的C末端融合。在本实施例中,每种双特异性抗体具有这样的结构,其中IGF1R结合性scFv的N末端VL与在Fc结构域中具有杵臼结构突变的抗α-syn抗体融合。抗IGF1R scFv经由肽接头仅与含有“臼”突变的重链(“臼重链”)融合。
抗IGF1R scFv基于WO 2020/251316中描述的F06(de2)(StoP)克隆。scFv形式的单价缀合F06(de2)(StoP)在本文中被称为“Grabody B”(SEQ ID NO:54)。Grabody B从N末端到C末端由VL(SEQ ID NO:45)、(G4S)4接头(SEQ ID NO:49)和VH(SEQ ID NO:50)组成。Grabody B的LCDR1-3分别在SEQ ID NO:46-48中示出,并且其HCDR1-3分别在SEQ ID NO:51-53中示出。
抗α-syn/IGF1R双特异性抗体在结构上是不对称的。它们各自包括在其C末端通过肽接头(G4S)3(SEQ ID NO:44)连接到Grabody B的N末端的一条抗α-syn IgG1重链,以及未连接到Grabody B的一条抗α-syn IgG1重链。为了在抗体产生期间促进这种异二聚体重链组合,将杵臼结构(KIH)突变引入IgG1重链Fc结构域中。“臼”突变是CH3结构域中的T366S、L368A和Y406V,并且“杵”突变在CH3结构域中被T366W替换(全部按Eu编号)。已经引入杵突变的IgG1重链恒定区的序列在SEQ ID NO:39中示出;已经引入臼突变的IgG1重链恒定区的序列在SEQ ID NO:40中示出。已经进一步引入M428L突变的“杵”IgG1重链恒定区的序列在SEQ ID NO:41中示出;并且已经进一步引入M428L突变的“臼”IgG1重链恒定区的序列在SEQID NO:42中示出。引入M428L突变以通过增加抗体对FcRn的亲和力并因此增加体内循环来增加抗体的血清半衰期。
除非另外指示,否则使用hIgG1重链恒定区(杵)(M428L)(SEQ ID NO:41)和hIgG1重链恒定区(臼)(M428L)(SEQ ID NO:42)来构建双特异性抗体。将人κ轻链(SEQ ID NO:43)用作轻链的来源。
连接到抗IGF1R scFv的hIgG1重链恒定区(hIgG1(恒定)-Grabody B(臼))具有在SEQ ID NO:55中示出的序列。未连接到抗IGF1R scFv的hIgG1重链恒定区(hIgG1(恒定)(杵))具有在SEQ ID NO:39中示出的序列。hIgG1重链恒定区即hIgG1(恒定,M428L)-Grabody B(臼)和hIgG1(恒定,M428L)(杵)分别具有在SEQ ID NO:56和41中示出的序列,其中两条重链都含有M428L突变。
通过用编码臼重链、杵重链和轻链的表达载体以0.5:0.5:1的比率转染ExpiCHOTM细胞(Gibco)来产生双特异性抗体。转染前一天,将CHO细胞以3x106至4x106个活细胞/mL的浓度接种在ExpiCHOTM表达培养基(Gibco)中,然后在8% CO2、37℃和120rpm下培养一天。
在转染当天,将细胞用新鲜培养基从7x106至10x106个活细胞/mL的浓度(活率为95%或更高)稀释至6x106个活细胞/mL的浓度。
对于亲本细胞的转染,使用ExpiFectamineTM CHO转染试剂盒(Gibco)。将质粒DNA和ExpiFectamineTM CHO试剂混合以产生ExpiFectamineTM CHO/质粒DNA复合物。将复合物接种在冷OptiPROTM SFM培养基(Gibco)中。将所得混合物在室温下保持5分钟并添加到亲本细胞中。转染后一天,将ExpiFectamineTMCHO增强剂和ExpiCHOTM补料添加到转染的细胞中。转染后五天,将第二体积的补料添加到细胞培养物中。在8% CO2、37℃和120rpm的条件下培养十天后,将细胞培养物转移到离心瓶中,在4℃和6,500rpm下离心30分钟。将上清液通过0.2μm过滤器过滤以去除悬浮物,然后进一步纯化以获得双特异性抗体。
实施例4:用于评价抗体对α-syn预形成原纤维的亲和力的夹心ELISA测试
夹心ELISA使用来自StressMarq的人α-syn PFF(人α突触核蛋白预形成原纤维II型,SPR-317)分析1E4嵌合和人源化抗体对α-syn预形成原纤维(PFF)的结合亲和力。具体地,通过从400nM至0.009nM进行六倍连续稀释,将抗体用PBS稀释。将稀释的抗体以100μL/孔添加到96孔板中进行包被。将板密封并在4℃下孵育16小时。在用含有的磷酸盐缓冲盐水(PBS-T;0.05%/>20)洗涤五次后,将板用5% BSA的PBS溶液200μL/孔在37℃下封闭2小时。在用PBS-T洗涤五次后,将α-syn PFF(2μg/mL,100μL/孔,在2%BSA的PBS溶液中)添加到板中,并且在37℃下孵育2小时。在用PBS-T洗涤五次后,添加7B7-生物素抗体(抗α-syn抗体;1μg/mL/100μL/孔,在2% BSA的PBS溶液中),并且在37℃下孵育2小时。在用PBS-T洗涤五次后,将板与辣根过氧化物酶(HRP)结合的链霉亲和素在含2% BSA的PBS(1:5000,1mg/mL原液,20ng/孔,100μL/孔)中一起在37℃下孵育1小时。在用PBS-T洗涤五次后,添加3,3',5,5'-四甲基联苯胺(TMB)(100μL/孔),并且在室温下孵育5分钟。通过添加0.5NH2SO4(50μL/孔)终止反应。通过使用读板器测量450nm处的吸光度,从读数中减去650nm处的吸光度。
图1和图2示出了嵌合和单特异性人源化1E4抗体与PFF结合的结果。下表4和表5示出了嵌合1E4抗体和从ELISA中选择的单特异性人源化1E4(hu1E4)抗体的EC50值。
表4.嵌合和人源化1E4抗体与α-syn PFF结合的EC50
克隆名称 | EC50(nM) |
ch1E4 | 0.876 |
hu1E4(V1_VL1) | 0.619 |
hu1E4(V2_VL2) | 0.570 |
hu1E4(V3_VL2) | 0.577 |
hu1E4(V7_VL2) | 0.339 |
hu1E4(V4_VL2) | 0.228 |
表5.另外的人源化1E4抗体与α-syn PFF结合的EC50
克隆名称 | EC50(nM) |
ch1E4 | 0.209 |
hu1E4(V8_VL4) | 0.139 |
hu1E4(V9_VL4) | 0.114 |
hIgG1 | 不可测量 |
这些数据表明,所测试的所有嵌合和人源化1E4抗体都对α-syn PFF表现出高结合亲和力,并且人源化抗体表现出比嵌合抗体更高的结合亲和力。由于嵌合抗体含有亲本小鼠1E4抗体的VH和VL,因此这些结果表明人源化过程提高1E4抗体的抗原结合亲和力。
图3和图4示出了嵌合和双特异性1E4抗体的ELISA结果。下表6和表7示出了来自夹心ELISA的这些抗体的EC50值。
表6.双特异性抗α-syn/IGF1R抗体与α-syn PFF结合的EC50
表7.另外的双特异性抗体与α-syn PFF结合的EC50
抗体克隆名称 | EC50(nM) |
ch1E4 | 0.484 |
hu1E4(V5_VL3)x Grabody B | 1.098 |
hu1E4(V5_VL5)x Grabody B | 0.215 |
hu1E4(V6_VL3)x Grabody B | 1.118 |
hu1E4(V6_VL4)x Grabody B | 0.233 |
hu1E4(V5_VL4)x Grabody B | 0.284 |
以上数据表明,所测试的所有双特异性抗体都对α-syn PFF表现出高结合亲和力,其中一些表现出比嵌合抗体更高的结合亲和力。
接下来,使用夹心ELISA评价对α-syn PFF的结合亲和力,并且直接在小鼠1E4(rm1E4)、嵌合1E4(ch1E4)和单特异性人源化1E4(V1_VL1)之间进行比较,如上所述。如图5和下表8所示,与小鼠或嵌合1E4相比,hu1E4抗体对α-syn PFF表现出更高的亲和力。
表8.小鼠、嵌合和人源化1E4抗体的比较
抗体克隆名称 | EC50(nM) |
rm1E4 | 2.588 |
ch1E4 | 1.609 |
hu1E4(V1_VL1) | 1.098 |
还通过夹心ELISA评价对α-syn PFF的结合亲和力,并且在hu1E4(V1_VL1)和另一种小鼠抗α-syn抗体hu11F11(ver.2)的人源化形式(参见WO 2019/098763)之间进行比较。如实施例3中所述,两种抗体都被构造成包括融合的Grabody B。如图6和表9所示,双特异性“hu1E4(V1_VL1)x Grabody B”抗体对α-syn PFF表现出比双特异性“hu11F11(ver.2)xGrabody B”抗体高得多的亲和力。
表9.双特异性hu1E4和hu11F11抗体的比较
抗体克隆名称 | EC50(nM) |
hu11F11(ver.2)x Grabody B | 2.537 |
hu1E4(V1_VL1)x Grabody B | 0.236 |
实施例5:用于评价抗体对寡聚体α-syn的亲和力的夹心ELISA
与α-syn PFF不同,多巴胺HCl稳定的α-syn寡聚体具有很少的β-折叠,并且被认为是与PFF不同类型的聚集体,因为寡聚体具有较小的球状形状。结合α-syn PFF和多巴胺HCl稳定的α-syn寡聚体的抗体可以广泛作用于处于不同阶段的突触核蛋白病(诸如帕金森病)的患者脑中存在的各种类型的聚集体。
为了评价hu1E4抗体对寡聚体α-syn的结合亲和力并将它们与现有的抗α-syn抗体进行比较,如上所述使用单特异性hu1E4(V1_VL1)、双特异性hu1E4(ver.1_VL1)xGrabodyB、单特异性hu11F11(ver.2)、嵌合9E4抗体(Roche)、NI-202抗体(Biogen)和hy1E4(其为小鼠1E4抗体)进行夹心ELISA。在测定中将来自StressMarq的人α-syn寡聚体(多巴胺HCl稳定的人重组α突触核蛋白寡聚体,SPR-466)用作寡聚体α-syn。
在此夹心ELISA中,通过从80nM至0.005nM进行五倍连续稀释,将测试抗体用PBS稀释。将连续稀释的抗体以100μL/孔添加到96孔板中进行包被。将板密封并在4℃下孵育16小时。在用PBS-T洗涤五次后,将板用5% BSA的PBS溶液200μL/孔在37℃下封闭2小时。在用PBS-T洗涤五次后,添加寡聚体α-syn(2μg/mL,100μL/孔,在2% BSA的PBS溶液中),并且在37℃下孵育2小时。在用PBS-T洗涤五次后,添加7B7-生物素抗体(1μg/mL,100μL/孔,在2%BSA的PBS溶液中),并且在37℃下孵育2小时。在用PBS-T洗涤五次后,将板与链霉亲和素-HRP在2% BSA的PBS溶液(1:5000,1mg/mL原液,20ng/孔,100μL/孔)中一起在37℃下孵育1小时。在用PBS-T洗涤五次后,添加TMB(100μL/孔),并且在室温下孵育5分钟。通过添加0.5NH2SO4(50μL/孔)终止反应。通过使用读板器测量450nm处的吸光度,从读数中减去650nm处的吸光度。
如图7和下表10所示,hu1E4(V1_VL1)及其双特异性形式比所测试的所有其他比较物更好地结合α-syn寡聚体。
表10.对寡聚体α-syn的结合亲和力的比较
*n/m:不可测量。
这些结果表明,与现有的商业化抗α-syn抗体相比,本发明的人源化1E4抗体的单特异性和双特异性形式两者都表现出优异的结合亲和力。
接下来,评价对寡聚体α-syn的结合亲和力,并且在与Grabody B的双特异性抗体形式的hu1E4(V1_VL1)和hu11F11(ver.2)之间进行比较。如图8和表11所示,“hu1E4(V1_VL1)x Grabody B”双特异性抗体对寡聚体α-syn表现出比“hu11F11(ver.2)x Grabody B”双特异性抗体更高的结合。
表11.双特异性抗体与寡聚体α-syn结合的比较
抗体 | EC50(nM) |
hu11F11(ver.2)x Grabody B | 11.51 |
hu1E4(V1_VL1)x Grabody B | 3.82 |
实施例6:抗体对α-syn PFF的结合亲和力的评价
进行表面等离子共振(SPR)分析以定量分析嵌合和人源化抗α-syn 1E4抗体的结合亲和力。所使用的设备是(GE Healthcare,型号T200)。将蛋白A(GEHealthcare,目录:29-1275-56)用作芯片,将10mM甘氨酸-HCl pH 1.5(GE Healthcare,目录:BR-1003-54)用作再生缓冲液,并且将HBS-EP用作运行缓冲液以及分析物稀释和样品稀释缓冲液。将抗体用1X HBS-EP稀释,并且将α-syn原纤维蛋白溶液(PFF,2.6mg/mL)(分析物)连续稀释两倍,以分析浓度为0、0.15625、0.3125、0.625、1.25和2.5nM的六个样品。在60秒的接触时间下进行捕获阶段,并且使用30μL/min的流速,稳定期为60秒,其中将原纤维的目标共振单位(RU)设定为10(理论值)。在缔合阶段,将缔合时间设定为60秒,并且将流速设定为60μL/min。在解离阶段,将解离时间设定为180秒,并且将流速设定为60μL/min。在再生阶段,将流速设定为30μL/min,并且将再生时间设定为60秒。使用1:1结合模型进行拟合,并且使用/>T200评价软件(GE Healthcare)进行评价。
如表12所示,一些人源化1E4克隆表现出与嵌合1E4相当的结合亲和力水平,并且与嵌合1E4相比,一些克隆(诸如hu1E4(V1_VL1))甚至表现出优异的结合亲和力。hu1E4(V1_VL1)的kd值比ch1E4更好,这意味着hu1E4(V1_VL1)一旦与α-syn结合,它就保持结合且不易解离。这也可以通过高亲和力(低KD值)来证明。因为在人源化期间通常难以保持小鼠和嵌合抗体的初始结合亲和力,所以这些结果是令人惊讶的。
表12.嵌合和人源化1E4抗体的结合亲和力和动力学
将hu1E4(V1_VL1)克隆格式化为与Grabody B的抗α-syn/IGF1R双特异性抗体。然后,如上所述测试抗体对α-syn PFF的结合亲和力。如表13所示,证实hu1E4(V1_VL1)单特异性抗体和双特异性抗体(BsAb)在1:1结合模型中具有类似的KD值。这些数据表明,当将Grabody B部分用作双特异性抗体配偶体时,它对hu1E4对α-syn PFF的结合亲和力没有负面影响。
表13.单特异性和双特异性hu1E4抗体的比较
将各种人源化1E4克隆制备成与Grabody B的抗α-syn/IGF1R BsAb,并且如上所述测试它们对PFF的亲和力,并且与ch1E4的SPR结果进行比较。如表14所示,双特异性人源化1E4抗体在1:1结合模型中也表现出与嵌合1E4相当的结合亲和力。与单特异性嵌合1E4抗体相比,一些克隆(诸如hu1E4(V1_VL1))在BsAb形式下表现出优异的结合亲和力。
表14.嵌合1E4和hu1E4 BsAb的结合亲和力和动力学
为了确认hu1E4(V1_VL1)相对于之前的抗α-syn人源化抗体hu11F11的优异性,使用SPR分析来定量分析hu1E4(V1_VL1)x Grabody B和hu11F11(ver.2)x Grabody B对α-synPFF的结合亲和力。所使用的设备是通过胺偶联将在乙酸盐缓冲液(pH 5.0)中稀释的抗hFab(Sigma,I5260-1ML)固定在CM3芯片(GE Healthcare)的表面上。然后,将测试品用HBS-EP缓冲液稀释,并且将稀释的样品在30μL/min下以约10RU(对于hu1E4(V1_VL1)xGrabody B)或50RU(对于hu11F11(ver.2)x Grabody B)捕获在抗hFab芯片表面上。通过进行3倍连续稀释,将α-syn PFF用HBS-EP缓冲液稀释,对于hu1E4(V1_VL1)xGrabody B,浓度为0、0.012、0.037、0.111、0.333和1nM,或者对于hu11F11(ver.2)x Grabody B,浓度为0、0.111、0.333、1、3和9nM。将每种稀释的α-syn PFF溶液以60μL/min注射到抗体捕获的芯片表面上保持60sec,然后在表面上用HBS-EP(1X)缓冲液洗涤180sec。缔合和解离阶段的所有程序都是在单循环动力学中完成的。使用1:1结合模型进行拟合,并且使用/>T200评价软件进行评价。
表15和图9所示的结果表明,hu1E4(V1_VL1)BsAb具有比hu11F11(ver.2)双特异性抗体好得多的α-syn PFF结合亲和力。
表15.hu1E4和hu11F11 BsAb的比较
如上所述通过SPR分析评价对α-syn PFF的结合亲和力,并且在hu1E4(V1_VL1)xGrabody B和其他市售抗α-syn抗体之间进行比较。表16和图10中的数据表明,hu1E4(V1_VL1)x Grabody B对α-syn PFF的平衡解离常数(KD)为2.5x10-11 M,因此与现有的抗α-syn抗体相比,表现出优异的α-syn PFF结合亲和力。
表16.hu1E4 BsAb和市售抗体的比较
这些数据证明,即使在BsAb形式下,与现有的抗α-syn单特异性抗体相比,本公开文本的人源化抗体也具有优异的α-syn PFF结合亲和力。
实施例7:抗体对α-syn单体的结合亲和力的评价
评价hu1E4(V1_VL1)和hu1E4(V8_VL4)对单体α-syn的结合亲和力,并且与现有的抗α-syn抗体ch9E4(Roche/Prothena;普尼珠单抗)进行比较。将无关人IgG1(hIgG1)用作阴性对照。使用SPR分析来定量分析对单体α-syn(活性人重组α突触核蛋白单体II型,StressMarq,SPR-316)的结合亲和力。所使用的设备是T200。将抗α-syn单特异性抗体或抗α-syn/IGF1R双特异性抗体用1X HBS-EPT稀释。将稀释的抗体样品在30μL/min下以约800RU捕获在蛋白A芯片(GE Healthcare,目录:29-1275-56)的表面上。通过从50nM至3.125nM进行两倍连续稀释,将α-突触核蛋白单体用1X HBS-EP缓冲液稀释。将每个稀释的单体样品以60μL/min注射到蛋白A芯片表面上保持60秒,然后用1X HBS-EP缓冲液洗涤。评价解离速率180秒。缔合/解离阶段的所有程序都是在单循环动力学中完成的。通过以30μL/min将10mM甘氨酸-HCl pH 1.5(GE Healthcare)注射到芯片表面上保持60秒来使芯片表面再生,从而去除残留的α-syn单体/抗体复合物。使用1:1结合模型进行拟合,并且使用/>T200评价软件进行评价。
表17-表19和图11中的数据表明,本公开文本的单特异性和双特异性hu1E4抗体对单体α-syn表现出非常低的结合亲和力。相比之下,ch9E4抗体对单体以很强的亲和力结合。
表17.ch9E4和单特异性hu1E4(V1_VL1)抗体的比较
表18.ch9E4和双特异性hu1E4抗体的比较
表19.ch9E4和单特异性hu1E4(V8_VL4)抗体的比较
这些结果证明,本公开文本的抗α-syn抗体优先与α-syn聚集体结合,并且对α-syn单体没有可检测的结合亲和力。
实施例8:抗体产量的评价
如上所述使用编码小鼠、嵌合和人源化1E4抗体的表达构建体来转染宿主细胞。使用MabSelectTMSuReTM(MSS)树脂(GE Healthcare)分离和纯化在细胞中产生的抗体。通过使用Thermo ScientificTM NanoDropTM分光光度计测量抗体产量。首先,加载1X PBS以确认零点。然后,加载预定量的纯化的抗体样品,并且在280nm的UV波长下测量每个测试样品的蛋白质量,并且通过将由NanoDropTM测定的蛋白质浓度乘以测试样品的总体积进行计算。使用HLC-001(Agilent 1200系列)系统通过高效液相色谱法分析纯化的抗体样品的纯度,并且量化主峰的比率。
下表20示出了所选抗体的产率值(以洗脱物质量/收获的细胞培养液(HCCF)体积表示)。
表20.所选抗体的产率
以上数据表明,嵌合1E4抗体、人源化1E4抗体及其双特异性抗体的产量明显高于小鼠1E4抗体的产量。
为了比较嵌合和人源化1E4单特异性抗体克隆之间的产率,通过MSS柱纯化30mL培养液,并且使用NanodropTM分析纯化的产物中的抗体量。如表21所示,与嵌合1E4克隆相比,所有人源化1E4单特异性抗体克隆都具有优异的产率。
表21.所选1E4抗体的产率
抗体克隆名称 | 产率(mg) |
小鼠1E4 | N/A |
ch1E4 | 0.611或0.358 |
hu1E4(V1_VL1) | 2.33 |
hu1E4(V2_VL2) | 2.16 |
hu1E4(V3_VL2) | N/A |
hu1E4(V4_VL2) | 1.942 |
hu1E4(V7_VL2) | 2.267 |
hu1E4(V8_VL4) | 2.05 |
hu1E4(V9_VL4) | 2.23 |
实施例9:人源化抗体的免疫原性的评价
使用免疫表位数据库(IEDB)T细胞表位预测软件通过计算机分析评价hu1E4(V1_VL1)的免疫原性,并且与ch1E4的免疫原性进行比较。
基于与MHC II复合物结合的能力,对具有跨越Fv区整个抗体序列的15个残基的单独肽进行评分。所选的MHC II等位基因是11个人HLA DRB1等位基因和4个人HLA DRB3/4/5等位基因。将与12-15(得分为8至10)或6-11(得分为4至7)个MHC II分子结合的非冗余肽分别标记为高混杂和中混杂,表明可能是潜在的T细胞表位。
下表22中的数据表明,轻链中与6-11个MHC II分子结合的非冗余肽(标记为中混杂)的数量在ch1E4中为三(3),而在hu1E4 VL1中为零。与MHC II分子结合的非冗余肽的数量较多可以被解释为ch1E4可能具有比hu1E4高的免疫原性。
表22.所选1E4重链和轻链的免疫原性
实施例10:hu1E4抗体在促进α-syn PFF的吞噬方面显示出优异的功效
评价ch1E4和hu1E4抗体(单特异性形式或与Grabody B的双特异性形式)的小胶质细胞吞噬促进活性或单核细胞吞噬促进活性。在ch1E4、hu1E4、现有的抗α-syn抗体ch9E4、以前的人源化抗α-syn抗体11F11(ver.2)和hIgG1对照之间进行比较。
使BV-2细胞(一种小胶质细胞系)在补充有10%胎牛血清的RPMI1640中生长,并且将其以2.5x105个细胞/孔添加到96孔板中。在单独的试管中,将α-syn PFF和不同浓度的测试抗体混合,并且孵育20min。抗体的浓度在表23中示出。
表23.用于α-syn PFF吞噬测定的抗体浓度
抗体浓度(μg/mL)(nM) |
0.03125(0.208125) |
0.0625(0.41625) |
0.125(0.8325) |
0.25(1.665) |
0.5(3.33) |
1(6.66) |
2(13.32) |
4(26.64) |
将混合物添加到BV-2细胞中并在37℃下孵育20分钟。孵育后,将板离心并弃去上清液。将细胞用PBS(调节至pH 2.5)洗涤,重悬并离心,然后弃去上清液以消除细胞表面的非内化PFF-Ab复合物。将此洗涤和离心重复两次。
将细胞用4%多聚甲醛固定30分钟,然后用PBS洗涤。然后,将100μL 0.5%X-100溶液添加到细胞中,将其进一步孵育20min。将细胞用1X PBS(pH 7.4)洗涤两次,然后添加100μL 1%牛血清白蛋白的PBS溶液进行封闭。将细胞用1X PBS(pH 7.4)洗涤两次,然后在室温下与100μL一抗(抗α-syn,Santacruz,目录:SC-10717,1:1000)一起孵育1h。然后,添加100μL PBS(含0.05% TweenTM20),并且将溶液重悬并离心(2000rpm,3min,4℃);弃去上清液。重复以上洗涤步骤,然后将二抗(抗兔alexa488,Cell Signal,目录:4412S,1:1000)添加到细胞中,并且在黑暗中孵育1h。再次添加100μL PBS(含0.05%TweenTM20),并且将溶液重悬并离心(2000rpm,3min,4℃)。弃去上清液,并且重复洗涤步骤。然后将细胞用PBS重悬并进行FACS分析,其结果被量化为跨所测试抗体浓度的几何平均荧光强度(gMFI),并且在图12中示出。
图12中的数据表明,在BV-2细胞中,ch1E4促进α-syn PFF的吞噬的程度比hIgG1对照大得多,并且比ch9E4(Roche/Prothena)的速率高两倍。这些结果表明,ch1E4促进小胶质细胞去除α-syn聚集体,这已经与神经元中的神经毒性、炎症和神经变性以及帕金森病的病因相关联。因此,这些结果表明ch1E4比ch9E4具有更强的治疗潜力。
接下来,将ch1E4 x Grabody B抗体的单核细胞吞噬促进活性与hIgG1的单核细胞吞噬促进活性进行比较。如上所述进行测定,不同的是使用THP-1细胞代替BV-2细胞。THP-1是一种具有吞噬功能的人单核细胞白血病细胞。图13中的数据表明,在THP-1细胞中,ch1E4x Grabody B促进α-syn PFF的吞噬的程度比hIgG1对照更大。考虑到THP-1细胞表达与小胶质细胞上的细胞表面标志物类似的细胞表面标志物并以类似的方式吞噬,这些结果表明ch1E4和ch1E4 x Grabody B BsAb两者都促进人小胶质细胞对细胞外α-syn PFF的吞噬。
比较另外的hu1E4 BsAb在促进小胶质细胞吞噬作用方面的活性。图14中的数据表明,在所测试的BsAb中,hu1E4(V1_VL1)x Grabody B在促进吞噬方面表现出最高活性。
图15比较了ch1E4和hu1E4(V1_VL1)x Grabody B的吞噬促进活性。hu1E4(V1_VL1)显示出与ch1E4一样高的吞噬促进活性,甚至略高,尽管它与Grabody B组合。图16比较了hu1E4(V1_VL1)x Grabody B和ch9E4的吞噬促进活性。图17比较了hu1E4(V1_VL1)xGrabody B和hu11F11(ver.2)x Grabody B的吞噬促进活性。这些图中的数据证明,与hIgG1、ch9E4、hu11F11(ver.2)和ch1E4相比,hu1E4(V1_VL1)x Grabody B表现出优异的吞噬促进活性。因此,hu1E4(V1_VL1)的更高PFF结合亲和力与更大治疗潜力相关。
实施例11:ch1E4在mThy-1小鼠中显示出优异的结合人α-syn的能力
测试ch1E4和其他α-syn抗体在mThy-1小鼠(UC San Diego)(一种过表达人α-syn的转基因小鼠模型)中识别α-syn聚集体的能力。
用1X PBS对11月龄的mThy-1雌性小鼠进行心内灌注。此后,通过浸入4%PFA/1XPBS溶液中将脑固定。在固定12小时后,将脑转移到30%蔗糖/1X PBS溶液中并保存3天。然后使用低温切片机将固定的脑切成40μm厚的小块。将切片用1X PBS洗涤两次并用3%过氧化氢封闭。将所有用作一抗的抗α-syn抗体用1X PBS稀释至1mg/mL,以1:1000的比率添加到封闭的切片中,然后在4℃下孵育12小时。在将封闭的切片用1X PBS充分洗涤后,以1:200的比率添加抗人IgG抗体,并且将封闭的切片用3,3'-二氨基联苯胺(DAB)染色。使用明场显微镜对染色的切片进行成像和分析。
如图18和图19所示,ch1E4识别所分析脑的所有部分中的神经毡和α-syn聚集体。市售抗体(例如,NI202和BA149)对α-syn聚集体表现出非常弱的识别。ch9E4表现出识别能力,但是在杏仁体和海马体中的识别度较差,并且显示出不规则且脏污的染色模式。BA149不能很好地识别神经毡α-syn聚集体,并且仅在脑的一些区域中表现出识别能力。
实施例12:使用ch1E4对患有帕金森病的死后人脑进行染色
为了验证1E4识别患有突触核蛋白病的患者的脑组织中的聚集α-syn,使用ch1E4对死亡前4.5年被诊断患有帕金森病痴呆的74岁男性患者的死后脑组织进行染色。将来自已故患者的石蜡包埋的脑切片进一步切成4μm厚的小块。将这些脑切片固定在载玻片上,用二甲苯去石蜡,然后用分级乙醇溶液再水化。抗原修复后,通过使用3%过氧化氢和0.005%X-100的PBS溶液淬灭脑切片。将脑切片与一抗即市售抗磷酸化α-syn的抗体Syn303(BioLegend,目录号:824301)或ch1E4一起在4℃下孵育12小时。在将切片用1X PBS洗涤后,根据制造商手册进行DAB反应。将染色的切片放在载玻片上,并且通过使用明场显微镜进行分析来拍摄它们的图像。
已知磷酸化α-syn是路易体和路易神经突的主要组分,其导致帕金森病中的神经变性和脑功能障碍。如图20所示,ch1E4以与Syn303(其用于相邻切片中)类似的灵敏度识别磷酸化α-syn。磷酸化α-syn的识别模式与文献中报道的路易体和路易神经突的识别模式类似。这些结果证明,ch1E4识别帕金森病患者的脑组织中的路易体和路易神经突。
实施例13:脑对ch1E4抗体的暴露
分析在mThy-1转基因小鼠中对ch1E4和ch1E4 x Grabody B的暴露情况。以50mg/kg腹膜内施用单特异性或双特异性ch1E4抗体中的每一种,每三天一次,持续11天(在0、72、144和216小时施用)。将七月龄的雄性mThy-1小鼠分为单特异性抗体测试组(n=3)和双特异性抗体测试组(n=2)。在0、72和264小时收集血浆。根据人道脑病理学分析的规定,在264小时用水合氯醛麻醉动物。然后,用0.9%生理盐水对动物进行心内灌注。
接下来,将一半灌注脑(矢状切片)保存在4%多聚甲醛(pH 7.4,4℃)的磷酸盐缓冲液溶液中,直到分析。将另一半脑立即以冷冻状态(-70℃)保存。
如下进行病理学分析。使用振动切片机以自由浮动方式将固定在多聚甲醛中的一半脑切成厚度为40μm的连续切片。为了确定每个动物组中的脑中磷酸化α-syn的表达水平,将包括皮层、海马体和纹状体的切片与磷酸化α-syn抗体一起在4℃下孵育过夜。用于聚集α-syn的标志物包括磷酸化-129α-syn抗体(Abcam,#ab59264)或全长α-syn抗体(CellSignaling Technology,#2642)。然后根据制造商手册使用DAB对标志物进行染色。在明场显微镜下对免疫染色的组织切片进行成像。
在相邻切片中,通过免疫荧光染色分析人IgG的水平。使不同脑区的切片在4℃下与缀合有荧光染料Alexa488的抗人IgG抗体反应12小时。然后用1X PBS洗涤脑切片。为了定位神经元,用抗神经元标志物NeuN的抗体(Chemicon,#MAB377)处理切片。在共聚焦显微镜下分析切片以测量细胞的光密度。
图21中的数据表明,与单特异性ch1E4相比,ch1E4 BsAb在脑中的暴露水平更高。具体地,双特异性抗体在皮层、海马体和黑质中的暴露水平分别比单特异性抗体高7.39倍、4.28倍和6.04倍。结果表明,Grabody B显著提高1E4在不同脑区中的血脑屏障(BBB)穿过能力。
实施例14:体内磷酸化α-syn的减少
在本实施例中,以与实施例13类似的方式进行实验,不同的是在将测试1E4抗体施用到小鼠体内后,用抗p-129α-syn的抗体对小鼠脑组织中的皮质、杏仁体和海马体进行染色。p-129α-syn是这样形式的α-syn,其中位置129处的丝氨酸残基被磷酸化,并且已经牵涉在帕金森病的发病机制中。在本实验中,在用抗p-129α-syn抗体染色的组织中以深棕色点或聚集体的形式观察到这种形式的α-syn。
图22中的数据表明,单特异性和双特异性ch1E4两者都具有在体内去除α-syn聚集体的能力。数据还表明,与单特异性ch1E4相比,与Grabody B的双特异性ch1E4减少脑中(包括大脑皮层、海马体和杏仁体中)的p-129α-syn的能力增强。具体地,双特异性抗体具有使皮层、杏仁体和海马中的p-129α-syn分别减少26%、34%和40%的优异效果。因此,与单特异性形式相比,ch1E4 x Grabody B在帕金森病动物模型中降低p-129α-syn及其聚集体的水平的效率高得多。这些结果与实施例13中的结果一致,并且证实由于与单特异性抗α-syn抗体相比BBB穿透能力提高,更大量的1E4 BsAb可以到达脑,从而使得双特异性抗体成为治疗突触核蛋白病的改进的治疗工具。
利用基于Grabody B的双特异性人源化抗α-syn抗体进行类似的实验。图23中的数据表明,hu1E4(V1_VL1)x Grabody B比hu11F11 x Grabody B更大程度地降低mThy-1小鼠中的p-129α-syn水平,表明hu1E4在抑制神经元之间的α-syn传递方面更有效。
总之,此处的结果证明,双特异性hu1E4(诸如hu1E4(V1_VL1)x Grabody B)在体内从脑中去除p-129α-syn方面非常有效。
实施例15:hu1E4减少多巴胺能神经元中的α-syn传播
测试hu1E4(V1_VL1)和hu11F11抑制源自来源于帕金森病患者的诱导多能干细胞(iPSC)的多巴胺能神经元中的α-syn传播的能力。如图24所示,在5μg/ml时,hu1E4(V1_VL1)比hu11F11在更大程度上改善这些神经元中的α-syn传播。在hu1E4 mAb处理30天后,多巴胺能神经元中与多巴胺能神经元细胞标志物酪氨酸羟化酶共定位的α-syn染色的强度显著且呈剂量依赖性降低。在hu11F11 mAb的情况下,共定位强度的降低不如hu1E4 mAb显著。这些结果表明,hu1E4在抑制神经元之间的α-syn传递方面更有效,因此可能对治疗帕金森病和其他α-突触核蛋白病更有效。
除非本文另外定义,否则结合本公开文本使用的科学和技术术语应当具有本领域普通技术人员通常理解的含义。此处描述了示例性方法和材料,但在本公开文本的实践或测试中也可以使用与本文所述的那些方法和材料类似或等效的方法和材料。将本说明书中提及的所有出版物、专利申请、授权专利和其他文件都通过引用并入本文,如同具体且单独地指示将每个单独的出版物、专利申请、授权专利或其他文件通过引用以其整体并入一样。尽管本文引用了许多文件,但此引用并不意味着承认这些文件中的任一个构成本领域公知常识的一部分。在发生冲突的情况下,应以包括定义在内的本说明书为准。此外,除非上下文另外要求,否则单数术语应当包括复数,并且复数术语应当包括单数。在整个本说明书和实施方案中,词语“具有(have)”和“包含(comprise)”或变型(诸如“具有(has)”、“具有(having)”、“包含(comprises)”或“包含(comprising)”)应被理解为暗示包括所陈述的整数或整数组,但是不排除任何其他整数或整数组。如本文所用,术语“约”是指在所陈述量附近10%或更少的量。此外,本文提供的标题仅是为了方便,并不解释所要求保护的实施方案的范围或含义。
序列
下面列出了本公开文本中提供的氨基酸和核苷酸(nt)序列(SEQ:SEQ ID NO)。
除非另外通过“nt”指示,否则所有序列都为氨基酸序列。
/>
/>
/>
/>
/>
/>
/>
/>
序列表
<110> ABL生物公司
<120> 用于治疗α-突触核蛋白病的抗体
<130> 122548.WO015
<150> KR 10-2021-0061407
<151> 2021-05-12
<160> 77
<170> PatentIn 3.5版
<210> 1
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.1)
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 2
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.2)
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 3
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.3)
<400> 3
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Val Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 4
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.4)
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 5
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.5)
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 6
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.6)
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 7
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.7)
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 8
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.8)
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 9
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.9)
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 10
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成:ch1E4 (CPF)_VH
<400> 10
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 11
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL1)
<400> 11
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 12
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL2)
<400> 12
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 13
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL3)
<400> 13
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 14
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL4)
<400> 14
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 15
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL5)
<400> 15
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 16
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成:ch1E4 (CPF)_VL
<400> 16
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 17
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.1)
<400> 17
caggtgcaac tggtccaatc tggtgccgaa gtgaaaaagc ccggtgcaag tgttaaagtt 60
tcctgcaaag catctggcta tacttttact aattatctga tagaatgggt acgacaagct 120
ccaggtcaag gtcttgaatg gatgggcgtg attaacccag ggagtggagg aactaattac 180
aatgagaagt tcaaaggacg agtgacaatg acccgtgata ccagtattag caccgcatac 240
atggagttga gcaggcttcg tagcgacgac accgcagtat attattgtgc ttccggcaat 300
tatgatacct attgggggca ggggactctc gtaaccgtct ccagt 345
<210> 18
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.2)
<400> 18
caagttcagc ttgtgcaaag cggagctgag gtcaaaaaac caggagcatc tgtgaaagtg 60
tcatgcaaag catctggtta cacttttact aactatctca ttgagtgggt cagacaggct 120
ccaggacaag ggttggaatg gattggggtc atcaaccctg ggtcaggggg gacaaattac 180
aatgaaaaat ttaaagggaa ggtgacactc acagcagata agtctatttc aaccgcttat 240
atggaacttt cccgccttag gagcgatgat acagcagtct attattgcgc ttcagggaac 300
tacgacactt actgggggca aggcacactc gttacagtgt cctcc 345
<210> 19
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.3)
<400> 19
caagtgcagc tggtgcagtc tggcgcagaa gtgaagaaac ctggggcttc tgtgaaggtc 60
agctgtaaag cttctgggta tgcttttaca aactatctca tagaatgggt caaacaagct 120
ccaggtcagg gcctggagtg gatcggtgta atcaaccctg gtagtggcgg aacaaactac 180
aatgagaagt tcaaaggcaa agtgactctt accgccgaca aaagcatttc tacagcttat 240
atggagttgt caaggttgag aagcgacgac acagcagttt actattgcgc ttcaggaaat 300
tatgacacat actggggtca gggtacactg gtgactgtgt cctct 345
<210> 20
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.4)
<400> 20
caagtccaat tggtccagag tggagctgaa gttgttaaac caggagcaag cgttaaagtt 60
agttgtaagg catcaggtta cgccttcacc aactacttga ttgaatgggt aaagcaacgt 120
cccggtcagg gccttgagtg gattggggtt ataaatcctg gttctggggg aactaattac 180
aacgagaagt tcaagggcaa ggccaccctt actgccgaca agtccataag caccgcctat 240
atggaattga gcagattgcg aagtgatgac accgccgtct actattgtgc ttcaggtaat 300
tatgatacct attgggggca aggaacactg gtgaccgtat cttcc 345
<210> 21
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.5)
<400> 21
caagtccaac tggttcagtc tggagctgaa gtaaaaaagc ctggggccag tgtgaaagta 60
tcctgcaaag ccagcggcta cgcatttact aattatctga ttgaatgggt caagcaggca 120
ccaggacagg gtctggaatg gattggggtt ataaatccag gaagtggggg gactaattac 180
aatgagaaat ttaaaggccg agcaaccttg acacgcgata cctcaataag taccgcatat 240
atggaactca gtcgtctgcg aagtgatgat accgctgttt atttctgtgc tagtggcaac 300
tatgacacat actggggaca gggtacattg gtaacagtga gtagc 345
<210> 22
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.6)
<400> 22
caagtgcagc tggtacagtc cggagctgaa gtcaagaaac caggggcctc agtgaaagtt 60
tcatgtaagg cttctggata tgcctttacc aactacctta tcgagtgggt taaacaggcc 120
ccagggcaag gattggagtg gatcggggtc atcaatccag gatcaggtgg tacaaactat 180
aatgagaaat tcaagggtag agctactctg acagccgata caagtatcag cactgcatat 240
atggagttga gccgtctccg cagcgacgac acagccgtat atttctgtgc atctggcaat 300
tatgacacat actggggcca gggaactctt gtcaccgtct cctca 345
<210> 23
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.7)
<400> 23
caggtccaat tggtgcaatc aggggccgag gtcaaaaaac ctggagcaag tgttaaagtg 60
agctgtaagg cctctggcta cgcctttaca aattatctca tcgaatgggt aaagcaagca 120
ccagggcaag gactcgaatg gatgggcgtg attaacccag gatcaggggg aaccaattac 180
aacgaaaagt ttaaggggaa ggctacactg actgctgata aatccatatc tactgcatac 240
atggaactga gccggctccg ttctgacgac actgctgtct attattgcgc ttctggcaat 300
tatgatactt attgggggca aggcactctg gttacagtca gctcc 345
<210> 24
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.8)
<400> 24
caagtccagc tcgtacaaag tggtgccgag gttaagaaac ctggtgctag tgtgaaagtc 60
tcatgcaagg ctagtggcta cacttttacc aattacctga ttgaatgggt ccgacaagcc 120
ccaggtcagg gattggagtg gatgggagtc attaaccctg gctcaggtgg cactaattat 180
aacgaaaagt ttaaaggccg tgtgactatg accgccgaca agagcatctc tactgcatac 240
atggaactca gccgtctgcg ttctgatgat actgctgtgt attattgtgc atctgggaac 300
tacgacactt attggggaca gggcactctt gtaaccgtat cctct 345
<210> 25
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (ver.9)
<400> 25
caagtgcagt tggtgcaaag tggcgctgaa gttaagaagc ctggtgcttc agtcaaagta 60
tcttgcaaag ctagtggtta cacctttacc aactacctga tcgaatgggt caggcaggca 120
cccggacaag gtttggaatg gattggagtc ataaaccccg gctccggagg aactaactac 180
aacgagaaat tcaaaggcag ggccactctc accgctgata aaagtatttc aactgcatat 240
atggaacttt ctaggcttcg gtcagatgac actgctgtct actattgtgc atccggcaat 300
tacgatactt attggggcca ggggacattg gtcacagtgt cttct 345
<210> 26
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成:ch1E4 (CPF)_VH
<400> 26
caagtccaac tccaacaaag tggagcagag ttggtgcgcc caggcacaag tgtcaaagtt 60
agctgtaagg cttcaggcta tgcatttaca aattacttga ttgagtgggt gaaacagcga 120
cccggacaag gcttggaatg gatcggtgtc atcaatccag gatctggggg aacaaattat 180
aacgaaaaat tcaaggggaa agccacactc accgccgata aaagttcatc caccgcatat 240
atgcagctta gctctctcac atctgacgat agcgcagtgt atttctgcgc atccggtaat 300
tacgatactt attggggcca aggtactctg gtgaccgtta gcgcc 345
<210> 27
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL1)
<400> 27
gacattgtga tgactcagac tccccttagt cttagtgtta cccccgggca accagcatca 60
atatcatgcc gcagctcaca gagtctggtt cactctaatg gcaacactta tcttcactgg 120
tatctccaga aacccggtca atctccacaa ctgttgatct acaaagtgtc caatcgcttt 180
tcaggcgtgc ccgaccgatt tagtggtagc gggtcaggga ccgactttac tctgaaaatt 240
tcaagagtag aggctgaaga tgtaggagtc tactactgct ctcaaagtac ccatgttccc 300
agaacattcg gccagggcac caaactggag attaag 336
<210> 28
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL2)
<400> 28
gatgtagtga tgacacaaac ccctttgtca ttgagcgtca cccccggaca gcccgcttcc 60
attagttgcc gaagctcaca gagtctcgtc cactccaacg gtaacacata cctccactgg 120
tacttgcaga agcctggaca gagcccccaa ttgctgatat ataaagtgtc aaacagattt 180
agcggggtgc ccgatagatt ctccggtagc ggctcaggca ccgactttac attgaagatc 240
agtcgcgtcg aagcagagga tgttggcgtg tattattgca gtcaaagcac acatgttcct 300
aggacttttg ggcagggtac taagttggaa ataaag 336
<210> 29
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL3)
<400> 29
gatgtagtaa tgactcaatc tccacttagc ctccccgtga cactcggcca accagcaagc 60
atatcctgtc gttccagcca gtccctcgtg cattctaacg gcaacaccta cttgcattgg 120
ttccaacagc gtccaggaca gagtcctcgg cgtttgatat ataaggtgtc caaccgattc 180
agcggggttc ctgataggtt ttctggatct ggttcaggca ccgatttcac tttgaaaata 240
tctcgcgttg aggccgaaga cgtaggtgtg tattactgtt cccagtccac ccatgtgcct 300
cgaaccttcg ggggaggtac aaaagtggaa atcaaa 336
<210> 30
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL4)
<400> 30
gatgtggtaa tgacacagtc ccctctctca ttgcccgtga cactggggca gcccgcttcc 60
attagctgtc gaagtagtca gagcttggtt catagcaatg gtaatacata tttgcactgg 120
tatcaacaac gtccaggcca atcaccacga ctccttattt acaaagtctc taaccggttt 180
agcggtgtac cagaccgttt ctctggttca gggagtggga ccgatttcac tcttaaaatt 240
agtcgggtcg aagccgaaga cgttggcgtc tactattgca gccagtcaac tcatgtacca 300
cgaactttcg gcggcggtac caaggttgag attaag 336
<210> 31
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:hu1E4 (VL5)
<400> 31
gatgttgtga tgacacagtc cccactctct ctgcccgtca cattgggtca acccgcaagc 60
atctcctgtc gttccagcca gagtcttgta cattccaatg gcaatactta cctccattgg 120
taccaacaga gacccggtca aagccctcgt ctcttgatat ataaggtttc aaacaggttc 180
tcaggggtac ccgaccgatt cagcggttca gggtccggga cagacttcac cctcaaaatt 240
agtcgtgtgg aggctgagga cgtgggtgta tatttctgta gccagagtac ccatgtacct 300
cgcacctttg ggggaggcac caaggttgaa attaaa 336
<210> 32
<211> 336
<212> DNA
<213> 人工序列
<220>
<223> 合成:ch1E4 (CPF)_VL
<400> 32
gacgttgtaa tgactcaaac accactttct ttgccagtat cacttggaga tcaagcttct 60
atctcatgta ggagctccca gtcactggtg cattcaaacg gaaacacata ccttcactgg 120
tatctgcaaa aaccaggcca atcaccaaag cttttgatat acaaagtgtc aaatcgtttt 180
agcggagtac cagaccgatt cagcgggagc ggaagcggga ctgacttcac acttaagatt 240
agcagagtgg aagccgaaga cctgggtgtc tatttttgca gccagagcac ccatgtcccc 300
cgcacattcg gaggtggaac caagctggag ataaaa 336
<210> 33
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成:HCDR1
<400> 33
Asn Tyr Leu Ile Glu
1 5
<210> 34
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成:HCDR2
<400> 34
Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 35
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成:HCDR3
<400> 35
Gly Asn Tyr Asp Thr Tyr
1 5
<210> 36
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成:LCDR1
<400> 36
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 37
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成:LCDR2
<400> 37
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 38
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成:LCDR3
<400> 38
Ser Gln Ser Thr His Val Pro Arg Thr
1 5
<210> 39
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成:1E4 hIgG1重链恒定区 (杵)
<400> 39
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 40
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成:1E4 hIgG1重链恒定区 (臼)
<400> 40
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 41
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成:1E4 hIgG1重链恒定区 (杵) (M428L)
<400> 41
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 42
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成:1E4 hIgG1重链恒定区 (臼) (M428L)
<400> 42
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 43
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成:1E4 hIgG1轻链 (人κ) 恒定区
<400> 43
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> 44
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成:(G4S)3接头 - 1E4 hIgG1和Grabody B scFv之间的接头
<400> 44
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 45
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,VL
<400> 45
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Val Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Ala Gly Ser Leu
85 90 95
Asn Ala Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 46
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,LCDR1
<400> 46
Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser
1 5 10
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,LCDR2
<400> 47
Ala Asn Val Asn Arg Pro Ser
1 5
<210> 48
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,LCDR3
<400> 48
Gly Thr Trp Ala Gly Ser Leu Asn Ala Tyr Val
1 5 10
<210> 49
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成:VL和VH之间的(G4S)4接头
<400> 49
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 50
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,VH
<400> 50
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Tyr Asp Asn Ala Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Val Leu Thr Thr Leu Met Asn Trp Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 51
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,HCDR1
<400> 51
Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser
1 5 10
<210> 52
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,HCDR2
<400> 52
Ala Ile Ser Tyr Asp Asn Ala Asn Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 53
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,HCDR3
<400> 53
Gly Val Leu Thr Thr Leu Met Asn Trp Phe Asp Tyr
1 5 10
<210> 54
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成:Gra-body B抗IGF1R scFv,全scFv序列
<400> 54
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Asn Val Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Ala Gly Ser Leu
85 90 95
Asn Ala Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
130 135 140
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
145 150 155 160
Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu
165 170 175
Trp Val Ser Ala Ile Ser Tyr Asp Asn Ala Asn Thr Tyr Tyr Ala Asp
180 185 190
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
195 200 205
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Lys Gly Val Leu Thr Thr Leu Met Asn Trp Phe Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 55
<211> 596
<212> PRT
<213> 人工序列
<220>
<223> 合成:hIgG1- Grabody B恒定区,包括Grabody B scFv
(臼)
<400> 55
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly
325 330 335
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro
340 345 350
Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr
355 360 365
Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln
370 375 380
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ala Asn Val Asn Arg
385 390 395 400
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
405 410 415
Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr
420 425 430
Tyr Cys Gly Thr Trp Ala Gly Ser Leu Asn Ala Tyr Val Phe Gly Cys
435 440 445
Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu
465 470 475 480
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
485 490 495
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val
500 505 510
Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Ala Ile Ser Tyr
515 520 525
Asp Asn Ala Asn Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
530 535 540
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
545 550 555 560
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Gly Val Leu
565 570 575
Thr Thr Leu Met Asn Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
580 585 590
Thr Val Ser Ser
595
<210> 56
<211> 596
<212> PRT
<213> 人工序列
<220>
<223> 合成:hIgG1 (M428L)-Grabody B恒定区,包括Grabody
B scFv (臼)
<400> 56
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly
325 330 335
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro
340 345 350
Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Thr
355 360 365
Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln
370 375 380
Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ala Asn Val Asn Arg
385 390 395 400
Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser
405 410 415
Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr
420 425 430
Tyr Cys Gly Thr Trp Ala Gly Ser Leu Asn Ala Tyr Val Phe Gly Cys
435 440 445
Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu
465 470 475 480
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
485 490 495
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met Ser Trp Val
500 505 510
Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Ala Ile Ser Tyr
515 520 525
Asp Asn Ala Asn Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
530 535 540
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
545 550 555 560
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Gly Val Leu
565 570 575
Thr Thr Leu Met Asn Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
580 585 590
Thr Val Ser Ser
595
<210> 57
<211> 711
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 IgG1 (V1_VL1) x Grabody B (M428L) 重链
具有Grabody B scFv (臼)
<400> 57
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Val Leu
450 455 460
Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile
465 470 475 480
Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser Trp
485 490 495
Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ala Asn
500 505 510
Val Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser
515 520 525
Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu
530 535 540
Ala Asp Tyr Tyr Cys Gly Thr Trp Ala Gly Ser Leu Asn Ala Tyr Val
545 550 555 560
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
580 585 590
Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
595 600 605
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Asp Met
610 615 620
Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Ala
625 630 635 640
Ile Ser Tyr Asp Asn Ala Asn Thr Tyr Tyr Ala Asp Ser Val Lys Gly
645 650 655
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
660 665 670
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
675 680 685
Gly Val Leu Thr Thr Leu Met Asn Trp Phe Asp Tyr Trp Gly Gln Gly
690 695 700
Thr Leu Val Thr Val Ser Ser
705 710
<210> 58
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 合成:hu1E4 IgG1 (V1_VL1) x Grabody B (M428L) 重链
没有Grabody B (杵)
<400> 58
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asn Tyr Asp Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 59
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成:轻链
<400> 59
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 60
<211> 140
<212> PRT
<213> 人工序列
<220>
<223> 合成:智人 (Homo sapiens) α-突触核蛋白
<400> 60
Met Asp Val Phe Met Lys Gly Leu Ser Lys Ala Lys Glu Gly Val Val
1 5 10 15
Ala Ala Ala Glu Lys Thr Lys Gln Gly Val Ala Glu Ala Ala Gly Lys
20 25 30
Thr Lys Glu Gly Val Leu Tyr Val Gly Ser Lys Thr Lys Glu Gly Val
35 40 45
Val His Gly Val Ala Thr Val Ala Glu Lys Thr Lys Glu Gln Val Thr
50 55 60
Asn Val Gly Gly Ala Val Val Thr Gly Val Thr Ala Val Ala Gln Lys
65 70 75 80
Thr Val Glu Gly Ala Gly Ser Ile Ala Ala Ala Thr Gly Phe Val Lys
85 90 95
Lys Asp Gln Leu Gly Lys Asn Glu Glu Gly Ala Pro Gln Glu Gly Ile
100 105 110
Leu Glu Asp Met Pro Val Asp Pro Asp Asn Glu Ala Tyr Glu Met Pro
115 120 125
Ser Glu Glu Gly Tyr Gln Asp Tyr Glu Pro Glu Ala
130 135 140
<210> 61
<211> 30
<212> PRT
<213> 智人 (Homo sapiens)
<220>
<221> 位点
<222> (1)..(30)
<223> 人VH1-02 FR1
<400> 61
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 62
<211> 14
<212> PRT
<213> 智人 (Homo sapiens)
<220>
<221> 位点
<222> (1)..(14)
<223> 人VH1-02 FR2
<400> 62
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 63
<211> 32
<212> PRT
<213> 智人 (Homo sapiens)
<220>
<221> 位点
<222> (1)..(32)
<223> 人VH1-02 FR3
<400> 63
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 64
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4V1 HCDR1 (IMGT)
<400> 64
Gly Tyr Thr Phe Thr Asn Tyr Leu
1 5
<210> 65
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4V1 HCDR2 (IMGT)
<400> 65
Ile Asn Pro Gly Ser Gly Gly Thr
1 5
<210> 66
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4V1 HCDR3 (IMGT)
<400> 66
Ala Ser Gly Asn Tyr Asp Thr Tyr
1 5
<210> 67
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4VL1 LCDR1 (IMGT)
<400> 67
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 68
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4VL1 LCDR2 (IMGT)
<400> 68
Lys Val Ser
1
<210> 69
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成:Hu1E4VL1 LCDR3 (IMGT)
<400> 69
Ser Gln Ser Thr His Val Pro Arg Thr
1 5
<210> 70
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<220>
<221> 重复
<222> (1)..(5)
<223> 重复n次,其中n是至少为1的整数
<400> 70
Gly Ser Gly Gly Ser
1 5
<210> 71
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<220>
<221> 重复
<222> (1)..(5)
<223> 重复n次,其中n是至少为1的整数
<400> 71
Gly Gly Gly Gly Ser
1 5
<210> 72
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<220>
<221> 重复
<222> (1)..(4)
<223> 重复n次,其中n是至少为1的整数
<400> 72
Gly Gly Gly Ser
1
<210> 73
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<400> 73
Ala Ala Glu Pro Lys Ser Ser
1 5
<210> 74
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<400> 74
Ala Ala Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10 15
Pro
<210> 75
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<400> 75
Gly Gly Gly Gly
1
<210> 76
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成:肽接头
<400> 76
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10
<210> 77
<211> 1367
<212> PRT
<213> 智人 (Homo sapiens)
<220>
<221> 位点
<222> (1)..(1367)
<223> 人IGF1R
<400> 77
Met Lys Ser Gly Ser Gly Gly Gly Ser Pro Thr Ser Leu Trp Gly Leu
1 5 10 15
Leu Phe Leu Ser Ala Ala Leu Ser Leu Trp Pro Thr Ser Gly Glu Ile
20 25 30
Cys Gly Pro Gly Ile Asp Ile Arg Asn Asp Tyr Gln Gln Leu Lys Arg
35 40 45
Leu Glu Asn Cys Thr Val Ile Glu Gly Tyr Leu His Ile Leu Leu Ile
50 55 60
Ser Lys Ala Glu Asp Tyr Arg Ser Tyr Arg Phe Pro Lys Leu Thr Val
65 70 75 80
Ile Thr Glu Tyr Leu Leu Leu Phe Arg Val Ala Gly Leu Glu Ser Leu
85 90 95
Gly Asp Leu Phe Pro Asn Leu Thr Val Ile Arg Gly Trp Lys Leu Phe
100 105 110
Tyr Asn Tyr Ala Leu Val Ile Phe Glu Met Thr Asn Leu Lys Asp Ile
115 120 125
Gly Leu Tyr Asn Leu Arg Asn Ile Thr Arg Gly Ala Ile Arg Ile Glu
130 135 140
Lys Asn Ala Asp Leu Cys Tyr Leu Ser Thr Val Asp Trp Ser Leu Ile
145 150 155 160
Leu Asp Ala Val Ser Asn Asn Tyr Ile Val Gly Asn Lys Pro Pro Lys
165 170 175
Glu Cys Gly Asp Leu Cys Pro Gly Thr Met Glu Glu Lys Pro Met Cys
180 185 190
Glu Lys Thr Thr Ile Asn Asn Glu Tyr Asn Tyr Arg Cys Trp Thr Thr
195 200 205
Asn Arg Cys Gln Lys Met Cys Pro Ser Thr Cys Gly Lys Arg Ala Cys
210 215 220
Thr Glu Asn Asn Glu Cys Cys His Pro Glu Cys Leu Gly Ser Cys Ser
225 230 235 240
Ala Pro Asp Asn Asp Thr Ala Cys Val Ala Cys Arg His Tyr Tyr Tyr
245 250 255
Ala Gly Val Cys Val Pro Ala Cys Pro Pro Asn Thr Tyr Arg Phe Glu
260 265 270
Gly Trp Arg Cys Val Asp Arg Asp Phe Cys Ala Asn Ile Leu Ser Ala
275 280 285
Glu Ser Ser Asp Ser Glu Gly Phe Val Ile His Asp Gly Glu Cys Met
290 295 300
Gln Glu Cys Pro Ser Gly Phe Ile Arg Asn Gly Ser Gln Ser Met Tyr
305 310 315 320
Cys Ile Pro Cys Glu Gly Pro Cys Pro Lys Val Cys Glu Glu Glu Lys
325 330 335
Lys Thr Lys Thr Ile Asp Ser Val Thr Ser Ala Gln Met Leu Gln Gly
340 345 350
Cys Thr Ile Phe Lys Gly Asn Leu Leu Ile Asn Ile Arg Arg Gly Asn
355 360 365
Asn Ile Ala Ser Glu Leu Glu Asn Phe Met Gly Leu Ile Glu Val Val
370 375 380
Thr Gly Tyr Val Lys Ile Arg His Ser His Ala Leu Val Ser Leu Ser
385 390 395 400
Phe Leu Lys Asn Leu Arg Leu Ile Leu Gly Glu Glu Gln Leu Glu Gly
405 410 415
Asn Tyr Ser Phe Tyr Val Leu Asp Asn Gln Asn Leu Gln Gln Leu Trp
420 425 430
Asp Trp Asp His Arg Asn Leu Thr Ile Lys Ala Gly Lys Met Tyr Phe
435 440 445
Ala Phe Asn Pro Lys Leu Cys Val Ser Glu Ile Tyr Arg Met Glu Glu
450 455 460
Val Thr Gly Thr Lys Gly Arg Gln Ser Lys Gly Asp Ile Asn Thr Arg
465 470 475 480
Asn Asn Gly Glu Arg Ala Ser Cys Glu Ser Asp Val Leu His Phe Thr
485 490 495
Ser Thr Thr Thr Ser Lys Asn Arg Ile Ile Ile Thr Trp His Arg Tyr
500 505 510
Arg Pro Pro Asp Tyr Arg Asp Leu Ile Ser Phe Thr Val Tyr Tyr Lys
515 520 525
Glu Ala Pro Phe Lys Asn Val Thr Glu Tyr Asp Gly Gln Asp Ala Cys
530 535 540
Gly Ser Asn Ser Trp Asn Met Val Asp Val Asp Leu Pro Pro Asn Lys
545 550 555 560
Asp Val Glu Pro Gly Ile Leu Leu His Gly Leu Lys Pro Trp Thr Gln
565 570 575
Tyr Ala Val Tyr Val Lys Ala Val Thr Leu Thr Met Val Glu Asn Asp
580 585 590
His Ile Arg Gly Ala Lys Ser Glu Ile Leu Tyr Ile Arg Thr Asn Ala
595 600 605
Ser Val Pro Ser Ile Pro Leu Asp Val Leu Ser Ala Ser Asn Ser Ser
610 615 620
Ser Gln Leu Ile Val Lys Trp Asn Pro Pro Ser Leu Pro Asn Gly Asn
625 630 635 640
Leu Ser Tyr Tyr Ile Val Arg Trp Gln Arg Gln Pro Gln Asp Gly Tyr
645 650 655
Leu Tyr Arg His Asn Tyr Cys Ser Lys Asp Lys Ile Pro Ile Arg Lys
660 665 670
Tyr Ala Asp Gly Thr Ile Asp Ile Glu Glu Val Thr Glu Asn Pro Lys
675 680 685
Thr Glu Val Cys Gly Gly Glu Lys Gly Pro Cys Cys Ala Cys Pro Lys
690 695 700
Thr Glu Ala Glu Lys Gln Ala Glu Lys Glu Glu Ala Glu Tyr Arg Lys
705 710 715 720
Val Phe Glu Asn Phe Leu His Asn Ser Ile Phe Val Pro Arg Pro Glu
725 730 735
Arg Lys Arg Arg Asp Val Met Gln Val Ala Asn Thr Thr Met Ser Ser
740 745 750
Arg Ser Arg Asn Thr Thr Ala Ala Asp Thr Tyr Asn Ile Thr Asp Pro
755 760 765
Glu Glu Leu Glu Thr Glu Tyr Pro Phe Phe Glu Ser Arg Val Asp Asn
770 775 780
Lys Glu Arg Thr Val Ile Ser Asn Leu Arg Pro Phe Thr Leu Tyr Arg
785 790 795 800
Ile Asp Ile His Ser Cys Asn His Glu Ala Glu Lys Leu Gly Cys Ser
805 810 815
Ala Ser Asn Phe Val Phe Ala Arg Thr Met Pro Ala Glu Gly Ala Asp
820 825 830
Asp Ile Pro Gly Pro Val Thr Trp Glu Pro Arg Pro Glu Asn Ser Ile
835 840 845
Phe Leu Lys Trp Pro Glu Pro Glu Asn Pro Asn Gly Leu Ile Leu Met
850 855 860
Tyr Glu Ile Lys Tyr Gly Ser Gln Val Glu Asp Gln Arg Glu Cys Val
865 870 875 880
Ser Arg Gln Glu Tyr Arg Lys Tyr Gly Gly Ala Lys Leu Asn Arg Leu
885 890 895
Asn Pro Gly Asn Tyr Thr Ala Arg Ile Gln Ala Thr Ser Leu Ser Gly
900 905 910
Asn Gly Ser Trp Thr Asp Pro Val Phe Phe Tyr Val Gln Ala Lys Thr
915 920 925
Gly Tyr Glu Asn Phe Ile His Leu Ile Ile Ala Leu Pro Val Ala Val
930 935 940
Leu Leu Ile Val Gly Gly Leu Val Ile Met Leu Tyr Val Phe His Arg
945 950 955 960
Lys Arg Asn Asn Ser Arg Leu Gly Asn Gly Val Leu Tyr Ala Ser Val
965 970 975
Asn Pro Glu Tyr Phe Ser Ala Ala Asp Val Tyr Val Pro Asp Glu Trp
980 985 990
Glu Val Ala Arg Glu Lys Ile Thr Met Ser Arg Glu Leu Gly Gln Gly
995 1000 1005
Ser Phe Gly Met Val Tyr Glu Gly Val Ala Lys Gly Val Val Lys
1010 1015 1020
Asp Glu Pro Glu Thr Arg Val Ala Ile Lys Thr Val Asn Glu Ala
1025 1030 1035
Ala Ser Met Arg Glu Arg Ile Glu Phe Leu Asn Glu Ala Ser Val
1040 1045 1050
Met Lys Glu Phe Asn Cys His His Val Val Arg Leu Leu Gly Val
1055 1060 1065
Val Ser Gln Gly Gln Pro Thr Leu Val Ile Met Glu Leu Met Thr
1070 1075 1080
Arg Gly Asp Leu Lys Ser Tyr Leu Arg Ser Leu Arg Pro Glu Met
1085 1090 1095
Glu Asn Asn Pro Val Leu Ala Pro Pro Ser Leu Ser Lys Met Ile
1100 1105 1110
Gln Met Ala Gly Glu Ile Ala Asp Gly Met Ala Tyr Leu Asn Ala
1115 1120 1125
Asn Lys Phe Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Val
1130 1135 1140
Ala Glu Asp Phe Thr Val Lys Ile Gly Asp Phe Gly Met Thr Arg
1145 1150 1155
Asp Ile Tyr Glu Thr Asp Tyr Tyr Arg Lys Gly Gly Lys Gly Leu
1160 1165 1170
Leu Pro Val Arg Trp Met Ser Pro Glu Ser Leu Lys Asp Gly Val
1175 1180 1185
Phe Thr Thr Tyr Ser Asp Val Trp Ser Phe Gly Val Val Leu Trp
1190 1195 1200
Glu Ile Ala Thr Leu Ala Glu Gln Pro Tyr Gln Gly Leu Ser Asn
1205 1210 1215
Glu Gln Val Leu Arg Phe Val Met Glu Gly Gly Leu Leu Asp Lys
1220 1225 1230
Pro Asp Asn Cys Pro Asp Met Leu Phe Glu Leu Met Arg Met Cys
1235 1240 1245
Trp Gln Tyr Asn Pro Lys Met Arg Pro Ser Phe Leu Glu Ile Ile
1250 1255 1260
Ser Ser Ile Lys Glu Glu Met Glu Pro Gly Phe Arg Glu Val Ser
1265 1270 1275
Phe Tyr Tyr Ser Glu Glu Asn Lys Leu Pro Glu Pro Glu Glu Leu
1280 1285 1290
Asp Leu Glu Pro Glu Asn Met Glu Ser Val Pro Leu Asp Pro Ser
1295 1300 1305
Ala Ser Ser Ser Ser Leu Pro Leu Pro Asp Arg His Ser Gly His
1310 1315 1320
Lys Ala Glu Asn Gly Pro Gly Pro Gly Val Leu Val Leu Arg Ala
1325 1330 1335
Ser Phe Asp Glu Arg Gln Pro Tyr Ala His Met Asn Gly Gly Arg
1340 1345 1350
Lys Asn Glu Arg Ala Leu Pro Leu Pro Gln Ser Ser Thr Cys
1355 1360 1365
Claims (35)
1.一种与人α-突触核蛋白结合的人源化抗体或其抗原结合片段,其中所述抗体或所述抗原结合片段包含:
重链可变区(VH),所述重链可变区包含(i)分别在SEQ ID NO:33-35中示出的重链互补决定区(CDR)1-3,和(ii)来自人VH1-02基因的重链框架区(FR)1、2和/或3;以及
轻链可变区(VL),所述轻链可变区包含分别在SEQ ID NO:36-38中示出的轻链CDR1-3。
2.根据权利要求1所述的抗体或抗原结合片段,其中所述重链FR1、FR2或FR3相对于由所述人VH1-02基因编码的相应FR包含不超过六个突变。
3.根据权利要求1或2所述的抗体或抗原结合片段,所述抗体或抗原结合片段包含来自人JH1、JH4或JH5基因的重链FR4。
4.一种与人α-突触核蛋白结合的人源化抗体或其抗原结合片段,其中所述抗体或所述抗原结合片段包含:
重链可变区(VH),所述重链可变区包含分别在SEQ ID NO:64-66中示出的重链互补决定区(CDR)1-3;以及
轻链可变区(VL),所述轻链可变区包含分别在SEQ ID NO:67-69中示出的轻链CDR1-3。
5.根据权利要求1-4中任一项所述的抗体或抗原结合片段,其中
所述VH包含SEQ ID NO:1至9中的任一个;并且
所述VL包含SEQ ID NO:11至15中的任一个。
6.根据权利要求5所述的抗体或抗原结合片段,其中所述VH和所述VL分别包含:
SEQ ID NO:1和11、
SEQ ID NO:2和12、
SEQ ID NO:3和12、
SEQ ID NO:4和12、
SEQ ID NO:7和12、
SEQ ID NO:5和13、
SEQ ID NO:5和15、
SEQ ID NO:6和13、
SEQ ID NO:6和14、
SEQ ID NO:5和14、
SEQ ID NO:8和14或
SEQ ID NO:9和14。
7.根据权利要求5所述的抗体或抗原结合片段,其中所述VH包含SEQ ID NO:1,和/或所述VL包含SEQ ID NO:11。
8.根据权利要求1-7中任一项所述的抗体或抗原结合片段,其中所述抗体包含人κ轻链恒定区,任选地其中所述人κ轻链恒定区包含SEQ ID NO:43。
9.根据权利要求1-8中任一项所述的抗体,其中所述抗体包含人IgG1恒定区。
10.根据权利要求9所述的抗体,其中
所述抗体的一条重链包含一个或多个杵突变,任选地其中所述一个或多个杵突变包括T366W,并且
所述抗体的另一条重链包含一个或多个臼突变,任选地其中所述一个或多个臼突变包括T366S、L368A和Y407V(Eu编号)。
11.根据权利要求1-8中任一项所述的抗原结合片段,其中所述抗原结合片段是单链可变片段(scFv)。
12.根据权利要求1-11中任一项所述的抗体或抗原结合片段,其中所述抗体或抗原结合片段是双特异性的。
13.根据权利要求12所述的抗体或抗原结合片段,其中所述双特异性抗体或抗原结合片段包含结合胰岛素样生长因子1受体(IGF1R)的部分。
14.根据权利要求13所述的抗体或抗原结合片段,其中所述IGF1R结合部分包含VH和VL,其中
所述VH包含分别在SEQ ID NO:51-53中示出的重链CDR1-3,并且
所述VL包含分别在SEQ ID NO:46-48中示出的轻链CDR1-3。
15.根据权利要求14所述的抗体或抗原结合片段,其中所述IGF1R结合部分的VH和VL分别包含SEQ ID NO:50和45。
16.根据权利要求13-15中任一项所述的抗体或抗原结合片段,其中所述IGF1R结合部分是任选地包含SEQ ID NO:54的scFv。
17.根据权利要求13-16中任一项所述的抗体,其中所述IGF1R结合部分与所述抗体的两条重链的C末端融合。
18.根据权利要求13-16中任一项所述的抗体,其中所述IGF1R结合部分与所述抗体的仅一条重链的C末端融合。
19.根据权利要求13-18中任一项所述的抗体,其中
所述抗体的一条重链包含一个或多个杵突变,任选地其中所述一个或多个杵突变包括T366W,并且
所述抗体的另一条重链包含一个或多个臼突变,任选地其中所述一个或多个臼突变包括T366S、L368A和Y407V(Eu编号)。
20.根据权利要求10或19所述的抗体,其中所述杵重链包含SEQ ID NO:39,和/或所述臼重链包含SEQ ID NO:40。
21.根据权利要求1-20中任一项所述的抗体,其中所述抗体的重链进一步包含M428L突变(Eu编号)。
22.根据权利要求21所述的抗体,其中所述杵重链包含SEQ ID NO:41,并且所述臼重链包含SEQ ID NO:42。
23.根据权利要求19-22中任一项所述的抗体,其中所述IGF1R结合部分位于所述杵重链的C末端处。
24.根据权利要求19-22中任一项所述的抗体,其中所述IGF1R结合部分位于所述臼重链的C末端处,任选地其中所述臼重链包含SEQ ID NO:55或56。
25.根据权利要求24所述的抗体,其中所述抗体包含含有SEQ ID NO:57的重链和含有SEQ ID NO:58的重链;以及各自含有SEQ ID NO:59的两条轻链。
26.根据权利要求1-25中任一项所述的抗体或抗原结合片段,其中所述抗体或抗原结合片段
任选地以不超过200pM、100pM、50pM、30pM、20pM或10pM的KD与聚集或寡聚体α-突触核蛋白结合,并且
任选地不与单体α-突触核蛋白结合。
27.一种药物组合物,所述药物组合物包含根据权利要求1-26中任一项所述的抗体或抗原结合片段以及药学上可接受的载体。
28.一种或多种核酸分子,所述一种或多种核酸分子编码根据权利要求1-26中任一项所述的抗体或抗原结合片段。
29.根据权利要求28所述的一种或多种核酸分子,其中所述一种或多种核酸分子是任选地包含选自SEQ ID NO:17-25的核苷酸序列和选自SEQ ID NO:27-31的核苷酸序列的表达构建体。
30.一种宿主细胞,所述宿主细胞包含根据权利要求28或29所述的一种或多种核酸分子,任选地其中所述宿主细胞是哺乳动物细胞。
31.一种产生抗体或抗原结合片段的方法,所述方法包括:
在允许所述抗体或抗原结合片段表达的条件下培养根据权利要求30所述的宿主细胞,以及
从所述细胞培养物中分离所述抗体或抗原结合片段。
32.一种治疗有需要的人类受试者的α-突触核蛋白病的方法,所述方法包括将治疗有效量的根据权利要求1-26中任一项所述的抗体或抗原结合片段施用给所述受试者。
33.根据权利要求1-26中任一项所述的抗体或抗原结合片段用于制造用以治疗有需要的人类受试者的α-突触核蛋白病的药物的用途。
34.根据权利要求1-26中任一项所述的抗体或抗原结合片段或者根据权利要求27所述的药物组合物,用于在治疗有需要的人类受试者的α-突触核蛋白病中使用。
35.根据权利要求32所述的方法、根据权利要求33所述的用途或者根据权利要求34所述的用于所述用途的抗体、抗原结合片段或药物组合物,其中所述α-突触核蛋白病是帕金森病、路易体痴呆、多系统萎缩或杏仁体路易体阿尔茨海默病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0061407 | 2021-05-12 | ||
KR20210061407 | 2021-05-12 | ||
PCT/IB2022/054445 WO2022238961A1 (en) | 2021-05-12 | 2022-05-12 | Antibodies for treating alpha-synucleinopathies |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117858721A true CN117858721A (zh) | 2024-04-09 |
Family
ID=84028418
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280034495.2A Pending CN117858721A (zh) | 2021-05-12 | 2022-05-12 | 用于治疗α-突触核蛋白病的抗体 |
Country Status (14)
Country | Link |
---|---|
US (1) | US20220380446A1 (zh) |
EP (1) | EP4340881A1 (zh) |
JP (1) | JP2024520905A (zh) |
KR (1) | KR20240031229A (zh) |
CN (1) | CN117858721A (zh) |
AR (1) | AR125857A1 (zh) |
AU (1) | AU2022271678A1 (zh) |
BR (1) | BR112023023284A2 (zh) |
CA (1) | CA3219659A1 (zh) |
CO (1) | CO2023015859A2 (zh) |
IL (1) | IL308393A (zh) |
MX (1) | MX2023013392A (zh) |
TW (1) | TW202309076A (zh) |
WO (1) | WO2022238961A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110494445B (zh) | 2017-01-06 | 2023-10-20 | Abl生物公司 | 抗α-SYN抗体及其用途 |
EP3725806A4 (en) | 2017-12-14 | 2022-03-30 | ABL Bio Inc. | BISPECIFIC ANTIBODIES AGAINST A-SYN/IGF1R AND ASSOCIATED USE |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018128454A1 (ko) * | 2017-01-06 | 2018-07-12 | 에이비엘바이오 주식회사 | 항 α-SYN 항체 및 그 용도 |
MX2020004674A (es) * | 2017-11-17 | 2020-08-13 | Abl Bio Inc | Anticuerpos contra alfa-sinucleina y usos de los mismos. |
CN117024589A (zh) * | 2019-06-14 | 2023-11-10 | Abl生物公司 | 抗a-syn/igf1r的双特异性抗体及其用途 |
-
2022
- 2022-05-12 TW TW111117860A patent/TW202309076A/zh unknown
- 2022-05-12 MX MX2023013392A patent/MX2023013392A/es unknown
- 2022-05-12 WO PCT/IB2022/054445 patent/WO2022238961A1/en active Application Filing
- 2022-05-12 KR KR1020237042723A patent/KR20240031229A/ko unknown
- 2022-05-12 IL IL308393A patent/IL308393A/en unknown
- 2022-05-12 AU AU2022271678A patent/AU2022271678A1/en active Pending
- 2022-05-12 BR BR112023023284A patent/BR112023023284A2/pt unknown
- 2022-05-12 EP EP22806958.9A patent/EP4340881A1/en active Pending
- 2022-05-12 AR ARP220101267A patent/AR125857A1/es unknown
- 2022-05-12 JP JP2023569822A patent/JP2024520905A/ja active Pending
- 2022-05-12 CA CA3219659A patent/CA3219659A1/en active Pending
- 2022-05-12 CN CN202280034495.2A patent/CN117858721A/zh active Pending
- 2022-05-12 US US17/743,177 patent/US20220380446A1/en active Pending
-
2023
- 2023-11-22 CO CONC2023/0015859A patent/CO2023015859A2/es unknown
Also Published As
Publication number | Publication date |
---|---|
IL308393A (en) | 2024-01-01 |
EP4340881A1 (en) | 2024-03-27 |
JP2024520905A (ja) | 2024-05-27 |
TW202309076A (zh) | 2023-03-01 |
CA3219659A1 (en) | 2022-11-17 |
US20220380446A1 (en) | 2022-12-01 |
CO2023015859A2 (es) | 2024-02-26 |
AR125857A1 (es) | 2023-08-16 |
KR20240031229A (ko) | 2024-03-07 |
MX2023013392A (es) | 2024-02-15 |
AU2022271678A1 (en) | 2024-01-04 |
WO2022238961A1 (en) | 2022-11-17 |
BR112023023284A2 (pt) | 2024-01-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102224556B1 (ko) | Ig 및 itim 도메인을 갖는 t 세포 면역 수용체 (tigit)에 대한 항체 및 이것의 사용 | |
WO2018147245A1 (ja) | 抗gprc5d抗体及び該抗体を含む分子 | |
WO2017071625A1 (zh) | 一种抗pd-1单克隆抗体、其药物组合物及其用途 | |
CN112566662A (zh) | 针对cd47的阻断抗体及其使用方法 | |
JP2020524991A (ja) | 二重特異性抗体を製造する方法、二重特異性抗体及びこのような抗体の治療的使用 | |
WO2021115240A1 (zh) | 抗tslp抗体及其用途 | |
JP7212391B2 (ja) | a-syn/IGF1Rに対する二重特異抗体およびその用途 | |
CN117858721A (zh) | 用于治疗α-突触核蛋白病的抗体 | |
KR102444797B1 (ko) | α-SYN/IGF1R에 대한 이중 특이 항체 및 그 용도 | |
CN114206931A (zh) | 抗pd-1抗体及其用途 | |
CN116209680A (zh) | 与人CD3ε结合的新型人抗体 | |
CN114667296B (zh) | 一种双特异性抗体及其用途 | |
US20240059769A1 (en) | Engineered dual binding antibodies and uses thereof | |
WO2023030511A1 (en) | Bi-functional fusion protein and uses thereof | |
WO2023074888A1 (ja) | 新規なNav1.7モノクローナル抗体 | |
JP2024532540A (ja) | 二機能性融合タンパク質およびその用途 | |
EA047717B1 (ru) | БИСПЕЦИФИЧНОЕ АНТИТЕЛО К α-SYN/IGF1R И ЕГО ПРИМЕНЕНИЕ |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |