KR20210118112A - 오토페를린 유전자을 회복시키는 aav-매개된 유전자 치료요법 - Google Patents
오토페를린 유전자을 회복시키는 aav-매개된 유전자 치료요법 Download PDFInfo
- Publication number
- KR20210118112A KR20210118112A KR1020217026056A KR20217026056A KR20210118112A KR 20210118112 A KR20210118112 A KR 20210118112A KR 1020217026056 A KR1020217026056 A KR 1020217026056A KR 20217026056 A KR20217026056 A KR 20217026056A KR 20210118112 A KR20210118112 A KR 20210118112A
- Authority
- KR
- South Korea
- Prior art keywords
- leu
- glu
- lys
- asp
- val
- Prior art date
Links
- 108090000623 proteins and genes Proteins 0.000 title claims description 63
- 238000001415 gene therapy Methods 0.000 title description 32
- 230000001404 mediated effect Effects 0.000 title description 6
- 239000013598 vector Substances 0.000 claims abstract description 104
- 206010011878 Deafness Diseases 0.000 claims abstract description 52
- 208000016354 hearing loss disease Diseases 0.000 claims abstract description 44
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 37
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 37
- 101001134169 Homo sapiens Otoferlin Proteins 0.000 claims abstract description 36
- 229920001184 polypeptide Polymers 0.000 claims abstract description 36
- 102100034198 Otoferlin Human genes 0.000 claims abstract description 33
- 231100000895 deafness Toxicity 0.000 claims abstract description 33
- 230000014509 gene expression Effects 0.000 claims abstract description 32
- 201000006093 autosomal recessive nonsyndromic deafness 9 Diseases 0.000 claims abstract description 30
- 208000032337 autosomal recessive nonsyndromic hearing loss 9 Diseases 0.000 claims abstract description 30
- 239000012634 fragment Substances 0.000 claims abstract description 27
- 230000035772 mutation Effects 0.000 claims abstract description 26
- 241000282414 Homo sapiens Species 0.000 claims description 54
- 108091033319 polynucleotide Proteins 0.000 claims description 52
- 102000040430 polynucleotide Human genes 0.000 claims description 52
- 239000002157 polynucleotide Substances 0.000 claims description 52
- 210000000067 inner hair cell Anatomy 0.000 claims description 42
- 108020005067 RNA Splice Sites Proteins 0.000 claims description 28
- 241000702423 Adeno-associated virus - 2 Species 0.000 claims description 27
- 239000002245 particle Substances 0.000 claims description 23
- 108091026890 Coding region Proteins 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 210000004899 c-terminal region Anatomy 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 210000000234 capsid Anatomy 0.000 claims description 12
- 241000702421 Dependoparvovirus Species 0.000 claims description 8
- 230000008488 polyadenylation Effects 0.000 claims description 7
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 5
- 102220024085 rs397515607 Human genes 0.000 claims description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 241000699670 Mus sp. Species 0.000 abstract description 124
- 239000002299 complementary DNA Substances 0.000 abstract description 25
- 239000013607 AAV vector Substances 0.000 abstract description 11
- 238000013459 approach Methods 0.000 abstract description 9
- 238000010172 mouse model Methods 0.000 abstract description 5
- 238000011813 knockout mouse model Methods 0.000 abstract description 3
- 101150006256 Otof gene Proteins 0.000 description 80
- 210000004027 cell Anatomy 0.000 description 75
- 210000003477 cochlea Anatomy 0.000 description 44
- 239000007924 injection Substances 0.000 description 42
- 238000002347 injection Methods 0.000 description 42
- 108010050848 glycylleucine Proteins 0.000 description 28
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 27
- 230000004044 response Effects 0.000 description 26
- 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 25
- 108020004414 DNA Proteins 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 23
- 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 22
- 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 22
- 235000018102 proteins Nutrition 0.000 description 22
- 108010029485 Protein Isoforms Proteins 0.000 description 21
- 102000001708 Protein Isoforms Human genes 0.000 description 21
- 108010073969 valyllysine Proteins 0.000 description 18
- 108010061238 threonyl-glycine Proteins 0.000 description 17
- 108010038633 aspartylglutamate Proteins 0.000 description 15
- 230000001225 therapeutic effect Effects 0.000 description 15
- 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 14
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 14
- 210000002569 neuron Anatomy 0.000 description 14
- 239000002773 nucleotide Substances 0.000 description 14
- 125000003729 nucleotide group Chemical group 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- WGNOPSQMIQERPK-UHFFFAOYSA-N Leu-Asn-Pro Natural products CC(C)CC(N)C(=O)NC(CC(=O)N)C(=O)N1CCCC1C(=O)O WGNOPSQMIQERPK-UHFFFAOYSA-N 0.000 description 13
- 108010093581 aspartyl-proline Proteins 0.000 description 13
- 108010054155 lysyllysine Proteins 0.000 description 13
- 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 12
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 12
- 108010060035 arginylproline Proteins 0.000 description 12
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 12
- 108010089804 glycyl-threonine Proteins 0.000 description 12
- 108010015792 glycyllysine Proteins 0.000 description 12
- 108010009298 lysylglutamic acid Proteins 0.000 description 12
- 241000282412 Homo Species 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 241000700605 Viruses Species 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 11
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 11
- 108010047857 aspartylglycine Proteins 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000011084 recovery Methods 0.000 description 11
- 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 10
- 238000000585 Mann–Whitney U test Methods 0.000 description 10
- 108010047495 alanylglycine Proteins 0.000 description 10
- 230000002068 genetic effect Effects 0.000 description 10
- 108010057821 leucylproline Proteins 0.000 description 10
- 108010012581 phenylalanylglutamate Proteins 0.000 description 10
- 238000010361 transduction Methods 0.000 description 10
- 230000026683 transduction Effects 0.000 description 10
- 241000701022 Cytomegalovirus Species 0.000 description 9
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 description 9
- 108010054813 diprotin B Proteins 0.000 description 9
- 238000009826 distribution Methods 0.000 description 9
- 230000009977 dual effect Effects 0.000 description 9
- 231100000888 hearing loss Toxicity 0.000 description 9
- 230000010370 hearing loss Effects 0.000 description 9
- 108010018006 histidylserine Proteins 0.000 description 9
- 108010070643 prolylglutamic acid Proteins 0.000 description 9
- 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 8
- HQLSBZFLOUHQJK-STECZYCISA-N Ile-Tyr-Arg Chemical compound CC[C@H](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 HQLSBZFLOUHQJK-STECZYCISA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 8
- XNXRTQZTFVMJIJ-DCAQKATOSA-N Ser-Met-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O XNXRTQZTFVMJIJ-DCAQKATOSA-N 0.000 description 8
- 108010092854 aspartyllysine Proteins 0.000 description 8
- 108010016616 cysteinylglycine Proteins 0.000 description 8
- 210000003027 ear inner Anatomy 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 108010078144 glutaminyl-glycine Proteins 0.000 description 8
- 108010049041 glutamylalanine Proteins 0.000 description 8
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 8
- 210000002768 hair cell Anatomy 0.000 description 8
- 230000035800 maturation Effects 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 108010015796 prolylisoleucine Proteins 0.000 description 8
- 230000001953 sensory effect Effects 0.000 description 8
- 108010071207 serylmethionine Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 7
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 7
- WGNOPSQMIQERPK-GARJFASQSA-N Leu-Asn-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N WGNOPSQMIQERPK-GARJFASQSA-N 0.000 description 7
- FQPQPTHMHZKGFM-XQXXSGGOSA-N Thr-Ala-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O FQPQPTHMHZKGFM-XQXXSGGOSA-N 0.000 description 7
- AQAMPXBRJJWPNI-JHEQGTHGSA-N Thr-Gly-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AQAMPXBRJJWPNI-JHEQGTHGSA-N 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 108010062796 arginyllysine Proteins 0.000 description 7
- 210000000133 brain stem Anatomy 0.000 description 7
- 210000003855 cell nucleus Anatomy 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000003623 enhancer Substances 0.000 description 7
- 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 7
- 108010078274 isoleucylvaline Proteins 0.000 description 7
- 108010068488 methionylphenylalanine Proteins 0.000 description 7
- 108010031719 prolyl-serine Proteins 0.000 description 7
- 210000000225 synapse Anatomy 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 108010080629 tryptophan-leucine Proteins 0.000 description 7
- DVWVZSJAYIJZFI-FXQIFTODSA-N Ala-Arg-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DVWVZSJAYIJZFI-FXQIFTODSA-N 0.000 description 6
- WDIYWDJLXOCGRW-ACZMJKKPSA-N Ala-Asp-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WDIYWDJLXOCGRW-ACZMJKKPSA-N 0.000 description 6
- RTFWCVDISAMGEQ-SRVKXCTJSA-N Asn-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N RTFWCVDISAMGEQ-SRVKXCTJSA-N 0.000 description 6
- LTCKTLYKRMCFOC-KKUMJFAQSA-N Asp-Phe-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LTCKTLYKRMCFOC-KKUMJFAQSA-N 0.000 description 6
- LGYZYFFDELZWRS-DCAQKATOSA-N Glu-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O LGYZYFFDELZWRS-DCAQKATOSA-N 0.000 description 6
- LRPXYSGPOBVBEH-IUCAKERBSA-N Glu-Gly-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O LRPXYSGPOBVBEH-IUCAKERBSA-N 0.000 description 6
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 6
- IOUQWHIEQYQVFD-JYJNAYRXSA-N Glu-Leu-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IOUQWHIEQYQVFD-JYJNAYRXSA-N 0.000 description 6
- YPHPEHMXOYTEQG-LAEOZQHASA-N Glu-Val-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O YPHPEHMXOYTEQG-LAEOZQHASA-N 0.000 description 6
- ZQIMMEYPEXIYBB-IUCAKERBSA-N Gly-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN ZQIMMEYPEXIYBB-IUCAKERBSA-N 0.000 description 6
- FXGRXIATVXUAHO-WEDXCCLWSA-N Gly-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN FXGRXIATVXUAHO-WEDXCCLWSA-N 0.000 description 6
- 241000880493 Leptailurus serval Species 0.000 description 6
- VDIARPPNADFEAV-WEDXCCLWSA-N Leu-Thr-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O VDIARPPNADFEAV-WEDXCCLWSA-N 0.000 description 6
- AAKRWBIIGKPOKQ-ONGXEEELSA-N Leu-Val-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AAKRWBIIGKPOKQ-ONGXEEELSA-N 0.000 description 6
- NCTDKZKNBDZDOL-GARJFASQSA-N Lys-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)C(=O)O NCTDKZKNBDZDOL-GARJFASQSA-N 0.000 description 6
- IMAKMJCBYCSMHM-AVGNSLFASA-N Lys-Glu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN IMAKMJCBYCSMHM-AVGNSLFASA-N 0.000 description 6
- 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 6
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 6
- SUENWIFTSTWUKD-AVGNSLFASA-N Pro-Leu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SUENWIFTSTWUKD-AVGNSLFASA-N 0.000 description 6
- YBXMGKCLOPDEKA-NUMRIWBASA-N Thr-Asp-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YBXMGKCLOPDEKA-NUMRIWBASA-N 0.000 description 6
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 6
- 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 6
- 108010043240 arginyl-leucyl-glycine Proteins 0.000 description 6
- 108010060199 cysteinylproline Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000003060 endolymph Anatomy 0.000 description 6
- 108010079547 glutamylmethionine Proteins 0.000 description 6
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 6
- 108010034529 leucyl-lysine Proteins 0.000 description 6
- 108010056582 methionylglutamic acid Proteins 0.000 description 6
- 210000004049 perilymph Anatomy 0.000 description 6
- 108010051242 phenylalanylserine Proteins 0.000 description 6
- 108010020432 prolyl-prolylisoleucine Proteins 0.000 description 6
- 210000001323 spiral ganglion Anatomy 0.000 description 6
- 230000000946 synaptic effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 102000007469 Actins Human genes 0.000 description 5
- 108010085238 Actins Proteins 0.000 description 5
- 241001164825 Adeno-associated virus - 8 Species 0.000 description 5
- 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 5
- MPLOSMWGDNJSEV-WHFBIAKZSA-N Ala-Gly-Asp Chemical compound [H]N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MPLOSMWGDNJSEV-WHFBIAKZSA-N 0.000 description 5
- CNQAFFMNJIQYGX-DRZSPHRISA-N Ala-Phe-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 CNQAFFMNJIQYGX-DRZSPHRISA-N 0.000 description 5
- GXCSUJQOECMKPV-CIUDSAMLSA-N Arg-Ala-Gln Chemical compound C[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O GXCSUJQOECMKPV-CIUDSAMLSA-N 0.000 description 5
- NIUDXSFNLBIWOB-DCAQKATOSA-N Arg-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NIUDXSFNLBIWOB-DCAQKATOSA-N 0.000 description 5
- OVQJAKFLFTZDNC-GUBZILKMSA-N Arg-Pro-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O OVQJAKFLFTZDNC-GUBZILKMSA-N 0.000 description 5
- FMYQECOAIFGQGU-CYDGBPFRSA-N Arg-Val-Ile 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)CC)C(O)=O FMYQECOAIFGQGU-CYDGBPFRSA-N 0.000 description 5
- WOZDCBHUGJVJPL-AVGNSLFASA-N Arg-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N WOZDCBHUGJVJPL-AVGNSLFASA-N 0.000 description 5
- 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 5
- QCLHLXDWRKOHRR-GUBZILKMSA-N Asp-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N QCLHLXDWRKOHRR-GUBZILKMSA-N 0.000 description 5
- 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 5
- 102000002110 C2 domains Human genes 0.000 description 5
- 108050009459 C2 domains Proteins 0.000 description 5
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 5
- 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 5
- 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 5
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 5
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 5
- GUOWMVFLAJNPDY-CIUDSAMLSA-N Glu-Ser-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O GUOWMVFLAJNPDY-CIUDSAMLSA-N 0.000 description 5
- 102000018899 Glutamate Receptors Human genes 0.000 description 5
- 108010027915 Glutamate Receptors Proteins 0.000 description 5
- QSTLUOIOYLYLLF-WDSKDSINSA-N Gly-Asp-Glu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QSTLUOIOYLYLLF-WDSKDSINSA-N 0.000 description 5
- XLFHCWHXKSFVIB-BQBZGAKWSA-N Gly-Gln-Gln Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O XLFHCWHXKSFVIB-BQBZGAKWSA-N 0.000 description 5
- 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 5
- DMHGKBGOUAJRHU-UHFFFAOYSA-N Ile-Arg-Pro Natural products CCC(C)C(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O DMHGKBGOUAJRHU-UHFFFAOYSA-N 0.000 description 5
- 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 5
- KFKWRHQBZQICHA-STQMWFEESA-N L-leucyl-L-phenylalanine Natural products CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KFKWRHQBZQICHA-STQMWFEESA-N 0.000 description 5
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 5
- WRLPVDVHNWSSCL-MELADBBJSA-N Leu-His-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N WRLPVDVHNWSSCL-MELADBBJSA-N 0.000 description 5
- JFSGIJSCJFQGSZ-MXAVVETBSA-N Leu-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(C)C)N JFSGIJSCJFQGSZ-MXAVVETBSA-N 0.000 description 5
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 5
- PTRKPHUGYULXPU-KKUMJFAQSA-N Leu-Phe-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O PTRKPHUGYULXPU-KKUMJFAQSA-N 0.000 description 5
- VULJUQZPSOASBZ-SRVKXCTJSA-N Leu-Pro-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O VULJUQZPSOASBZ-SRVKXCTJSA-N 0.000 description 5
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 5
- 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 5
- IUWMQCZOTYRXPL-ZPFDUUQYSA-N Lys-Ile-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O IUWMQCZOTYRXPL-ZPFDUUQYSA-N 0.000 description 5
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 5
- PYFNONMJYNJENN-AVGNSLFASA-N Lys-Lys-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PYFNONMJYNJENN-AVGNSLFASA-N 0.000 description 5
- YUAXTFMFMOIMAM-QWRGUYRKSA-N Lys-Lys-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O YUAXTFMFMOIMAM-QWRGUYRKSA-N 0.000 description 5
- 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 5
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 5
- FKFCKDROTNIVSO-JYJNAYRXSA-N Phe-Pro-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O FKFCKDROTNIVSO-JYJNAYRXSA-N 0.000 description 5
- QCMYJBKTMIWZAP-AVGNSLFASA-N Pro-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 QCMYJBKTMIWZAP-AVGNSLFASA-N 0.000 description 5
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 5
- 108700019146 Transgenes Proteins 0.000 description 5
- KXUKIBHIVRYOIP-ZKWXMUAHSA-N Val-Asp-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N KXUKIBHIVRYOIP-ZKWXMUAHSA-N 0.000 description 5
- ZSZFTYVFQLUWBF-QXEWZRGKSA-N Val-Asp-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N ZSZFTYVFQLUWBF-QXEWZRGKSA-N 0.000 description 5
- VXDSPJJQUQDCKH-UKJIMTQDSA-N Val-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N VXDSPJJQUQDCKH-UKJIMTQDSA-N 0.000 description 5
- VPGCVZRRBYOGCD-AVGNSLFASA-N Val-Lys-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O VPGCVZRRBYOGCD-AVGNSLFASA-N 0.000 description 5
- YKNOJPJWNVHORX-UNQGMJICSA-N Val-Phe-Thr Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=CC=C1 YKNOJPJWNVHORX-UNQGMJICSA-N 0.000 description 5
- 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 5
- 108010045350 alanyl-tyrosyl-alanine Proteins 0.000 description 5
- 108010044940 alanylglutamine Proteins 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 108010013835 arginine glutamate Proteins 0.000 description 5
- 108010008355 arginyl-glutamine Proteins 0.000 description 5
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 5
- 108010091092 arginyl-glycyl-proline Proteins 0.000 description 5
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 5
- 108010018691 arginyl-threonyl-arginine Proteins 0.000 description 5
- 108010036533 arginylvaline Proteins 0.000 description 5
- 108010077245 asparaginyl-proline Proteins 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 108010040856 glutamyl-cysteinyl-alanine Proteins 0.000 description 5
- 239000005090 green fluorescent protein Substances 0.000 description 5
- 108010025306 histidylleucine Proteins 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 108010044056 leucyl-phenylalanine Proteins 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 108010022588 methionyl-lysyl-proline Proteins 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 108010089198 phenylalanyl-prolyl-arginine Proteins 0.000 description 5
- 230000001242 postsynaptic effect Effects 0.000 description 5
- 108010077112 prolyl-proline Proteins 0.000 description 5
- 108010029020 prolylglycine Proteins 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 4
- FJVAQLJNTSUQPY-CIUDSAMLSA-N Ala-Ala-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN FJVAQLJNTSUQPY-CIUDSAMLSA-N 0.000 description 4
- GWFSQQNGMPGBEF-GHCJXIJMSA-N Ala-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N GWFSQQNGMPGBEF-GHCJXIJMSA-N 0.000 description 4
- YSMPVONNIWLJML-FXQIFTODSA-N Ala-Asp-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(O)=O YSMPVONNIWLJML-FXQIFTODSA-N 0.000 description 4
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 4
- DHBKYZYFEXXUAK-ONGXEEELSA-N Ala-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 DHBKYZYFEXXUAK-ONGXEEELSA-N 0.000 description 4
- KWKQGHSSNHPGOW-BQBZGAKWSA-N Arg-Ala-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)NCC(O)=O KWKQGHSSNHPGOW-BQBZGAKWSA-N 0.000 description 4
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 4
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 4
- IZSMEUDYADKZTJ-KJEVXHAQSA-N Arg-Tyr-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IZSMEUDYADKZTJ-KJEVXHAQSA-N 0.000 description 4
- FXGMURPOWCKNAZ-JYJNAYRXSA-N Arg-Val-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FXGMURPOWCKNAZ-JYJNAYRXSA-N 0.000 description 4
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 4
- 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 4
- HOQGTAIGQSDCHR-SRVKXCTJSA-N Asp-Asn-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HOQGTAIGQSDCHR-SRVKXCTJSA-N 0.000 description 4
- VPSHHQXIWLGVDD-ZLUOBGJFSA-N Asp-Asp-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O VPSHHQXIWLGVDD-ZLUOBGJFSA-N 0.000 description 4
- XJQRWGXKUSDEFI-ACZMJKKPSA-N Asp-Glu-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O XJQRWGXKUSDEFI-ACZMJKKPSA-N 0.000 description 4
- PYXXJFRXIYAESU-PCBIJLKTSA-N Asp-Ile-Phe 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=CC=C1)C(O)=O PYXXJFRXIYAESU-PCBIJLKTSA-N 0.000 description 4
- KLYPOCBLKMPBIQ-GHCJXIJMSA-N Asp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N KLYPOCBLKMPBIQ-GHCJXIJMSA-N 0.000 description 4
- 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 4
- UJGRZQYSNYTCAX-SRVKXCTJSA-N Asp-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UJGRZQYSNYTCAX-SRVKXCTJSA-N 0.000 description 4
- NZWDWXSWUQCNMG-GARJFASQSA-N Asp-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)C(=O)O NZWDWXSWUQCNMG-GARJFASQSA-N 0.000 description 4
- VIOQRFNAZDMVLO-NRPADANISA-N Cys-Val-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VIOQRFNAZDMVLO-NRPADANISA-N 0.000 description 4
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 4
- HWEINOMSWQSJDC-SRVKXCTJSA-N Gln-Leu-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O HWEINOMSWQSJDC-SRVKXCTJSA-N 0.000 description 4
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 description 4
- PHONAZGUEGIOEM-GLLZPBPUSA-N Glu-Glu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PHONAZGUEGIOEM-GLLZPBPUSA-N 0.000 description 4
- 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 4
- ZPASCJBSSCRWMC-GVXVVHGQSA-N Glu-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N ZPASCJBSSCRWMC-GVXVVHGQSA-N 0.000 description 4
- VGUYMZGLJUJRBV-YVNDNENWSA-N Glu-Ile-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O VGUYMZGLJUJRBV-YVNDNENWSA-N 0.000 description 4
- JJSVALISDCNFCU-SZMVWBNQSA-N Glu-Leu-Trp Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O JJSVALISDCNFCU-SZMVWBNQSA-N 0.000 description 4
- YKBUCXNNBYZYAY-MNXVOIDGSA-N Glu-Lys-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YKBUCXNNBYZYAY-MNXVOIDGSA-N 0.000 description 4
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 4
- UDEPRBFQTWGLCW-CIUDSAMLSA-N Glu-Pro-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O UDEPRBFQTWGLCW-CIUDSAMLSA-N 0.000 description 4
- DXVOKNVIKORTHQ-GUBZILKMSA-N Glu-Pro-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O DXVOKNVIKORTHQ-GUBZILKMSA-N 0.000 description 4
- 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 4
- RMWAOBGCZZSJHE-UMNHJUIQSA-N Glu-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N RMWAOBGCZZSJHE-UMNHJUIQSA-N 0.000 description 4
- OVSKVOOUFAKODB-UWVGGRQHSA-N Gly-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OVSKVOOUFAKODB-UWVGGRQHSA-N 0.000 description 4
- UXJHNZODTMHWRD-WHFBIAKZSA-N Gly-Asn-Ala Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O UXJHNZODTMHWRD-WHFBIAKZSA-N 0.000 description 4
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 4
- MOJKRXIRAZPZLW-WDSKDSINSA-N Gly-Glu-Ala Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MOJKRXIRAZPZLW-WDSKDSINSA-N 0.000 description 4
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 4
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 4
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 4
- 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 4
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 4
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 4
- RGSOCXHDOPQREB-ZPFDUUQYSA-N Ile-Asp-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N RGSOCXHDOPQREB-ZPFDUUQYSA-N 0.000 description 4
- LGMUPVWZEYYUMU-YVNDNENWSA-N Ile-Glu-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N LGMUPVWZEYYUMU-YVNDNENWSA-N 0.000 description 4
- LPFBXFILACZHIB-LAEOZQHASA-N Ile-Gly-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)O)N LPFBXFILACZHIB-LAEOZQHASA-N 0.000 description 4
- BZUOLKFQVVBTJY-SLBDDTMCSA-N Ile-Trp-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)N)C(=O)O)N BZUOLKFQVVBTJY-SLBDDTMCSA-N 0.000 description 4
- OMDWJWGZGMCQND-CFMVVWHZSA-N Ile-Tyr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OMDWJWGZGMCQND-CFMVVWHZSA-N 0.000 description 4
- YWCJXQKATPNPOE-UKJIMTQDSA-N Ile-Val-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N YWCJXQKATPNPOE-UKJIMTQDSA-N 0.000 description 4
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 description 4
- 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 4
- WIDZHJTYKYBLSR-DCAQKATOSA-N Leu-Glu-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WIDZHJTYKYBLSR-DCAQKATOSA-N 0.000 description 4
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 4
- QJXHMYMRGDOHRU-NHCYSSNCSA-N Leu-Ile-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O QJXHMYMRGDOHRU-NHCYSSNCSA-N 0.000 description 4
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 4
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 4
- LVTJJOJKDCVZGP-QWRGUYRKSA-N Leu-Lys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LVTJJOJKDCVZGP-QWRGUYRKSA-N 0.000 description 4
- 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 4
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 4
- FDBTVENULFNTAL-XQQFMLRXSA-N Leu-Val-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N FDBTVENULFNTAL-XQQFMLRXSA-N 0.000 description 4
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 4
- IWWMPCPLFXFBAF-SRVKXCTJSA-N Lys-Asp-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O IWWMPCPLFXFBAF-SRVKXCTJSA-N 0.000 description 4
- FHIAJWBDZVHLAH-YUMQZZPRSA-N Lys-Gly-Ser Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FHIAJWBDZVHLAH-YUMQZZPRSA-N 0.000 description 4
- 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 4
- LOGFVTREOLYCPF-RHYQMDGZSA-N Lys-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-RHYQMDGZSA-N 0.000 description 4
- ZVZRQKJOQQAFCF-ULQDDVLXSA-N Lys-Tyr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ZVZRQKJOQQAFCF-ULQDDVLXSA-N 0.000 description 4
- AXHNAGAYRGCDLG-UWVGGRQHSA-N Met-Lys-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AXHNAGAYRGCDLG-UWVGGRQHSA-N 0.000 description 4
- 108050006335 Otoferlin Proteins 0.000 description 4
- WKTSCAXSYITIJJ-PCBIJLKTSA-N Phe-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O WKTSCAXSYITIJJ-PCBIJLKTSA-N 0.000 description 4
- MGLBSROLWAWCKN-FCLVOEFKSA-N Phe-Phe-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MGLBSROLWAWCKN-FCLVOEFKSA-N 0.000 description 4
- 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 4
- QSKCKTUQPICLSO-AVGNSLFASA-N Pro-Arg-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O QSKCKTUQPICLSO-AVGNSLFASA-N 0.000 description 4
- 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 4
- CMOIIANLNNYUTP-SRVKXCTJSA-N Pro-Gln-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O CMOIIANLNNYUTP-SRVKXCTJSA-N 0.000 description 4
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 4
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 4
- 108010025216 RVF peptide Proteins 0.000 description 4
- DSGYZICNAMEJOC-AVGNSLFASA-N Ser-Glu-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DSGYZICNAMEJOC-AVGNSLFASA-N 0.000 description 4
- BKZYBLLIBOBOOW-GHCJXIJMSA-N Ser-Ile-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O BKZYBLLIBOBOOW-GHCJXIJMSA-N 0.000 description 4
- 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 4
- BYCVMHKULKRVPV-GUBZILKMSA-N Ser-Lys-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O BYCVMHKULKRVPV-GUBZILKMSA-N 0.000 description 4
- JAWGSPUJAXYXJA-IHRRRGAJSA-N Ser-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)N)CC1=CC=CC=C1 JAWGSPUJAXYXJA-IHRRRGAJSA-N 0.000 description 4
- KKKVOZNCLALMPV-XKBZYTNZSA-N Ser-Thr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O KKKVOZNCLALMPV-XKBZYTNZSA-N 0.000 description 4
- TYVAWPFQYFPSBR-BFHQHQDPSA-N Thr-Ala-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)NCC(O)=O TYVAWPFQYFPSBR-BFHQHQDPSA-N 0.000 description 4
- 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 4
- 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 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
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 4
- TZNNEYFZZAHLBL-BPUTZDHNSA-N Trp-Arg-Asp Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O TZNNEYFZZAHLBL-BPUTZDHNSA-N 0.000 description 4
- GTNCSPKYWCJZAC-XIRDDKMYSA-N Trp-Asp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N GTNCSPKYWCJZAC-XIRDDKMYSA-N 0.000 description 4
- 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 4
- USYGMBIIUDLYHJ-GVARAGBVSA-N Tyr-Ile-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 USYGMBIIUDLYHJ-GVARAGBVSA-N 0.000 description 4
- MNWINJDPGBNOED-ULQDDVLXSA-N Tyr-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 MNWINJDPGBNOED-ULQDDVLXSA-N 0.000 description 4
- DJSYPCWZPNHQQE-FHWLQOOXSA-N Tyr-Tyr-Gln Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CC=C(O)C=C1 DJSYPCWZPNHQQE-FHWLQOOXSA-N 0.000 description 4
- GOPQNCQSXBJAII-ULQDDVLXSA-N Tyr-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N GOPQNCQSXBJAII-ULQDDVLXSA-N 0.000 description 4
- LABUITCFCAABSV-UHFFFAOYSA-N Val-Ala-Tyr Natural products CC(C)C(N)C(=O)NC(C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LABUITCFCAABSV-UHFFFAOYSA-N 0.000 description 4
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 4
- XQVRMLRMTAGSFJ-QXEWZRGKSA-N Val-Asp-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N XQVRMLRMTAGSFJ-QXEWZRGKSA-N 0.000 description 4
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 4
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 4
- AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 4
- 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 4
- VTIAEOKFUJJBTC-YDHLFZDLSA-N Val-Tyr-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VTIAEOKFUJJBTC-YDHLFZDLSA-N 0.000 description 4
- RLVTVHSDKHBFQP-ULQDDVLXSA-N Val-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 RLVTVHSDKHBFQP-ULQDDVLXSA-N 0.000 description 4
- 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 4
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 4
- 108010005233 alanylglutamic acid Proteins 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 4
- 108010021908 aspartyl-aspartyl-glutamyl-aspartic acid Proteins 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 230000008827 biological function Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 108010077515 glycylproline Proteins 0.000 description 4
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 4
- 108010005942 methionylglycine Proteins 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 108010004914 prolylarginine Proteins 0.000 description 4
- 108010053725 prolylvaline Proteins 0.000 description 4
- 108010005652 splenotritin Proteins 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 108010084932 tryptophyl-proline Proteins 0.000 description 4
- 241000701161 unidentified adenovirus Species 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 3
- 241001634120 Adeno-associated virus - 5 Species 0.000 description 3
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 3
- STACJSVFHSEZJV-GHCJXIJMSA-N Ala-Asn-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STACJSVFHSEZJV-GHCJXIJMSA-N 0.000 description 3
- WXERCAHAIKMTKX-ZLUOBGJFSA-N Ala-Asp-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O WXERCAHAIKMTKX-ZLUOBGJFSA-N 0.000 description 3
- ZIWWTZWAKYBUOB-CIUDSAMLSA-N Ala-Asp-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O ZIWWTZWAKYBUOB-CIUDSAMLSA-N 0.000 description 3
- LSLIRHLIUDVNBN-CIUDSAMLSA-N Ala-Asp-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LSLIRHLIUDVNBN-CIUDSAMLSA-N 0.000 description 3
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 3
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 3
- YIGLXQRFQVWFEY-NRPADANISA-N Ala-Gln-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O YIGLXQRFQVWFEY-NRPADANISA-N 0.000 description 3
- PAIHPOGPJVUFJY-WDSKDSINSA-N Ala-Glu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O PAIHPOGPJVUFJY-WDSKDSINSA-N 0.000 description 3
- HXNNRBHASOSVPG-GUBZILKMSA-N Ala-Glu-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HXNNRBHASOSVPG-GUBZILKMSA-N 0.000 description 3
- WMYJZJRILUVVRG-WDSKDSINSA-N Ala-Gly-Gln Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O WMYJZJRILUVVRG-WDSKDSINSA-N 0.000 description 3
- 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 3
- CKLDHDOIYBVUNP-KBIXCLLPSA-N Ala-Ile-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O CKLDHDOIYBVUNP-KBIXCLLPSA-N 0.000 description 3
- DVJSJDDYCYSMFR-ZKWXMUAHSA-N Ala-Ile-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O DVJSJDDYCYSMFR-ZKWXMUAHSA-N 0.000 description 3
- CFPQUJZTLUQUTJ-HTFCKZLJSA-N Ala-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](C)N CFPQUJZTLUQUTJ-HTFCKZLJSA-N 0.000 description 3
- VHVVPYOJIIQCKS-QEJZJMRPSA-N Ala-Leu-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VHVVPYOJIIQCKS-QEJZJMRPSA-N 0.000 description 3
- PIXQDIGKDNNOOV-GUBZILKMSA-N Ala-Lys-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O PIXQDIGKDNNOOV-GUBZILKMSA-N 0.000 description 3
- 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 3
- KYDYGANDJHFBCW-DRZSPHRISA-N Ala-Phe-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KYDYGANDJHFBCW-DRZSPHRISA-N 0.000 description 3
- YNOCMHZSWJMGBB-GCJQMDKQSA-N Ala-Thr-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O YNOCMHZSWJMGBB-GCJQMDKQSA-N 0.000 description 3
- QKHWNPQNOHEFST-VZFHVOOUSA-N Ala-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C)N)O QKHWNPQNOHEFST-VZFHVOOUSA-N 0.000 description 3
- 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 3
- YFWTXMRJJDNTLM-LSJOCFKGSA-N Arg-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YFWTXMRJJDNTLM-LSJOCFKGSA-N 0.000 description 3
- RVDVDRUZWZIBJQ-CIUDSAMLSA-N Arg-Asn-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O RVDVDRUZWZIBJQ-CIUDSAMLSA-N 0.000 description 3
- YNSGXDWWPCGGQS-YUMQZZPRSA-N Arg-Gly-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O YNSGXDWWPCGGQS-YUMQZZPRSA-N 0.000 description 3
- PHHRSPBBQUFULD-UWVGGRQHSA-N Arg-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N PHHRSPBBQUFULD-UWVGGRQHSA-N 0.000 description 3
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 3
- GRRXPUAICOGISM-RWMBFGLXSA-N Arg-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GRRXPUAICOGISM-RWMBFGLXSA-N 0.000 description 3
- NIELFHOLFTUZME-HJWJTTGWSA-N Arg-Phe-Ile 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)CC)C(O)=O NIELFHOLFTUZME-HJWJTTGWSA-N 0.000 description 3
- UGZUVYDKAYNCII-ULQDDVLXSA-N Arg-Phe-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UGZUVYDKAYNCII-ULQDDVLXSA-N 0.000 description 3
- KZXPVYVSHUJCEO-ULQDDVLXSA-N Arg-Phe-Lys Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=CC=C1 KZXPVYVSHUJCEO-ULQDDVLXSA-N 0.000 description 3
- NGYHSXDNNOFHNE-AVGNSLFASA-N Arg-Pro-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O NGYHSXDNNOFHNE-AVGNSLFASA-N 0.000 description 3
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 3
- PYDIIVKGTBRIEL-SZMVWBNQSA-N Arg-Trp-Pro Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(O)=O PYDIIVKGTBRIEL-SZMVWBNQSA-N 0.000 description 3
- CTAPSNCVKPOOSM-KKUMJFAQSA-N Arg-Tyr-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O CTAPSNCVKPOOSM-KKUMJFAQSA-N 0.000 description 3
- CGWVCWFQGXOUSJ-ULQDDVLXSA-N Arg-Tyr-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O CGWVCWFQGXOUSJ-ULQDDVLXSA-N 0.000 description 3
- SUMJNGAMIQSNGX-TUAOUCFPSA-N Arg-Val-Pro Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N1CCC[C@@H]1C(O)=O SUMJNGAMIQSNGX-TUAOUCFPSA-N 0.000 description 3
- LUVODTFFSXVOAG-ACZMJKKPSA-N Asn-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N LUVODTFFSXVOAG-ACZMJKKPSA-N 0.000 description 3
- YRTOMUMWSTUQAX-FXQIFTODSA-N Asn-Pro-Asp Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O YRTOMUMWSTUQAX-FXQIFTODSA-N 0.000 description 3
- 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 3
- 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 3
- CBHVAFXKOYAHOY-NHCYSSNCSA-N Asn-Val-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O CBHVAFXKOYAHOY-NHCYSSNCSA-N 0.000 description 3
- WSWYMRLTJVKRCE-ZLUOBGJFSA-N Asp-Ala-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O WSWYMRLTJVKRCE-ZLUOBGJFSA-N 0.000 description 3
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 3
- XACXDSRQIXRMNS-OLHMAJIHSA-N Asp-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N)O XACXDSRQIXRMNS-OLHMAJIHSA-N 0.000 description 3
- FANQWNCPNFEPGZ-WHFBIAKZSA-N Asp-Asp-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O FANQWNCPNFEPGZ-WHFBIAKZSA-N 0.000 description 3
- LKIYSIYBKYLKPU-BIIVOSGPSA-N Asp-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O LKIYSIYBKYLKPU-BIIVOSGPSA-N 0.000 description 3
- VHQOCWWKXIOAQI-WDSKDSINSA-N Asp-Gln-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VHQOCWWKXIOAQI-WDSKDSINSA-N 0.000 description 3
- CJUKAWUWBZCTDQ-SRVKXCTJSA-N Asp-Leu-Lys Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O CJUKAWUWBZCTDQ-SRVKXCTJSA-N 0.000 description 3
- RRUWMFBLFLUZSI-LPEHRKFASA-N Asp-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N RRUWMFBLFLUZSI-LPEHRKFASA-N 0.000 description 3
- RCGVPVZHKAXDPA-NYVOZVTQSA-N Asp-Trp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)NC(=O)[C@H](CC(=O)O)N RCGVPVZHKAXDPA-NYVOZVTQSA-N 0.000 description 3
- NWAHPBGBDIFUFD-KKUMJFAQSA-N Asp-Tyr-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O NWAHPBGBDIFUFD-KKUMJFAQSA-N 0.000 description 3
- XWKBWZXGNXTDKY-ZKWXMUAHSA-N Asp-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O XWKBWZXGNXTDKY-ZKWXMUAHSA-N 0.000 description 3
- XQFLFQWOBXPMHW-NHCYSSNCSA-N Asp-Val-His Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O XQFLFQWOBXPMHW-NHCYSSNCSA-N 0.000 description 3
- 241000283707 Capra Species 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
- LBOLGUYQEPZSKM-YUMQZZPRSA-N Cys-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CS)N LBOLGUYQEPZSKM-YUMQZZPRSA-N 0.000 description 3
- TXGDWPBLUFQODU-XGEHTFHBSA-N Cys-Pro-Thr Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O TXGDWPBLUFQODU-XGEHTFHBSA-N 0.000 description 3
- GFAPBMCRSMSGDZ-XGEHTFHBSA-N Cys-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CS)N)O GFAPBMCRSMSGDZ-XGEHTFHBSA-N 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 206010011882 Deafness congenital Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 101000834253 Gallus gallus Actin, cytoplasmic 1 Proteins 0.000 description 3
- PONUFVLSGMQFAI-AVGNSLFASA-N Gln-Asn-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PONUFVLSGMQFAI-AVGNSLFASA-N 0.000 description 3
- UICOTGULOUGGLC-NUMRIWBASA-N Gln-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N)O UICOTGULOUGGLC-NUMRIWBASA-N 0.000 description 3
- COYGBRTZEVWZBW-XKBZYTNZSA-N Gln-Cys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(N)=O COYGBRTZEVWZBW-XKBZYTNZSA-N 0.000 description 3
- XFKUFUJECJUQTQ-CIUDSAMLSA-N Gln-Gln-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XFKUFUJECJUQTQ-CIUDSAMLSA-N 0.000 description 3
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 3
- 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 3
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 3
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 3
- KKCUFHUTMKQQCF-SRVKXCTJSA-N Glu-Arg-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O KKCUFHUTMKQQCF-SRVKXCTJSA-N 0.000 description 3
- YKLNMGJYMNPBCP-ACZMJKKPSA-N Glu-Asn-Asp Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YKLNMGJYMNPBCP-ACZMJKKPSA-N 0.000 description 3
- DSPQRJXOIXHOHK-WDSKDSINSA-N Glu-Asp-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O DSPQRJXOIXHOHK-WDSKDSINSA-N 0.000 description 3
- HJIFPJUEOGZWRI-GUBZILKMSA-N Glu-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N HJIFPJUEOGZWRI-GUBZILKMSA-N 0.000 description 3
- PBFGQTGPSKWHJA-QEJZJMRPSA-N Glu-Asp-Trp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O PBFGQTGPSKWHJA-QEJZJMRPSA-N 0.000 description 3
- 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 3
- ILGFBUGLBSAQQB-GUBZILKMSA-N Glu-Glu-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ILGFBUGLBSAQQB-GUBZILKMSA-N 0.000 description 3
- KUTPGXNAAOQSPD-LPEHRKFASA-N Glu-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O KUTPGXNAAOQSPD-LPEHRKFASA-N 0.000 description 3
- 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 3
- ZQYZDDXTNQXUJH-CIUDSAMLSA-N Glu-Met-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)O)N ZQYZDDXTNQXUJH-CIUDSAMLSA-N 0.000 description 3
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 3
- 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 3
- 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 3
- 102100030651 Glutamate receptor 2 Human genes 0.000 description 3
- 101710087631 Glutamate receptor 2 Proteins 0.000 description 3
- KKBWDNZXYLGJEY-UHFFFAOYSA-N Gly-Arg-Pro Natural products NCC(=O)NC(CCNC(=N)N)C(=O)N1CCCC1C(=O)O KKBWDNZXYLGJEY-UHFFFAOYSA-N 0.000 description 3
- IWAXHBCACVWNHT-BQBZGAKWSA-N Gly-Asp-Arg Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IWAXHBCACVWNHT-BQBZGAKWSA-N 0.000 description 3
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 3
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 3
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 3
- 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 3
- LIXWIUAORXJNBH-QWRGUYRKSA-N Gly-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN LIXWIUAORXJNBH-QWRGUYRKSA-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
- CLNSYANKYVMZNM-UWVGGRQHSA-N Gly-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N CLNSYANKYVMZNM-UWVGGRQHSA-N 0.000 description 3
- LOEANKRDMMVOGZ-YUMQZZPRSA-N Gly-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O LOEANKRDMMVOGZ-YUMQZZPRSA-N 0.000 description 3
- NTBOEZICHOSJEE-YUMQZZPRSA-N Gly-Lys-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NTBOEZICHOSJEE-YUMQZZPRSA-N 0.000 description 3
- OQQKUTVULYLCDG-ONGXEEELSA-N Gly-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)CN)C(O)=O OQQKUTVULYLCDG-ONGXEEELSA-N 0.000 description 3
- MKIAPEZXQDILRR-YUMQZZPRSA-N Gly-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN MKIAPEZXQDILRR-YUMQZZPRSA-N 0.000 description 3
- WSLHFAFASQFMSK-SFTDATJTSA-N Gly-Trp-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)CN)C(O)=O)=CNC2=C1 WSLHFAFASQFMSK-SFTDATJTSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- YAALVYQFVJNXIV-KKUMJFAQSA-N His-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 YAALVYQFVJNXIV-KKUMJFAQSA-N 0.000 description 3
- HYWZHNUGAYVEEW-KKUMJFAQSA-N His-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](CC2=CN=CN2)N HYWZHNUGAYVEEW-KKUMJFAQSA-N 0.000 description 3
- VCBWXASUBZIFLQ-IHRRRGAJSA-N His-Pro-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O VCBWXASUBZIFLQ-IHRRRGAJSA-N 0.000 description 3
- VXZZUXWAOMWWJH-QTKMDUPCSA-N His-Thr-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VXZZUXWAOMWWJH-QTKMDUPCSA-N 0.000 description 3
- VSZALHITQINTGC-GHCJXIJMSA-N Ile-Ala-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VSZALHITQINTGC-GHCJXIJMSA-N 0.000 description 3
- RWIKBYVJQAJYDP-BJDJZHNGSA-N Ile-Ala-Lys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN RWIKBYVJQAJYDP-BJDJZHNGSA-N 0.000 description 3
- SACHLUOUHCVIKI-GMOBBJLQSA-N Ile-Arg-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N SACHLUOUHCVIKI-GMOBBJLQSA-N 0.000 description 3
- WECYRWOMWSCWNX-XUXIUFHCSA-N Ile-Arg-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(C)C)C(O)=O WECYRWOMWSCWNX-XUXIUFHCSA-N 0.000 description 3
- DMHGKBGOUAJRHU-RVMXOQNASA-N Ile-Arg-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N DMHGKBGOUAJRHU-RVMXOQNASA-N 0.000 description 3
- UAVQIQOOBXFKRC-BYULHYEWSA-N Ile-Asn-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O UAVQIQOOBXFKRC-BYULHYEWSA-N 0.000 description 3
- GQKSJYINYYWPMR-NGZCFLSTSA-N Ile-Gly-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N1CCC[C@@H]1C(=O)O)N GQKSJYINYYWPMR-NGZCFLSTSA-N 0.000 description 3
- PHRWFSFCNJPWRO-PPCPHDFISA-N Ile-Leu-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N PHRWFSFCNJPWRO-PPCPHDFISA-N 0.000 description 3
- KXUKTDGKLAOCQK-LSJOCFKGSA-N Ile-Val-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O KXUKTDGKLAOCQK-LSJOCFKGSA-N 0.000 description 3
- 108010065920 Insulin Lispro Proteins 0.000 description 3
- 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 3
- 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 3
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 3
- YKNBJXOJTURHCU-DCAQKATOSA-N Leu-Asp-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YKNBJXOJTURHCU-DCAQKATOSA-N 0.000 description 3
- ZDSNOSQHMJBRQN-SRVKXCTJSA-N Leu-Asp-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZDSNOSQHMJBRQN-SRVKXCTJSA-N 0.000 description 3
- DLCOFDAHNMMQPP-SRVKXCTJSA-N Leu-Asp-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DLCOFDAHNMMQPP-SRVKXCTJSA-N 0.000 description 3
- RSFGIMMPWAXNML-MNXVOIDGSA-N Leu-Gln-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSFGIMMPWAXNML-MNXVOIDGSA-N 0.000 description 3
- 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 3
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 3
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 3
- LZHJZLHSRGWBBE-IHRRRGAJSA-N Leu-Lys-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LZHJZLHSRGWBBE-IHRRRGAJSA-N 0.000 description 3
- ZDBMWELMUCLUPL-QEJZJMRPSA-N Leu-Phe-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=CC=C1 ZDBMWELMUCLUPL-QEJZJMRPSA-N 0.000 description 3
- 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 3
- MAXILRZVORNXBE-PMVMPFDFSA-N Leu-Phe-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 MAXILRZVORNXBE-PMVMPFDFSA-N 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
- 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 3
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 3
- XOEDPXDZJHBQIX-ULQDDVLXSA-N Leu-Val-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XOEDPXDZJHBQIX-ULQDDVLXSA-N 0.000 description 3
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 3
- QQUJSUFWEDZQQY-AVGNSLFASA-N Lys-Gln-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCCN QQUJSUFWEDZQQY-AVGNSLFASA-N 0.000 description 3
- 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 3
- KNKJPYAZQUFLQK-IHRRRGAJSA-N Lys-His-Arg Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCCCN)N KNKJPYAZQUFLQK-IHRRRGAJSA-N 0.000 description 3
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 3
- YPLVCBKEPJPBDQ-MELADBBJSA-N Lys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N YPLVCBKEPJPBDQ-MELADBBJSA-N 0.000 description 3
- UQRZFMQQXXJTTF-AVGNSLFASA-N Lys-Lys-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O UQRZFMQQXXJTTF-AVGNSLFASA-N 0.000 description 3
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 3
- OBZHNHBAAVEWKI-DCAQKATOSA-N Lys-Pro-Asn Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O OBZHNHBAAVEWKI-DCAQKATOSA-N 0.000 description 3
- 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 3
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 3
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 3
- KDBDVESGGJYVEH-PMVMPFDFSA-N Lys-Trp-Phe Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCCN)C(O)=O)C1=CC=CC=C1 KDBDVESGGJYVEH-PMVMPFDFSA-N 0.000 description 3
- TXTZMVNJIRZABH-ULQDDVLXSA-N Lys-Val-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 TXTZMVNJIRZABH-ULQDDVLXSA-N 0.000 description 3
- IKXQOBUBZSOWDY-AVGNSLFASA-N Lys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N IKXQOBUBZSOWDY-AVGNSLFASA-N 0.000 description 3
- CTVJSFRHUOSCQQ-DCAQKATOSA-N Met-Arg-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O CTVJSFRHUOSCQQ-DCAQKATOSA-N 0.000 description 3
- DRINJBAHUGXNFC-DCAQKATOSA-N Met-Asp-His Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(O)=O DRINJBAHUGXNFC-DCAQKATOSA-N 0.000 description 3
- MTBVQFFQMXHCPC-CIUDSAMLSA-N Met-Glu-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MTBVQFFQMXHCPC-CIUDSAMLSA-N 0.000 description 3
- FYRUJIJAUPHUNB-IUCAKERBSA-N Met-Gly-Arg Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N FYRUJIJAUPHUNB-IUCAKERBSA-N 0.000 description 3
- JACAKCWAOHKQBV-UWVGGRQHSA-N Met-Gly-Lys Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN JACAKCWAOHKQBV-UWVGGRQHSA-N 0.000 description 3
- NBEFNGUZUOUGFG-KKUMJFAQSA-N Met-Tyr-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N NBEFNGUZUOUGFG-KKUMJFAQSA-N 0.000 description 3
- LPNWWHBFXPNHJG-AVGNSLFASA-N Met-Val-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN LPNWWHBFXPNHJG-AVGNSLFASA-N 0.000 description 3
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 3
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- ULECEJGNDHWSKD-QEJZJMRPSA-N Phe-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 ULECEJGNDHWSKD-QEJZJMRPSA-N 0.000 description 3
- 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 3
- IUVYJBMTHARMIP-PCBIJLKTSA-N Phe-Asp-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O IUVYJBMTHARMIP-PCBIJLKTSA-N 0.000 description 3
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 3
- CKJACGQPCPMWIT-UFYCRDLUSA-N Phe-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CKJACGQPCPMWIT-UFYCRDLUSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 3
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 3
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 3
- LSIWVWRUTKPXDS-DCAQKATOSA-N Pro-Gln-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LSIWVWRUTKPXDS-DCAQKATOSA-N 0.000 description 3
- PULPZRAHVFBVTO-DCAQKATOSA-N Pro-Glu-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PULPZRAHVFBVTO-DCAQKATOSA-N 0.000 description 3
- VOZIBWWZSBIXQN-SRVKXCTJSA-N Pro-Glu-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O VOZIBWWZSBIXQN-SRVKXCTJSA-N 0.000 description 3
- BBFRBZYKHIKFBX-GMOBBJLQSA-N Pro-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@@H]1CCCN1 BBFRBZYKHIKFBX-GMOBBJLQSA-N 0.000 description 3
- LNOWDSPAYBWJOR-PEDHHIEDSA-N Pro-Ile-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LNOWDSPAYBWJOR-PEDHHIEDSA-N 0.000 description 3
- HFNPOYOKIPGAEI-SRVKXCTJSA-N Pro-Leu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 HFNPOYOKIPGAEI-SRVKXCTJSA-N 0.000 description 3
- DWGFLKQSGRUQTI-IHRRRGAJSA-N Pro-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 DWGFLKQSGRUQTI-IHRRRGAJSA-N 0.000 description 3
- XZBYTHCRAVAXQQ-DCAQKATOSA-N Pro-Met-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XZBYTHCRAVAXQQ-DCAQKATOSA-N 0.000 description 3
- WIPAMEKBSHNFQE-IUCAKERBSA-N Pro-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@@H]1CCCN1 WIPAMEKBSHNFQE-IUCAKERBSA-N 0.000 description 3
- DWPXHLIBFQLKLK-CYDGBPFRSA-N Pro-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 DWPXHLIBFQLKLK-CYDGBPFRSA-N 0.000 description 3
- 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 3
- FIODMZKLZFLYQP-GUBZILKMSA-N Pro-Val-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FIODMZKLZFLYQP-GUBZILKMSA-N 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- 238000010240 RT-PCR analysis Methods 0.000 description 3
- BTKUIVBNGBFTTP-WHFBIAKZSA-N Ser-Ala-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(O)=O BTKUIVBNGBFTTP-WHFBIAKZSA-N 0.000 description 3
- BRKHVZNDAOMAHX-BIIVOSGPSA-N Ser-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N BRKHVZNDAOMAHX-BIIVOSGPSA-N 0.000 description 3
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 3
- SMIDBHKWSYUBRZ-ACZMJKKPSA-N Ser-Glu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O SMIDBHKWSYUBRZ-ACZMJKKPSA-N 0.000 description 3
- LWMQRHDTXHQQOV-MXAVVETBSA-N Ser-Ile-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LWMQRHDTXHQQOV-MXAVVETBSA-N 0.000 description 3
- IAORETPTUDBBGV-CIUDSAMLSA-N Ser-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N IAORETPTUDBBGV-CIUDSAMLSA-N 0.000 description 3
- 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 3
- HEYZPTCCEIWHRO-IHRRRGAJSA-N Ser-Met-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HEYZPTCCEIWHRO-IHRRRGAJSA-N 0.000 description 3
- ZKBKUWQVDWWSRI-BZSNNMDCSA-N Ser-Phe-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKBKUWQVDWWSRI-BZSNNMDCSA-N 0.000 description 3
- NVNPWELENFJOHH-CIUDSAMLSA-N Ser-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)N NVNPWELENFJOHH-CIUDSAMLSA-N 0.000 description 3
- 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 3
- 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 3
- UQGAAZXSCGWMFU-UBHSHLNASA-N Ser-Trp-Asp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N UQGAAZXSCGWMFU-UBHSHLNASA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 3
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 3
- VFEHSAJCWWHDBH-RHYQMDGZSA-N Thr-Arg-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VFEHSAJCWWHDBH-RHYQMDGZSA-N 0.000 description 3
- XDARBNMYXKUFOJ-GSSVUCPTSA-N Thr-Asp-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XDARBNMYXKUFOJ-GSSVUCPTSA-N 0.000 description 3
- FDALPRWYVKJCLL-PMVVWTBXSA-N Thr-His-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)NCC(O)=O FDALPRWYVKJCLL-PMVVWTBXSA-N 0.000 description 3
- GUHLYMZJVXUIPO-RCWTZXSCSA-N Thr-Met-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O GUHLYMZJVXUIPO-RCWTZXSCSA-N 0.000 description 3
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 3
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 3
- 108700009124 Transcription Initiation Site Proteins 0.000 description 3
- VKMOGXREKGVZAF-QEJZJMRPSA-N Trp-Asp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VKMOGXREKGVZAF-QEJZJMRPSA-N 0.000 description 3
- RRVUOLRWIZXBRQ-IHPCNDPISA-N Trp-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N RRVUOLRWIZXBRQ-IHPCNDPISA-N 0.000 description 3
- CRWOSTCODDFEKZ-HRCADAONSA-N Tyr-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O CRWOSTCODDFEKZ-HRCADAONSA-N 0.000 description 3
- NZFCWALTLNFHHC-JYJNAYRXSA-N Tyr-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NZFCWALTLNFHHC-JYJNAYRXSA-N 0.000 description 3
- JHORGUYURUBVOM-KKUMJFAQSA-N Tyr-His-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O JHORGUYURUBVOM-KKUMJFAQSA-N 0.000 description 3
- GYKDRHDMGQUZPU-MGHWNKPDSA-N Tyr-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=C(C=C1)O)N GYKDRHDMGQUZPU-MGHWNKPDSA-N 0.000 description 3
- KLOZTPOXVVRVAQ-DZKIICNBSA-N Tyr-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 KLOZTPOXVVRVAQ-DZKIICNBSA-N 0.000 description 3
- DJIJBQYBDKGDIS-JYJNAYRXSA-N Tyr-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C)C(O)=O DJIJBQYBDKGDIS-JYJNAYRXSA-N 0.000 description 3
- UEOOXDLMQZBPFR-ZKWXMUAHSA-N Val-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N UEOOXDLMQZBPFR-ZKWXMUAHSA-N 0.000 description 3
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 3
- COYSIHFOCOMGCF-WPRPVWTQSA-N Val-Arg-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-WPRPVWTQSA-N 0.000 description 3
- LNYOXPDEIZJDEI-NHCYSSNCSA-N Val-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N LNYOXPDEIZJDEI-NHCYSSNCSA-N 0.000 description 3
- 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 3
- DDNIHOWRDOXXPF-NGZCFLSTSA-N Val-Asp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N DDNIHOWRDOXXPF-NGZCFLSTSA-N 0.000 description 3
- URIRWLJVWHYLET-ONGXEEELSA-N Val-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C URIRWLJVWHYLET-ONGXEEELSA-N 0.000 description 3
- KZKMBGXCNLPYKD-YEPSODPASA-N Val-Gly-Thr Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O KZKMBGXCNLPYKD-YEPSODPASA-N 0.000 description 3
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 3
- 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 3
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 3
- GVJUTBOZZBTBIG-AVGNSLFASA-N Val-Lys-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N GVJUTBOZZBTBIG-AVGNSLFASA-N 0.000 description 3
- XPKCFQZDQGVJCX-RHYQMDGZSA-N Val-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N)O XPKCFQZDQGVJCX-RHYQMDGZSA-N 0.000 description 3
- BCBFMJYTNKDALA-UFYCRDLUSA-N Val-Phe-Phe Chemical compound N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O BCBFMJYTNKDALA-UFYCRDLUSA-N 0.000 description 3
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 3
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 3
- PDDJTOSAVNRJRH-UNQGMJICSA-N Val-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](C(C)C)N)O PDDJTOSAVNRJRH-UNQGMJICSA-N 0.000 description 3
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-N 0.000 description 3
- 108700005077 Viral Genes Proteins 0.000 description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 3
- 108010041407 alanylaspartic acid Proteins 0.000 description 3
- 108010070944 alanylhistidine Proteins 0.000 description 3
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000028023 exocytosis Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 3
- 108010008237 glutamyl-valyl-glycine Proteins 0.000 description 3
- 108010075431 glycyl-alanyl-phenylalanine Proteins 0.000 description 3
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 3
- 108010084389 glycyltryptophan Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 230000006801 homologous recombination Effects 0.000 description 3
- 238000002744 homologous recombination Methods 0.000 description 3
- 238000010166 immunofluorescence Methods 0.000 description 3
- 108010000761 leucylarginine Proteins 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000009126 molecular therapy Methods 0.000 description 3
- 108010091617 pentalysine Proteins 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 108010048818 seryl-histidine Proteins 0.000 description 3
- 108010026333 seryl-proline Proteins 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 108010051110 tyrosyl-lysine Proteins 0.000 description 3
- 108010078580 tyrosylleucine Proteins 0.000 description 3
- 210000004291 uterus Anatomy 0.000 description 3
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 3
- 230000001720 vestibular Effects 0.000 description 3
- 210000002845 virion Anatomy 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- NTUPOKHATNSWCY-PMPSAXMXSA-N (2s)-2-[[(2s)-1-[(2r)-2-amino-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=CC=C1 NTUPOKHATNSWCY-PMPSAXMXSA-N 0.000 description 2
- PQFMROVJTOPVDF-JBDRJPRFSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]butanedioic acid Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O PQFMROVJTOPVDF-JBDRJPRFSA-N 0.000 description 2
- RRBGTUQJDFBWNN-MUGJNUQGSA-N (2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-2,6-diaminohexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoic acid Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O RRBGTUQJDFBWNN-MUGJNUQGSA-N 0.000 description 2
- PIDRBUDUWHBYSR-UHFFFAOYSA-N 1-[2-[[2-[(2-amino-4-methylpentanoyl)amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O PIDRBUDUWHBYSR-UHFFFAOYSA-N 0.000 description 2
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 2
- 241000972680 Adeno-associated virus - 6 Species 0.000 description 2
- BUANFPRKJKJSRR-ACZMJKKPSA-N Ala-Ala-Gln Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](C)C(=O)N[C@H](C([O-])=O)CCC(N)=O BUANFPRKJKJSRR-ACZMJKKPSA-N 0.000 description 2
- QDRGPQWIVZNJQD-CIUDSAMLSA-N Ala-Arg-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QDRGPQWIVZNJQD-CIUDSAMLSA-N 0.000 description 2
- IMMKUCQIKKXKNP-DCAQKATOSA-N Ala-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCN=C(N)N IMMKUCQIKKXKNP-DCAQKATOSA-N 0.000 description 2
- YWWATNIVMOCSAV-UBHSHLNASA-N Ala-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YWWATNIVMOCSAV-UBHSHLNASA-N 0.000 description 2
- XEXJJJRVTFGWIC-FXQIFTODSA-N Ala-Asn-Arg Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N XEXJJJRVTFGWIC-FXQIFTODSA-N 0.000 description 2
- WKOBSJOZRJJVRZ-FXQIFTODSA-N Ala-Glu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WKOBSJOZRJJVRZ-FXQIFTODSA-N 0.000 description 2
- SIGTYDNEPYEXGK-ZANVPECISA-N Ala-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)[C@@H](N)C)C(O)=O)=CNC2=C1 SIGTYDNEPYEXGK-ZANVPECISA-N 0.000 description 2
- AAXVGJXZKHQQHD-LSJOCFKGSA-N Ala-His-Met Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCSC)C(=O)O)N AAXVGJXZKHQQHD-LSJOCFKGSA-N 0.000 description 2
- NYDBKUNVSALYPX-NAKRPEOUSA-N Ala-Ile-Arg Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NYDBKUNVSALYPX-NAKRPEOUSA-N 0.000 description 2
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 2
- 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 2
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 2
- 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 2
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-N 0.000 description 2
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 2
- QOIGKCBMXUCDQU-KDXUFGMBSA-N Ala-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C)N)O QOIGKCBMXUCDQU-KDXUFGMBSA-N 0.000 description 2
- XPBVBZPVNFIHOA-UVBJJODRSA-N Ala-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](C)N)=CNC2=C1 XPBVBZPVNFIHOA-UVBJJODRSA-N 0.000 description 2
- AENHOIXXHKNIQL-AUTRQRHGSA-N Ala-Tyr-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H]([NH3+])C)CC1=CC=C(O)C=C1 AENHOIXXHKNIQL-AUTRQRHGSA-N 0.000 description 2
- KLKARCOHVHLAJP-UWJYBYFXSA-N Ala-Tyr-Cys Chemical compound C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CS)C(O)=O KLKARCOHVHLAJP-UWJYBYFXSA-N 0.000 description 2
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 2
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 2
- OTOXOKCIIQLMFH-KZVJFYERSA-N Arg-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N OTOXOKCIIQLMFH-KZVJFYERSA-N 0.000 description 2
- KJGNDQCYBNBXDA-GUBZILKMSA-N Arg-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N KJGNDQCYBNBXDA-GUBZILKMSA-N 0.000 description 2
- PVSNBTCXCQIXSE-JYJNAYRXSA-N Arg-Arg-Phe Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PVSNBTCXCQIXSE-JYJNAYRXSA-N 0.000 description 2
- NONSEUUPKITYQT-BQBZGAKWSA-N Arg-Asn-Gly Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)O)N)CN=C(N)N NONSEUUPKITYQT-BQBZGAKWSA-N 0.000 description 2
- OTUQSEPIIVBYEM-IHRRRGAJSA-N Arg-Asn-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OTUQSEPIIVBYEM-IHRRRGAJSA-N 0.000 description 2
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 2
- BQBPFMNVOWDLHO-XIRDDKMYSA-N Arg-Gln-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N BQBPFMNVOWDLHO-XIRDDKMYSA-N 0.000 description 2
- HAVKMRGWNXMCDR-STQMWFEESA-N Arg-Gly-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HAVKMRGWNXMCDR-STQMWFEESA-N 0.000 description 2
- ZATRYQNPUHGXCU-DTWKUNHWSA-N Arg-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZATRYQNPUHGXCU-DTWKUNHWSA-N 0.000 description 2
- PCQXGEUALSFGIA-WDSOQIARSA-N Arg-His-Trp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O PCQXGEUALSFGIA-WDSOQIARSA-N 0.000 description 2
- CVXXSWQORBZAAA-SRVKXCTJSA-N Arg-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N CVXXSWQORBZAAA-SRVKXCTJSA-N 0.000 description 2
- OISWSORSLQOGFV-AVGNSLFASA-N Arg-Met-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CCCN=C(N)N OISWSORSLQOGFV-AVGNSLFASA-N 0.000 description 2
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 2
- WKPXXXUSUHAXDE-SRVKXCTJSA-N Arg-Pro-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O WKPXXXUSUHAXDE-SRVKXCTJSA-N 0.000 description 2
- DNBMCNQKNOKOSD-DCAQKATOSA-N Arg-Pro-Gln Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O DNBMCNQKNOKOSD-DCAQKATOSA-N 0.000 description 2
- JJIBHAOBNIFUEL-SRVKXCTJSA-N Arg-Pro-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)N JJIBHAOBNIFUEL-SRVKXCTJSA-N 0.000 description 2
- 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 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
- JOTRDIXZHNQYGP-DCAQKATOSA-N Arg-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N JOTRDIXZHNQYGP-DCAQKATOSA-N 0.000 description 2
- OQPAZKMGCWPERI-GUBZILKMSA-N Arg-Ser-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OQPAZKMGCWPERI-GUBZILKMSA-N 0.000 description 2
- AIFHRTPABBBHKU-RCWTZXSCSA-N Arg-Thr-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AIFHRTPABBBHKU-RCWTZXSCSA-N 0.000 description 2
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 2
- 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 2
- ZWASIOHRQWRWAS-UGYAYLCHSA-N Asn-Asp-Ile 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)CC)C(O)=O ZWASIOHRQWRWAS-UGYAYLCHSA-N 0.000 description 2
- 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 2
- XVAPVJNJGLWGCS-ACZMJKKPSA-N Asn-Glu-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N XVAPVJNJGLWGCS-ACZMJKKPSA-N 0.000 description 2
- JREOBWLIZLXRIS-GUBZILKMSA-N Asn-Glu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JREOBWLIZLXRIS-GUBZILKMSA-N 0.000 description 2
- BKDDABUWNKGZCK-XHNCKOQMSA-N Asn-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O BKDDABUWNKGZCK-XHNCKOQMSA-N 0.000 description 2
- GFFRWIJAFFMQGM-NUMRIWBASA-N Asn-Glu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GFFRWIJAFFMQGM-NUMRIWBASA-N 0.000 description 2
- 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 2
- 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 2
- OLISTMZJGQUOGS-GMOBBJLQSA-N Asn-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](CC(=O)N)N OLISTMZJGQUOGS-GMOBBJLQSA-N 0.000 description 2
- ACKNRKFVYUVWAC-ZPFDUUQYSA-N Asn-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N ACKNRKFVYUVWAC-ZPFDUUQYSA-N 0.000 description 2
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 2
- ALHMNHZJBYBYHS-DCAQKATOSA-N Asn-Lys-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ALHMNHZJBYBYHS-DCAQKATOSA-N 0.000 description 2
- MYVBTYXSWILFCG-BQBZGAKWSA-N Asn-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N MYVBTYXSWILFCG-BQBZGAKWSA-N 0.000 description 2
- KAZKWIKPEPABOO-IHRRRGAJSA-N Asn-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](CC(=O)N)N KAZKWIKPEPABOO-IHRRRGAJSA-N 0.000 description 2
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 2
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 2
- 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 2
- LMIWYCWRJVMAIQ-NHCYSSNCSA-N Asn-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N LMIWYCWRJVMAIQ-NHCYSSNCSA-N 0.000 description 2
- WSOKZUVWBXVJHX-CIUDSAMLSA-N Asp-Arg-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O WSOKZUVWBXVJHX-CIUDSAMLSA-N 0.000 description 2
- DBWYWXNMZZYIRY-LPEHRKFASA-N Asp-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O DBWYWXNMZZYIRY-LPEHRKFASA-N 0.000 description 2
- FAEIQWHBRBWUBN-FXQIFTODSA-N Asp-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N)CN=C(N)N FAEIQWHBRBWUBN-FXQIFTODSA-N 0.000 description 2
- UQBGYPFHWFZMCD-ZLUOBGJFSA-N Asp-Asn-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UQBGYPFHWFZMCD-ZLUOBGJFSA-N 0.000 description 2
- WCFCYFDBMNFSPA-ACZMJKKPSA-N Asp-Asp-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O WCFCYFDBMNFSPA-ACZMJKKPSA-N 0.000 description 2
- SBHUBSDEZQFJHJ-CIUDSAMLSA-N Asp-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O SBHUBSDEZQFJHJ-CIUDSAMLSA-N 0.000 description 2
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 2
- OVPHVTCDVYYTHN-AVGNSLFASA-N Asp-Glu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OVPHVTCDVYYTHN-AVGNSLFASA-N 0.000 description 2
- 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 2
- XDGBFDYXZCMYEX-NUMRIWBASA-N Asp-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)O XDGBFDYXZCMYEX-NUMRIWBASA-N 0.000 description 2
- WBDWQKRLTVCDSY-WHFBIAKZSA-N Asp-Gly-Asp Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O WBDWQKRLTVCDSY-WHFBIAKZSA-N 0.000 description 2
- PZXPWHFYZXTFBI-YUMQZZPRSA-N Asp-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PZXPWHFYZXTFBI-YUMQZZPRSA-N 0.000 description 2
- POTCZYQVVNXUIG-BQBZGAKWSA-N Asp-Gly-Pro Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O POTCZYQVVNXUIG-BQBZGAKWSA-N 0.000 description 2
- RWHHSFSWKFBTCF-KKUMJFAQSA-N Asp-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)O)N RWHHSFSWKFBTCF-KKUMJFAQSA-N 0.000 description 2
- GBSUGIXJAAKZOW-GMOBBJLQSA-N Asp-Ile-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O GBSUGIXJAAKZOW-GMOBBJLQSA-N 0.000 description 2
- YFSLJHLQOALGSY-ZPFDUUQYSA-N Asp-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N YFSLJHLQOALGSY-ZPFDUUQYSA-N 0.000 description 2
- 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 2
- 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 2
- OEDJQRXNDRUGEU-SRVKXCTJSA-N Asp-Leu-His Chemical compound N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O OEDJQRXNDRUGEU-SRVKXCTJSA-N 0.000 description 2
- VSMYBNPOHYAXSD-GUBZILKMSA-N Asp-Lys-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O VSMYBNPOHYAXSD-GUBZILKMSA-N 0.000 description 2
- 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 2
- GKWFMNNNYZHJHV-SRVKXCTJSA-N Asp-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O GKWFMNNNYZHJHV-SRVKXCTJSA-N 0.000 description 2
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 2
- MYLZFUMPZCPJCJ-NHCYSSNCSA-N Asp-Lys-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MYLZFUMPZCPJCJ-NHCYSSNCSA-N 0.000 description 2
- LIQNMKIBMPEOOP-IHRRRGAJSA-N Asp-Phe-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(=O)O)N LIQNMKIBMPEOOP-IHRRRGAJSA-N 0.000 description 2
- 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 2
- MVRGBQGZSDJBSM-GMOBBJLQSA-N Asp-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)N MVRGBQGZSDJBSM-GMOBBJLQSA-N 0.000 description 2
- YFGUZQQCSDZRBN-DCAQKATOSA-N Asp-Pro-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O YFGUZQQCSDZRBN-DCAQKATOSA-N 0.000 description 2
- XUVTWGPERWIERB-IHRRRGAJSA-N Asp-Pro-Phe Chemical compound N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O XUVTWGPERWIERB-IHRRRGAJSA-N 0.000 description 2
- ZVGRHIRJLWBWGJ-ACZMJKKPSA-N Asp-Ser-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZVGRHIRJLWBWGJ-ACZMJKKPSA-N 0.000 description 2
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 2
- UEFODXNXUAVPTC-VEVYYDQMSA-N Asp-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O UEFODXNXUAVPTC-VEVYYDQMSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 108090000565 Capsid Proteins Proteins 0.000 description 2
- 102100023321 Ceruloplasmin Human genes 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 206010010356 Congenital anomaly Diseases 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- AEJSNWMRPXAKCW-WHFBIAKZSA-N Cys-Ala-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O AEJSNWMRPXAKCW-WHFBIAKZSA-N 0.000 description 2
- JTNKVWLMDHIUOG-IHRRRGAJSA-N Cys-Arg-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JTNKVWLMDHIUOG-IHRRRGAJSA-N 0.000 description 2
- WXKWQSDHEXKKNC-ZKWXMUAHSA-N Cys-Asp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N WXKWQSDHEXKKNC-ZKWXMUAHSA-N 0.000 description 2
- QADHATDBZXHRCA-ACZMJKKPSA-N Cys-Gln-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CS)N QADHATDBZXHRCA-ACZMJKKPSA-N 0.000 description 2
- URDUGPGPLNXXES-WHFBIAKZSA-N Cys-Gly-Cys Chemical compound SC[C@H](N)C(=O)NCC(=O)N[C@@H](CS)C(O)=O URDUGPGPLNXXES-WHFBIAKZSA-N 0.000 description 2
- PQHYZJPCYRDYNE-QWRGUYRKSA-N Cys-Gly-Phe Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PQHYZJPCYRDYNE-QWRGUYRKSA-N 0.000 description 2
- YFAFBAPQHGULQT-HJPIBITLSA-N Cys-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CS)N YFAFBAPQHGULQT-HJPIBITLSA-N 0.000 description 2
- JLZCAZJGWNRXCI-XKBZYTNZSA-N Cys-Thr-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O JLZCAZJGWNRXCI-XKBZYTNZSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 2
- JFOKLAPFYCTNHW-SRVKXCTJSA-N Gln-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N JFOKLAPFYCTNHW-SRVKXCTJSA-N 0.000 description 2
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 2
- LPYPANUXJGFMGV-FXQIFTODSA-N Gln-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LPYPANUXJGFMGV-FXQIFTODSA-N 0.000 description 2
- PXAFHUATEHLECW-GUBZILKMSA-N Gln-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N PXAFHUATEHLECW-GUBZILKMSA-N 0.000 description 2
- TYRMVTKPOWPZBC-SXNHZJKMSA-N Gln-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCC(=O)N)N TYRMVTKPOWPZBC-SXNHZJKMSA-N 0.000 description 2
- VZRAXPGTUNDIDK-GUBZILKMSA-N Gln-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N VZRAXPGTUNDIDK-GUBZILKMSA-N 0.000 description 2
- FKXCBKCOSVIGCT-AVGNSLFASA-N Gln-Lys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FKXCBKCOSVIGCT-AVGNSLFASA-N 0.000 description 2
- FALJZCPMTGJOHX-SRVKXCTJSA-N Gln-Met-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O FALJZCPMTGJOHX-SRVKXCTJSA-N 0.000 description 2
- LGWNISYVKDNJRP-FXQIFTODSA-N Gln-Ser-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O LGWNISYVKDNJRP-FXQIFTODSA-N 0.000 description 2
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 2
- SOEXCCGNHQBFPV-DLOVCJGASA-N Gln-Val-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SOEXCCGNHQBFPV-DLOVCJGASA-N 0.000 description 2
- BPDVTFBJZNBHEU-HGNGGELXSA-N Glu-Ala-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 BPDVTFBJZNBHEU-HGNGGELXSA-N 0.000 description 2
- 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 2
- NCWOMXABNYEPLY-NRPADANISA-N Glu-Ala-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O NCWOMXABNYEPLY-NRPADANISA-N 0.000 description 2
- VTTSANCGJWLPNC-ZPFDUUQYSA-N Glu-Arg-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VTTSANCGJWLPNC-ZPFDUUQYSA-N 0.000 description 2
- JPHYJQHPILOKHC-ACZMJKKPSA-N Glu-Asp-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O JPHYJQHPILOKHC-ACZMJKKPSA-N 0.000 description 2
- XXCDTYBVGMPIOA-FXQIFTODSA-N Glu-Asp-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XXCDTYBVGMPIOA-FXQIFTODSA-N 0.000 description 2
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-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)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 2
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 2
- IQACOVZVOMVILH-FXQIFTODSA-N Glu-Glu-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O IQACOVZVOMVILH-FXQIFTODSA-N 0.000 description 2
- XOIATPHFYVWFEU-DCAQKATOSA-N Glu-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XOIATPHFYVWFEU-DCAQKATOSA-N 0.000 description 2
- VSRCAOIHMGCIJK-SRVKXCTJSA-N Glu-Leu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VSRCAOIHMGCIJK-SRVKXCTJSA-N 0.000 description 2
- PJBVXVBTTFZPHJ-GUBZILKMSA-N Glu-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N PJBVXVBTTFZPHJ-GUBZILKMSA-N 0.000 description 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 2
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 2
- BCYGDJXHAGZNPQ-DCAQKATOSA-N Glu-Lys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O BCYGDJXHAGZNPQ-DCAQKATOSA-N 0.000 description 2
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 2
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 2
- RBXSZQRSEGYDFG-GUBZILKMSA-N Glu-Lys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O RBXSZQRSEGYDFG-GUBZILKMSA-N 0.000 description 2
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-N 0.000 description 2
- BIYNPVYAZOUVFQ-CIUDSAMLSA-N Glu-Pro-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O BIYNPVYAZOUVFQ-CIUDSAMLSA-N 0.000 description 2
- YQAQQKPWFOBSMU-WDCWCFNPSA-N Glu-Thr-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O YQAQQKPWFOBSMU-WDCWCFNPSA-N 0.000 description 2
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 2
- VIPDPMHGICREIS-GVXVVHGQSA-N Glu-Val-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O VIPDPMHGICREIS-GVXVVHGQSA-N 0.000 description 2
- 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 2
- 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 2
- YMUFWNJHVPQNQD-ZKWXMUAHSA-N Gly-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN YMUFWNJHVPQNQD-ZKWXMUAHSA-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
- GWCRIHNSVMOBEQ-BQBZGAKWSA-N Gly-Arg-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O GWCRIHNSVMOBEQ-BQBZGAKWSA-N 0.000 description 2
- DTPOVRRYXPJJAZ-FJXKBIBVSA-N Gly-Arg-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N DTPOVRRYXPJJAZ-FJXKBIBVSA-N 0.000 description 2
- NZAFOTBEULLEQB-WDSKDSINSA-N Gly-Asn-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN NZAFOTBEULLEQB-WDSKDSINSA-N 0.000 description 2
- MHHUEAIBJZWDBH-YUMQZZPRSA-N Gly-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN MHHUEAIBJZWDBH-YUMQZZPRSA-N 0.000 description 2
- YZACQYVWLCQWBT-BQBZGAKWSA-N Gly-Cys-Arg Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O YZACQYVWLCQWBT-BQBZGAKWSA-N 0.000 description 2
- XTQFHTHIAKKCTM-YFKPBYRVSA-N Gly-Glu-Gly Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O XTQFHTHIAKKCTM-YFKPBYRVSA-N 0.000 description 2
- MBOAPAXLTUSMQI-JHEQGTHGSA-N Gly-Glu-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MBOAPAXLTUSMQI-JHEQGTHGSA-N 0.000 description 2
- 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 2
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 2
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 2
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 2
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 2
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 2
- PCPOYRCAHPJXII-UWVGGRQHSA-N Gly-Lys-Met Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O PCPOYRCAHPJXII-UWVGGRQHSA-N 0.000 description 2
- YYXJFBMCOUSYSF-RYUDHWBXSA-N Gly-Phe-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYXJFBMCOUSYSF-RYUDHWBXSA-N 0.000 description 2
- ZZJVYSAQQMDIRD-UWVGGRQHSA-N Gly-Pro-His Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O ZZJVYSAQQMDIRD-UWVGGRQHSA-N 0.000 description 2
- SSFWXSNOKDZNHY-QXEWZRGKSA-N Gly-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN SSFWXSNOKDZNHY-QXEWZRGKSA-N 0.000 description 2
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 2
- 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 2
- 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 2
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 2
- IMRNSEPSPFQNHF-STQMWFEESA-N Gly-Ser-Trp Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)O IMRNSEPSPFQNHF-STQMWFEESA-N 0.000 description 2
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- UMBDRSMLCUYIRI-DVJZZOLTSA-N Gly-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN)O UMBDRSMLCUYIRI-DVJZZOLTSA-N 0.000 description 2
- FLUVGKKRRMLNPU-CQDKDKBSSA-N His-Ala-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FLUVGKKRRMLNPU-CQDKDKBSSA-N 0.000 description 2
- TVQGUFGDVODUIF-LSJOCFKGSA-N His-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N TVQGUFGDVODUIF-LSJOCFKGSA-N 0.000 description 2
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 2
- FIMNVXRZGUAGBI-AVGNSLFASA-N His-Glu-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FIMNVXRZGUAGBI-AVGNSLFASA-N 0.000 description 2
- AKAPKBNIVNPIPO-KKUMJFAQSA-N His-His-Lys Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CC=1NC=NC=1)C1=CN=CN1 AKAPKBNIVNPIPO-KKUMJFAQSA-N 0.000 description 2
- PGRPSOUCWRBWKZ-DLOVCJGASA-N His-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CN=CN1 PGRPSOUCWRBWKZ-DLOVCJGASA-N 0.000 description 2
- YXXKBPJEIYFGOD-MGHWNKPDSA-N His-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CN=CN2)N YXXKBPJEIYFGOD-MGHWNKPDSA-N 0.000 description 2
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 2
- YSMZBYPVVYSGOT-SZMVWBNQSA-N His-Trp-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC3=CN=CN3)N YSMZBYPVVYSGOT-SZMVWBNQSA-N 0.000 description 2
- QTMKFZAYZKBFRC-BZSNNMDCSA-N His-Tyr-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC3=CN=CN3)N)O QTMKFZAYZKBFRC-BZSNNMDCSA-N 0.000 description 2
- SYPULFZAGBBIOM-GVXVVHGQSA-N His-Val-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N SYPULFZAGBBIOM-GVXVVHGQSA-N 0.000 description 2
- 101001001817 Homo sapiens Pejvakin Proteins 0.000 description 2
- YKRYHWJRQUSTKG-KBIXCLLPSA-N Ile-Ala-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKRYHWJRQUSTKG-KBIXCLLPSA-N 0.000 description 2
- AZEYWPUCOYXFOE-CYDGBPFRSA-N Ile-Arg-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](C(C)C)C(=O)O)N AZEYWPUCOYXFOE-CYDGBPFRSA-N 0.000 description 2
- UMYZBHKAVTXWIW-GMOBBJLQSA-N Ile-Asp-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N UMYZBHKAVTXWIW-GMOBBJLQSA-N 0.000 description 2
- IDAHFEPYTJJZFD-PEFMBERDSA-N Ile-Asp-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N IDAHFEPYTJJZFD-PEFMBERDSA-N 0.000 description 2
- GYAFMRQGWHXMII-IUKAMOBKSA-N Ile-Asp-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N GYAFMRQGWHXMII-IUKAMOBKSA-N 0.000 description 2
- QRTVJGKXFSYJGW-KBIXCLLPSA-N Ile-Glu-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N QRTVJGKXFSYJGW-KBIXCLLPSA-N 0.000 description 2
- SLQVFYWBGNNOTK-BYULHYEWSA-N Ile-Gly-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N SLQVFYWBGNNOTK-BYULHYEWSA-N 0.000 description 2
- CSQNHSGHAPRGPQ-YTFOTSKYSA-N Ile-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)O)N CSQNHSGHAPRGPQ-YTFOTSKYSA-N 0.000 description 2
- FFAUOCITXBMRBT-YTFOTSKYSA-N Ile-Lys-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FFAUOCITXBMRBT-YTFOTSKYSA-N 0.000 description 2
- GVNNAHIRSDRIII-AJNGGQMLSA-N Ile-Lys-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N GVNNAHIRSDRIII-AJNGGQMLSA-N 0.000 description 2
- AKOYRLRUFBZOSP-BJDJZHNGSA-N Ile-Lys-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N AKOYRLRUFBZOSP-BJDJZHNGSA-N 0.000 description 2
- CKRFDMPBSWYOBT-PPCPHDFISA-N Ile-Lys-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N CKRFDMPBSWYOBT-PPCPHDFISA-N 0.000 description 2
- FTUZWJVSNZMLPI-RVMXOQNASA-N Ile-Met-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N FTUZWJVSNZMLPI-RVMXOQNASA-N 0.000 description 2
- WYUHAXJAMDTOAU-IAVJCBSLSA-N Ile-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N WYUHAXJAMDTOAU-IAVJCBSLSA-N 0.000 description 2
- IITVUURPOYGCTD-NAKRPEOUSA-N Ile-Pro-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IITVUURPOYGCTD-NAKRPEOUSA-N 0.000 description 2
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 2
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 2
- ZNOBVZFCHNHKHA-KBIXCLLPSA-N Ile-Ser-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZNOBVZFCHNHKHA-KBIXCLLPSA-N 0.000 description 2
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 2
- WXLYNEHOGRYNFU-URLPEUOOSA-N Ile-Thr-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N WXLYNEHOGRYNFU-URLPEUOOSA-N 0.000 description 2
- CRYJOCSSSACEAA-VKOGCVSHSA-N Ile-Trp-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCSC)C(=O)O)N CRYJOCSSSACEAA-VKOGCVSHSA-N 0.000 description 2
- ZFWISYLMLXFBSX-KKPKCPPISA-N Ile-Trp-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O)N ZFWISYLMLXFBSX-KKPKCPPISA-N 0.000 description 2
- BCISUQVFDGYZBO-QSFUFRPTSA-N Ile-Val-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O BCISUQVFDGYZBO-QSFUFRPTSA-N 0.000 description 2
- DLEBSGAVWRPTIX-PEDHHIEDSA-N Ile-Val-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)[C@@H](C)CC DLEBSGAVWRPTIX-PEDHHIEDSA-N 0.000 description 2
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- MJOZZTKJZQFKDK-GUBZILKMSA-N Leu-Ala-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(N)=O MJOZZTKJZQFKDK-GUBZILKMSA-N 0.000 description 2
- REPPKAMYTOJTFC-DCAQKATOSA-N Leu-Arg-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O REPPKAMYTOJTFC-DCAQKATOSA-N 0.000 description 2
- YOZCKMXHBYKOMQ-IHRRRGAJSA-N Leu-Arg-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOZCKMXHBYKOMQ-IHRRRGAJSA-N 0.000 description 2
- VKOAHIRLIUESLU-ULQDDVLXSA-N Leu-Arg-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VKOAHIRLIUESLU-ULQDDVLXSA-N 0.000 description 2
- 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 2
- VCSBGUACOYUIGD-CIUDSAMLSA-N Leu-Asn-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O VCSBGUACOYUIGD-CIUDSAMLSA-N 0.000 description 2
- RIMMMMYKGIBOSN-DCAQKATOSA-N Leu-Asn-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O RIMMMMYKGIBOSN-DCAQKATOSA-N 0.000 description 2
- 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 2
- ILJREDZFPHTUIE-GUBZILKMSA-N Leu-Asp-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ILJREDZFPHTUIE-GUBZILKMSA-N 0.000 description 2
- NHHKSOGJYNQENP-SRVKXCTJSA-N Leu-Cys-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N NHHKSOGJYNQENP-SRVKXCTJSA-N 0.000 description 2
- ZFNLIDNJUWNIJL-WDCWCFNPSA-N Leu-Glu-Thr 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)O)C(O)=O ZFNLIDNJUWNIJL-WDCWCFNPSA-N 0.000 description 2
- OXRLYTYUXAQTHP-YUMQZZPRSA-N Leu-Gly-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(O)=O OXRLYTYUXAQTHP-YUMQZZPRSA-N 0.000 description 2
- LAPSXOAUPNOINL-YUMQZZPRSA-N Leu-Gly-Asp Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O LAPSXOAUPNOINL-YUMQZZPRSA-N 0.000 description 2
- YFBBUHJJUXXZOF-UWVGGRQHSA-N Leu-Gly-Pro Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O YFBBUHJJUXXZOF-UWVGGRQHSA-N 0.000 description 2
- CSFVADKICPDRRF-KKUMJFAQSA-N Leu-His-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=CN=CN1 CSFVADKICPDRRF-KKUMJFAQSA-N 0.000 description 2
- OHZIZVWQXJPBJS-IXOXFDKPSA-N Leu-His-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OHZIZVWQXJPBJS-IXOXFDKPSA-N 0.000 description 2
- KOSWSHVQIVTVQF-ZPFDUUQYSA-N Leu-Ile-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KOSWSHVQIVTVQF-ZPFDUUQYSA-N 0.000 description 2
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 2
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 2
- OVZLLFONXILPDZ-VOAKCMCISA-N Leu-Lys-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OVZLLFONXILPDZ-VOAKCMCISA-N 0.000 description 2
- CPONGMJGVIAWEH-DCAQKATOSA-N Leu-Met-Ala Chemical compound CSCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(O)=O CPONGMJGVIAWEH-DCAQKATOSA-N 0.000 description 2
- DDVHDMSBLRAKNV-IHRRRGAJSA-N Leu-Met-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O DDVHDMSBLRAKNV-IHRRRGAJSA-N 0.000 description 2
- QMKFDEUJGYNFMC-AVGNSLFASA-N Leu-Pro-Arg Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QMKFDEUJGYNFMC-AVGNSLFASA-N 0.000 description 2
- HGUUMQWGYCVPKG-DCAQKATOSA-N Leu-Pro-Cys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N HGUUMQWGYCVPKG-DCAQKATOSA-N 0.000 description 2
- 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 2
- PWPBLZXWFXJFHE-RHYQMDGZSA-N Leu-Pro-Thr Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O PWPBLZXWFXJFHE-RHYQMDGZSA-N 0.000 description 2
- 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 2
- 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 2
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 2
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 2
- YWFZWQKWNDOWPA-XIRDDKMYSA-N Leu-Trp-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O YWFZWQKWNDOWPA-XIRDDKMYSA-N 0.000 description 2
- WFCKERTZVCQXKH-KBPBESRZSA-N Leu-Tyr-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O WFCKERTZVCQXKH-KBPBESRZSA-N 0.000 description 2
- 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 2
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- FZIJIFCXUCZHOL-CIUDSAMLSA-N Lys-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN FZIJIFCXUCZHOL-CIUDSAMLSA-N 0.000 description 2
- MPOHDJKRBLVGCT-CIUDSAMLSA-N Lys-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N MPOHDJKRBLVGCT-CIUDSAMLSA-N 0.000 description 2
- YIBOAHAOAWACDK-QEJZJMRPSA-N Lys-Ala-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YIBOAHAOAWACDK-QEJZJMRPSA-N 0.000 description 2
- BRSGXFITDXFMFF-IHRRRGAJSA-N Lys-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](CCCCN)N BRSGXFITDXFMFF-IHRRRGAJSA-N 0.000 description 2
- CKSXSQUVEYCDIW-AVGNSLFASA-N Lys-Arg-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)N CKSXSQUVEYCDIW-AVGNSLFASA-N 0.000 description 2
- DNEJSAIMVANNPA-DCAQKATOSA-N Lys-Asn-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DNEJSAIMVANNPA-DCAQKATOSA-N 0.000 description 2
- SQXUUGUCGJSWCK-CIUDSAMLSA-N Lys-Asp-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N SQXUUGUCGJSWCK-CIUDSAMLSA-N 0.000 description 2
- 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 2
- AAORVPFVUIHEAB-YUMQZZPRSA-N Lys-Asp-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O AAORVPFVUIHEAB-YUMQZZPRSA-N 0.000 description 2
- ZXEUFAVXODIPHC-GUBZILKMSA-N Lys-Glu-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ZXEUFAVXODIPHC-GUBZILKMSA-N 0.000 description 2
- GRADYHMSAUIKPS-DCAQKATOSA-N Lys-Glu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRADYHMSAUIKPS-DCAQKATOSA-N 0.000 description 2
- PAMDBWYMLWOELY-SDDRHHMPSA-N Lys-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)C(=O)O PAMDBWYMLWOELY-SDDRHHMPSA-N 0.000 description 2
- VEGLGAOVLFODGC-GUBZILKMSA-N Lys-Glu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VEGLGAOVLFODGC-GUBZILKMSA-N 0.000 description 2
- PBLLTSKBTAHDNA-KBPBESRZSA-N Lys-Gly-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PBLLTSKBTAHDNA-KBPBESRZSA-N 0.000 description 2
- ZASPELYMPSACER-HOCLYGCPSA-N Lys-Gly-Trp Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ZASPELYMPSACER-HOCLYGCPSA-N 0.000 description 2
- HAUUXTXKJNVIFY-ONGXEEELSA-N Lys-Gly-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HAUUXTXKJNVIFY-ONGXEEELSA-N 0.000 description 2
- VMTYLUGCXIEDMV-QWRGUYRKSA-N Lys-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCN VMTYLUGCXIEDMV-QWRGUYRKSA-N 0.000 description 2
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 2
- RIJCHEVHFWMDKD-SRVKXCTJSA-N Lys-Lys-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RIJCHEVHFWMDKD-SRVKXCTJSA-N 0.000 description 2
- YXPJCVNIDDKGOE-MELADBBJSA-N Lys-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N)C(=O)O YXPJCVNIDDKGOE-MELADBBJSA-N 0.000 description 2
- URGPVYGVWLIRGT-DCAQKATOSA-N Lys-Met-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O URGPVYGVWLIRGT-DCAQKATOSA-N 0.000 description 2
- HYSVGEAWTGPMOA-IHRRRGAJSA-N Lys-Pro-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O HYSVGEAWTGPMOA-IHRRRGAJSA-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
- 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 2
- YRNRVKTYDSLKMD-KKUMJFAQSA-N Lys-Ser-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YRNRVKTYDSLKMD-KKUMJFAQSA-N 0.000 description 2
- GIKFNMZSGYAPEJ-HJGDQZAQSA-N Lys-Thr-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O GIKFNMZSGYAPEJ-HJGDQZAQSA-N 0.000 description 2
- JHNOXVASMSXSNB-WEDXCCLWSA-N Lys-Thr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O JHNOXVASMSXSNB-WEDXCCLWSA-N 0.000 description 2
- RPWTZTBIFGENIA-VOAKCMCISA-N Lys-Thr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O RPWTZTBIFGENIA-VOAKCMCISA-N 0.000 description 2
- XYLSGAWRCZECIQ-JYJNAYRXSA-N Lys-Tyr-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(O)=O)CC1=CC=C(O)C=C1 XYLSGAWRCZECIQ-JYJNAYRXSA-N 0.000 description 2
- LMMBAXJRYSXCOQ-ACRUOGEOSA-N Lys-Tyr-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O LMMBAXJRYSXCOQ-ACRUOGEOSA-N 0.000 description 2
- 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 2
- QEVRUYFHWJJUHZ-DCAQKATOSA-N Met-Ala-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(C)C QEVRUYFHWJJUHZ-DCAQKATOSA-N 0.000 description 2
- RAAVFTFEAUAVIY-DCAQKATOSA-N Met-Glu-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N RAAVFTFEAUAVIY-DCAQKATOSA-N 0.000 description 2
- RRIHXWPHQSXHAQ-XUXIUFHCSA-N Met-Ile-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(O)=O RRIHXWPHQSXHAQ-XUXIUFHCSA-N 0.000 description 2
- HGAJNEWOUHDUMZ-SRVKXCTJSA-N Met-Leu-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O HGAJNEWOUHDUMZ-SRVKXCTJSA-N 0.000 description 2
- 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 2
- KBTQZYASLSUFJR-KKUMJFAQSA-N Met-Phe-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KBTQZYASLSUFJR-KKUMJFAQSA-N 0.000 description 2
- 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 2
- PCTFVQATEGYHJU-FXQIFTODSA-N Met-Ser-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O PCTFVQATEGYHJU-FXQIFTODSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 2
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 102100036328 Pejvakin Human genes 0.000 description 2
- BJEYSVHMGIJORT-NHCYSSNCSA-N Phe-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 BJEYSVHMGIJORT-NHCYSSNCSA-N 0.000 description 2
- UHRNIXJAGGLKHP-DLOVCJGASA-N Phe-Ala-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O UHRNIXJAGGLKHP-DLOVCJGASA-N 0.000 description 2
- PLNHHOXNVSYKOB-JYJNAYRXSA-N Phe-Arg-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CC=CC=C1)N PLNHHOXNVSYKOB-JYJNAYRXSA-N 0.000 description 2
- MECSIDWUTYRHRJ-KKUMJFAQSA-N Phe-Asn-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O MECSIDWUTYRHRJ-KKUMJFAQSA-N 0.000 description 2
- DDYIRGBOZVKRFR-AVGNSLFASA-N Phe-Asp-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DDYIRGBOZVKRFR-AVGNSLFASA-N 0.000 description 2
- 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 2
- LLGTYVHITPVGKR-RYUDHWBXSA-N Phe-Gln-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O LLGTYVHITPVGKR-RYUDHWBXSA-N 0.000 description 2
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 2
- NPLGQVKZFGJWAI-QWHCGFSZSA-N Phe-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O NPLGQVKZFGJWAI-QWHCGFSZSA-N 0.000 description 2
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 2
- VADLTGVIOIOKGM-BZSNNMDCSA-N Phe-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CN=CN1 VADLTGVIOIOKGM-BZSNNMDCSA-N 0.000 description 2
- SPXWRYVHOZVYBU-ULQDDVLXSA-N Phe-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N SPXWRYVHOZVYBU-ULQDDVLXSA-N 0.000 description 2
- NRKNYPRRWXVELC-NQCBNZPSSA-N Phe-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CC=CC=C3)N NRKNYPRRWXVELC-NQCBNZPSSA-N 0.000 description 2
- KBVJZCVLQWCJQN-KKUMJFAQSA-N Phe-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KBVJZCVLQWCJQN-KKUMJFAQSA-N 0.000 description 2
- TXKWKTWYTIAZSV-KKUMJFAQSA-N Phe-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N TXKWKTWYTIAZSV-KKUMJFAQSA-N 0.000 description 2
- RSPUIENXSJYZQO-JYJNAYRXSA-N Phe-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RSPUIENXSJYZQO-JYJNAYRXSA-N 0.000 description 2
- KDYPMIZMXDECSU-JYJNAYRXSA-N Phe-Leu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 KDYPMIZMXDECSU-JYJNAYRXSA-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
- YCCUXNNKXDGMAM-KKUMJFAQSA-N Phe-Leu-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YCCUXNNKXDGMAM-KKUMJFAQSA-N 0.000 description 2
- MJAYDXWQQUOURZ-JYJNAYRXSA-N Phe-Lys-Gln Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O MJAYDXWQQUOURZ-JYJNAYRXSA-N 0.000 description 2
- 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 2
- PHJUFDQVVKVOPU-ULQDDVLXSA-N Phe-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=CC=C1)N PHJUFDQVVKVOPU-ULQDDVLXSA-N 0.000 description 2
- MRWOVVNKSXXLRP-IHPCNDPISA-N Phe-Ser-Trp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MRWOVVNKSXXLRP-IHPCNDPISA-N 0.000 description 2
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 2
- ZVJGAXNBBKPYOE-HKUYNNGSSA-N Phe-Trp-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(O)=O)C1=CC=CC=C1 ZVJGAXNBBKPYOE-HKUYNNGSSA-N 0.000 description 2
- APMXLWHMIVWLLR-BZSNNMDCSA-N Phe-Tyr-Ser Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(O)=O)C1=CC=CC=C1 APMXLWHMIVWLLR-BZSNNMDCSA-N 0.000 description 2
- 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 2
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 2
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 2
- NHDVNAKDACFHPX-GUBZILKMSA-N Pro-Arg-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O NHDVNAKDACFHPX-GUBZILKMSA-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
- ORPZXBQTEHINPB-SRVKXCTJSA-N Pro-Arg-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1)C(O)=O ORPZXBQTEHINPB-SRVKXCTJSA-N 0.000 description 2
- ILMLVTGTUJPQFP-FXQIFTODSA-N Pro-Asp-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ILMLVTGTUJPQFP-FXQIFTODSA-N 0.000 description 2
- 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 2
- VPFGPKIWSDVTOY-SRVKXCTJSA-N Pro-Glu-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O VPFGPKIWSDVTOY-SRVKXCTJSA-N 0.000 description 2
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 2
- DMKWYMWNEKIPFC-IUCAKERBSA-N Pro-Gly-Arg Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O DMKWYMWNEKIPFC-IUCAKERBSA-N 0.000 description 2
- 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 2
- QEWBZBLXDKIQPS-STQMWFEESA-N Pro-Gly-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QEWBZBLXDKIQPS-STQMWFEESA-N 0.000 description 2
- XQHGISDMVBTGAL-ULQDDVLXSA-N Pro-His-Phe Chemical compound C([C@@H](C(=O)[O-])NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1[NH2+]CCC1)C1=CC=CC=C1 XQHGISDMVBTGAL-ULQDDVLXSA-N 0.000 description 2
- NFLNBHLMLYALOO-DCAQKATOSA-N Pro-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@@H]1CCCN1 NFLNBHLMLYALOO-DCAQKATOSA-N 0.000 description 2
- MRYUJHGPZQNOAD-IHRRRGAJSA-N Pro-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 MRYUJHGPZQNOAD-IHRRRGAJSA-N 0.000 description 2
- ZUZINZIJHJFJRN-UBHSHLNASA-N Pro-Phe-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 ZUZINZIJHJFJRN-UBHSHLNASA-N 0.000 description 2
- JLMZKEQFMVORMA-SRVKXCTJSA-N Pro-Pro-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 JLMZKEQFMVORMA-SRVKXCTJSA-N 0.000 description 2
- RFWXYTJSVDUBBZ-DCAQKATOSA-N Pro-Pro-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 RFWXYTJSVDUBBZ-DCAQKATOSA-N 0.000 description 2
- QAAYIXYLEMRULP-SRVKXCTJSA-N Pro-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 QAAYIXYLEMRULP-SRVKXCTJSA-N 0.000 description 2
- 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 2
- CNUIHOAISPKQPY-HSHDSVGOSA-N Pro-Thr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O CNUIHOAISPKQPY-HSHDSVGOSA-N 0.000 description 2
- QDDJNKWPTJHROJ-UFYCRDLUSA-N Pro-Tyr-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 QDDJNKWPTJHROJ-UFYCRDLUSA-N 0.000 description 2
- OOZJHTXCLJUODH-QXEWZRGKSA-N Pro-Val-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 OOZJHTXCLJUODH-QXEWZRGKSA-N 0.000 description 2
- FUOGXAQMNJMBFG-WPRPVWTQSA-N Pro-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 FUOGXAQMNJMBFG-WPRPVWTQSA-N 0.000 description 2
- FHJQROWZEJFZPO-SRVKXCTJSA-N Pro-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 FHJQROWZEJFZPO-SRVKXCTJSA-N 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 2
- IYCBDVBJWDXQRR-FXQIFTODSA-N Ser-Ala-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O IYCBDVBJWDXQRR-FXQIFTODSA-N 0.000 description 2
- OOKCGAYXSNJBGQ-ZLUOBGJFSA-N Ser-Asn-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OOKCGAYXSNJBGQ-ZLUOBGJFSA-N 0.000 description 2
- KCFKKAQKRZBWJB-ZLUOBGJFSA-N Ser-Cys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O KCFKKAQKRZBWJB-ZLUOBGJFSA-N 0.000 description 2
- RNFKSBPHLTZHLU-WHFBIAKZSA-N Ser-Cys-Gly Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N)O RNFKSBPHLTZHLU-WHFBIAKZSA-N 0.000 description 2
- MAWSJXHRLWVJEZ-ACZMJKKPSA-N Ser-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N MAWSJXHRLWVJEZ-ACZMJKKPSA-N 0.000 description 2
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 2
- 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 2
- CLKKNZQUQMZDGD-SRVKXCTJSA-N Ser-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CN=CN1 CLKKNZQUQMZDGD-SRVKXCTJSA-N 0.000 description 2
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 2
- 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 2
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 2
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 2
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 2
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 2
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 2
- NIOYDASGXWLHEZ-CIUDSAMLSA-N Ser-Met-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O NIOYDASGXWLHEZ-CIUDSAMLSA-N 0.000 description 2
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 2
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 2
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-N 0.000 description 2
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 2
- 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 2
- ZUXQFMVPAYGPFJ-JXUBOQSCSA-N Thr-Ala-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN ZUXQFMVPAYGPFJ-JXUBOQSCSA-N 0.000 description 2
- VASYSJHSMSBTDU-LKXGYXEUSA-N Thr-Asn-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)O VASYSJHSMSBTDU-LKXGYXEUSA-N 0.000 description 2
- PZVGOVRNGKEFCB-KKHAAJSZSA-N Thr-Asn-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N)O PZVGOVRNGKEFCB-KKHAAJSZSA-N 0.000 description 2
- ZUUDNCOCILSYAM-KKHAAJSZSA-N Thr-Asp-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O ZUUDNCOCILSYAM-KKHAAJSZSA-N 0.000 description 2
- 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 2
- UDQBCBUXAQIZAK-GLLZPBPUSA-N Thr-Glu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UDQBCBUXAQIZAK-GLLZPBPUSA-N 0.000 description 2
- HJOSVGCWOTYJFG-WDCWCFNPSA-N Thr-Glu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O HJOSVGCWOTYJFG-WDCWCFNPSA-N 0.000 description 2
- NIEWSKWFURSECR-FOHZUACHSA-N Thr-Gly-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NIEWSKWFURSECR-FOHZUACHSA-N 0.000 description 2
- ODXKUIGEPAGKKV-KATARQTJSA-N Thr-Leu-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)O)N)O ODXKUIGEPAGKKV-KATARQTJSA-N 0.000 description 2
- UUSQVWOVUYMLJA-PPCPHDFISA-N Thr-Lys-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UUSQVWOVUYMLJA-PPCPHDFISA-N 0.000 description 2
- WVVOFCVMHAXGLE-LFSVMHDDSA-N Thr-Phe-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O WVVOFCVMHAXGLE-LFSVMHDDSA-N 0.000 description 2
- JAJOFWABAUKAEJ-QTKMDUPCSA-N Thr-Pro-His Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O JAJOFWABAUKAEJ-QTKMDUPCSA-N 0.000 description 2
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 2
- WKGAAMOJPMBBMC-IXOXFDKPSA-N Thr-Ser-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WKGAAMOJPMBBMC-IXOXFDKPSA-N 0.000 description 2
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 2
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 2
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 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
- QGVBFDIREUUSHX-IFFSRLJSSA-N Thr-Val-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O QGVBFDIREUUSHX-IFFSRLJSSA-N 0.000 description 2
- BPGDJSUFQKWUBK-KJEVXHAQSA-N Thr-Val-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BPGDJSUFQKWUBK-KJEVXHAQSA-N 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- MJBBMTOGSOSAKJ-HJXMPXNTSA-N Trp-Ala-Ile Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MJBBMTOGSOSAKJ-HJXMPXNTSA-N 0.000 description 2
- HQVKQINPFOCIIV-BVSLBCMMSA-N Trp-Arg-Tyr Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=C(O)C=C1 HQVKQINPFOCIIV-BVSLBCMMSA-N 0.000 description 2
- BXKWZPXTTSCOMX-AQZXSJQPSA-N Trp-Asn-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BXKWZPXTTSCOMX-AQZXSJQPSA-N 0.000 description 2
- PXQPYPMSLBQHJJ-WFBYXXMGSA-N Trp-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N PXQPYPMSLBQHJJ-WFBYXXMGSA-N 0.000 description 2
- UJRIVCPPPMYCNA-HOCLYGCPSA-N Trp-Leu-Gly Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N UJRIVCPPPMYCNA-HOCLYGCPSA-N 0.000 description 2
- ABEVJDLMFPTGPS-SZMVWBNQSA-N Trp-Met-Met Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(O)=O ABEVJDLMFPTGPS-SZMVWBNQSA-N 0.000 description 2
- YTVJTXJTNRWJCR-JBACZVJFSA-N Trp-Phe-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N YTVJTXJTNRWJCR-JBACZVJFSA-N 0.000 description 2
- XOLLWQIBBLBAHQ-WDSOQIARSA-N Trp-Pro-Leu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O XOLLWQIBBLBAHQ-WDSOQIARSA-N 0.000 description 2
- CDEZPHVWBQFJQQ-NKKJXINNSA-N Trp-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CNC5=CC=CC=C54)N)C(=O)O CDEZPHVWBQFJQQ-NKKJXINNSA-N 0.000 description 2
- VFJIWSJKZJTQII-SRVKXCTJSA-N Tyr-Asp-Ser 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](CO)C(O)=O VFJIWSJKZJTQII-SRVKXCTJSA-N 0.000 description 2
- GHUNBABNQPIETG-MELADBBJSA-N Tyr-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O GHUNBABNQPIETG-MELADBBJSA-N 0.000 description 2
- QHEGAOPHISYNDF-XDTLVQLUSA-N Tyr-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHEGAOPHISYNDF-XDTLVQLUSA-N 0.000 description 2
- LHTGRUZSZOIAKM-SOUVJXGZSA-N Tyr-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O LHTGRUZSZOIAKM-SOUVJXGZSA-N 0.000 description 2
- OLWFDNLLBWQWCP-STQMWFEESA-N Tyr-Gly-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O OLWFDNLLBWQWCP-STQMWFEESA-N 0.000 description 2
- QARCDOCCDOLJSF-HJPIBITLSA-N Tyr-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QARCDOCCDOLJSF-HJPIBITLSA-N 0.000 description 2
- KSCVLGXNQXKUAR-JYJNAYRXSA-N Tyr-Leu-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KSCVLGXNQXKUAR-JYJNAYRXSA-N 0.000 description 2
- BJCILVZEZRDIDR-PMVMPFDFSA-N Tyr-Leu-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=C(O)C=C1 BJCILVZEZRDIDR-PMVMPFDFSA-N 0.000 description 2
- QKXAEWMHAAVVGS-KKUMJFAQSA-N Tyr-Pro-Glu Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O QKXAEWMHAAVVGS-KKUMJFAQSA-N 0.000 description 2
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 2
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 2
- FZSPNKUFROZBSG-ZKWXMUAHSA-N Val-Ala-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O FZSPNKUFROZBSG-ZKWXMUAHSA-N 0.000 description 2
- LABUITCFCAABSV-BPNCWPANSA-N Val-Ala-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LABUITCFCAABSV-BPNCWPANSA-N 0.000 description 2
- VDPRBUOZLIFUIM-GUBZILKMSA-N Val-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N VDPRBUOZLIFUIM-GUBZILKMSA-N 0.000 description 2
- UBTBGUDNDFZLGP-SRVKXCTJSA-N Val-Arg-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](C(C)C)C(=O)O)N UBTBGUDNDFZLGP-SRVKXCTJSA-N 0.000 description 2
- CFSSLXZJEMERJY-NRPADANISA-N Val-Gln-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CFSSLXZJEMERJY-NRPADANISA-N 0.000 description 2
- CPTQYHDSVGVGDZ-UKJIMTQDSA-N Val-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N CPTQYHDSVGVGDZ-UKJIMTQDSA-N 0.000 description 2
- PWRITNSESKQTPW-NRPADANISA-N Val-Gln-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N PWRITNSESKQTPW-NRPADANISA-N 0.000 description 2
- VLDMQVZZWDOKQF-AUTRQRHGSA-N Val-Glu-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VLDMQVZZWDOKQF-AUTRQRHGSA-N 0.000 description 2
- JTWIMNMUYLQNPI-WPRPVWTQSA-N Val-Gly-Arg Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N JTWIMNMUYLQNPI-WPRPVWTQSA-N 0.000 description 2
- DJEVQCWNMQOABE-RCOVLWMOSA-N Val-Gly-Asp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N DJEVQCWNMQOABE-RCOVLWMOSA-N 0.000 description 2
- KNYHAWKHFQRYOX-PYJNHQTQSA-N Val-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N KNYHAWKHFQRYOX-PYJNHQTQSA-N 0.000 description 2
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 2
- BMOFUVHDBROBSE-DCAQKATOSA-N Val-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N BMOFUVHDBROBSE-DCAQKATOSA-N 0.000 description 2
- IEBGHUMBJXIXHM-AVGNSLFASA-N Val-Lys-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N IEBGHUMBJXIXHM-AVGNSLFASA-N 0.000 description 2
- RSGHLMMKXJGCMK-JYJNAYRXSA-N Val-Met-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N RSGHLMMKXJGCMK-JYJNAYRXSA-N 0.000 description 2
- WMRWZYSRQUORHJ-YDHLFZDLSA-N Val-Phe-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N WMRWZYSRQUORHJ-YDHLFZDLSA-N 0.000 description 2
- 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 2
- 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 2
- VIKZGAUAKQZDOF-NRPADANISA-N Val-Ser-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O VIKZGAUAKQZDOF-NRPADANISA-N 0.000 description 2
- PGQUDQYHWICSAB-NAKRPEOUSA-N Val-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N PGQUDQYHWICSAB-NAKRPEOUSA-N 0.000 description 2
- DLRZGNXCXUGIDG-KKHAAJSZSA-N Val-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O DLRZGNXCXUGIDG-KKHAAJSZSA-N 0.000 description 2
- 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 2
- 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 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 210000003030 auditory receptor cell Anatomy 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 108010006025 bovine growth hormone Proteins 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004624 confocal microscopy Methods 0.000 description 2
- 108010004073 cysteinylcysteine Proteins 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 2
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 108010040030 histidinoalanine Proteins 0.000 description 2
- 108010036413 histidylglycine Proteins 0.000 description 2
- 108010092114 histidylphenylalanine Proteins 0.000 description 2
- 108010085325 histidylproline Proteins 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- OCYSGIYOVXAGKQ-UHFFFAOYSA-N hydron;3-[1-hydroxy-2-(methylamino)ethyl]phenol;chloride Chemical compound Cl.CNCC(O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 229960004184 ketamine hydrochloride Drugs 0.000 description 2
- 229940015418 ketaset Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108010085203 methionylmethionine Proteins 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000004897 n-terminal region Anatomy 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 210000002985 organ of corti Anatomy 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 108010082795 phenylalanyl-arginyl-arginine Proteins 0.000 description 2
- 108010073101 phenylalanylleucine Proteins 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000029034 regulation of vesicle fusion Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 230000021966 synaptic vesicle transport Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 230000010415 tropism Effects 0.000 description 2
- 108010020532 tyrosyl-proline Proteins 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 230000036266 weeks of gestation Effects 0.000 description 2
- 108010000998 wheylin-2 peptide Proteins 0.000 description 2
- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 1
- BRPMXFSTKXXNHF-IUCAKERBSA-N (2s)-1-[2-[[(2s)-pyrrolidine-2-carbonyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H]1NCCC1 BRPMXFSTKXXNHF-IUCAKERBSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- TYJOQICPGZGYDT-UHFFFAOYSA-N 4-methylsulfonylbenzenesulfonyl chloride Chemical compound CS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 TYJOQICPGZGYDT-UHFFFAOYSA-N 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- 108010036211 5-HT-moduline Proteins 0.000 description 1
- 241000202702 Adeno-associated virus - 3 Species 0.000 description 1
- 241000580270 Adeno-associated virus - 4 Species 0.000 description 1
- 241001164823 Adeno-associated virus - 7 Species 0.000 description 1
- 241000649045 Adeno-associated virus 10 Species 0.000 description 1
- FSBCNCKIQZZASN-GUBZILKMSA-N Ala-Arg-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O FSBCNCKIQZZASN-GUBZILKMSA-N 0.000 description 1
- WYPUMLRSQMKIJU-BPNCWPANSA-N Ala-Arg-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WYPUMLRSQMKIJU-BPNCWPANSA-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
- PCIFXPRIFWKWLK-YUMQZZPRSA-N Ala-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N PCIFXPRIFWKWLK-YUMQZZPRSA-N 0.000 description 1
- NIZKGBJVCMRDKO-KWQFWETISA-N Ala-Gly-Tyr Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NIZKGBJVCMRDKO-KWQFWETISA-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
- WUHJHHGYVVJMQE-BJDJZHNGSA-N Ala-Leu-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WUHJHHGYVVJMQE-BJDJZHNGSA-N 0.000 description 1
- PMQXMXAASGFUDX-SRVKXCTJSA-N Ala-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCCN PMQXMXAASGFUDX-SRVKXCTJSA-N 0.000 description 1
- NINQYGGNRIBFSC-CIUDSAMLSA-N Ala-Lys-Ser Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CO)C(O)=O NINQYGGNRIBFSC-CIUDSAMLSA-N 0.000 description 1
- OSRZOHXQCUFIQG-FPMFFAJLSA-N Ala-Phe-Pro Chemical compound C([C@H](NC(=O)[C@@H]([NH3+])C)C(=O)N1[C@H](CCC1)C([O-])=O)C1=CC=CC=C1 OSRZOHXQCUFIQG-FPMFFAJLSA-N 0.000 description 1
- VQAVBBCZFQAAED-FXQIFTODSA-N Ala-Pro-Asn Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)N)C(=O)O)N VQAVBBCZFQAAED-FXQIFTODSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- 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
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012109 Alexa Fluor 568 Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- SGYSTDWPNPKJPP-GUBZILKMSA-N Arg-Ala-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SGYSTDWPNPKJPP-GUBZILKMSA-N 0.000 description 1
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 1
- NTAZNGWBXRVEDJ-FXQIFTODSA-N Arg-Asp-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NTAZNGWBXRVEDJ-FXQIFTODSA-N 0.000 description 1
- KBBKCNHWCDJPGN-GUBZILKMSA-N Arg-Gln-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KBBKCNHWCDJPGN-GUBZILKMSA-N 0.000 description 1
- RYRQZJVFDVWURI-SRVKXCTJSA-N Arg-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N RYRQZJVFDVWURI-SRVKXCTJSA-N 0.000 description 1
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 1
- VRZDJJWOFXMFRO-ZFWWWQNUSA-N Arg-Gly-Trp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O VRZDJJWOFXMFRO-ZFWWWQNUSA-N 0.000 description 1
- YBZMTKUDWXZLIX-UWVGGRQHSA-N Arg-Leu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YBZMTKUDWXZLIX-UWVGGRQHSA-N 0.000 description 1
- UZGFHWIJWPUPOH-IHRRRGAJSA-N Arg-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UZGFHWIJWPUPOH-IHRRRGAJSA-N 0.000 description 1
- BNYNOWJESJJIOI-XUXIUFHCSA-N Arg-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N BNYNOWJESJJIOI-XUXIUFHCSA-N 0.000 description 1
- PYZPXCZNQSEHDT-GUBZILKMSA-N Arg-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N PYZPXCZNQSEHDT-GUBZILKMSA-N 0.000 description 1
- UIUXXFIKWQVMEX-UFYCRDLUSA-N Arg-Phe-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UIUXXFIKWQVMEX-UFYCRDLUSA-N 0.000 description 1
- VUGWHBXPMAHEGZ-SRVKXCTJSA-N Arg-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N VUGWHBXPMAHEGZ-SRVKXCTJSA-N 0.000 description 1
- DNLQVHBBMPZUGJ-BQBZGAKWSA-N Arg-Ser-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O DNLQVHBBMPZUGJ-BQBZGAKWSA-N 0.000 description 1
- LFAUVOXPCGJKTB-DCAQKATOSA-N Arg-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N LFAUVOXPCGJKTB-DCAQKATOSA-N 0.000 description 1
- YHZQOSXDTFRZKU-WDSOQIARSA-N Arg-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N)=CNC2=C1 YHZQOSXDTFRZKU-WDSOQIARSA-N 0.000 description 1
- ISVACHFCVRKIDG-SRVKXCTJSA-N Arg-Val-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O ISVACHFCVRKIDG-SRVKXCTJSA-N 0.000 description 1
- QTAIIXQCOPUNBQ-QXEWZRGKSA-N Arg-Val-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QTAIIXQCOPUNBQ-QXEWZRGKSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 1
- ZDOQDYFZNGASEY-BIIVOSGPSA-N Asn-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O ZDOQDYFZNGASEY-BIIVOSGPSA-N 0.000 description 1
- KUYKVGODHGHFDI-ACZMJKKPSA-N Asn-Gln-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O KUYKVGODHGHFDI-ACZMJKKPSA-N 0.000 description 1
- QYXNFROWLZPWPC-FXQIFTODSA-N Asn-Glu-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QYXNFROWLZPWPC-FXQIFTODSA-N 0.000 description 1
- GNKVBRYFXYWXAB-WDSKDSINSA-N Asn-Glu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O GNKVBRYFXYWXAB-WDSKDSINSA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-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
- YSYTWUMRHSFODC-QWRGUYRKSA-N Asn-Tyr-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O YSYTWUMRHSFODC-QWRGUYRKSA-N 0.000 description 1
- RGKKALNPOYURGE-ZKWXMUAHSA-N Asp-Ala-Val Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O RGKKALNPOYURGE-ZKWXMUAHSA-N 0.000 description 1
- QHAJMRDEWNAIBQ-FXQIFTODSA-N Asp-Arg-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O QHAJMRDEWNAIBQ-FXQIFTODSA-N 0.000 description 1
- AXXCUABIFZPKPM-BQBZGAKWSA-N Asp-Arg-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O AXXCUABIFZPKPM-BQBZGAKWSA-N 0.000 description 1
- SDHFVYLZFBDSQT-DCAQKATOSA-N Asp-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)O)N SDHFVYLZFBDSQT-DCAQKATOSA-N 0.000 description 1
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 1
- SVFOIXMRMLROHO-SRVKXCTJSA-N Asp-Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SVFOIXMRMLROHO-SRVKXCTJSA-N 0.000 description 1
- XAJRHVUUVUPFQL-ACZMJKKPSA-N Asp-Glu-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O XAJRHVUUVUPFQL-ACZMJKKPSA-N 0.000 description 1
- VIRHEUMYXXLCBF-WDSKDSINSA-N Asp-Gly-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O VIRHEUMYXXLCBF-WDSKDSINSA-N 0.000 description 1
- QCVXMEHGFUMKCO-YUMQZZPRSA-N Asp-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O QCVXMEHGFUMKCO-YUMQZZPRSA-N 0.000 description 1
- JNNVNVRBYUJYGS-CIUDSAMLSA-N Asp-Leu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O JNNVNVRBYUJYGS-CIUDSAMLSA-N 0.000 description 1
- HKEZZWQWXWGASX-KKUMJFAQSA-N Asp-Leu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HKEZZWQWXWGASX-KKUMJFAQSA-N 0.000 description 1
- QNIACYURSSCLRP-GUBZILKMSA-N Asp-Lys-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O QNIACYURSSCLRP-GUBZILKMSA-N 0.000 description 1
- WOPJVEMFXYHZEE-SRVKXCTJSA-N Asp-Phe-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WOPJVEMFXYHZEE-SRVKXCTJSA-N 0.000 description 1
- LGGHQRZIJSYRHA-GUBZILKMSA-N Asp-Pro-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)N LGGHQRZIJSYRHA-GUBZILKMSA-N 0.000 description 1
- BKOIIURTQAJHAT-GUBZILKMSA-N Asp-Pro-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 BKOIIURTQAJHAT-GUBZILKMSA-N 0.000 description 1
- XXAMCEGRCZQGEM-ZLUOBGJFSA-N Asp-Ser-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O XXAMCEGRCZQGEM-ZLUOBGJFSA-N 0.000 description 1
- OFYVKOXTTDCUIL-FXQIFTODSA-N Asp-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N OFYVKOXTTDCUIL-FXQIFTODSA-N 0.000 description 1
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 1
- QOCFFCUFZGDHTP-NUMRIWBASA-N Asp-Thr-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOCFFCUFZGDHTP-NUMRIWBASA-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
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- WAEDSQFVZJUHLI-BYULHYEWSA-N Asp-Val-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WAEDSQFVZJUHLI-BYULHYEWSA-N 0.000 description 1
- GXIUDSXIUSTSLO-QXEWZRGKSA-N Asp-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N GXIUDSXIUSTSLO-QXEWZRGKSA-N 0.000 description 1
- SFJUYBCDQBAYAJ-YDHLFZDLSA-N Asp-Val-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SFJUYBCDQBAYAJ-YDHLFZDLSA-N 0.000 description 1
- 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 1
- 208000000477 Bilateral Hearing Loss Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000197194 Bulla Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 108091028732 Concatemer Proteins 0.000 description 1
- MBPKYKSYUAPLMY-DCAQKATOSA-N Cys-Arg-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O MBPKYKSYUAPLMY-DCAQKATOSA-N 0.000 description 1
- XGIAHEUULGOZHH-GUBZILKMSA-N Cys-Arg-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N XGIAHEUULGOZHH-GUBZILKMSA-N 0.000 description 1
- LDIKUWLAMDFHPU-FXQIFTODSA-N Cys-Cys-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LDIKUWLAMDFHPU-FXQIFTODSA-N 0.000 description 1
- ANPADMNVVOOYKW-DCAQKATOSA-N Cys-His-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ANPADMNVVOOYKW-DCAQKATOSA-N 0.000 description 1
- MKMKILWCRQLDFJ-DCAQKATOSA-N Cys-Lys-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MKMKILWCRQLDFJ-DCAQKATOSA-N 0.000 description 1
- BNCKELUXXUYRNY-GUBZILKMSA-N Cys-Lys-Glu Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N BNCKELUXXUYRNY-GUBZILKMSA-N 0.000 description 1
- XSQAWJCVYDEWPT-GUBZILKMSA-N Cys-Met-Arg Chemical compound SC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XSQAWJCVYDEWPT-GUBZILKMSA-N 0.000 description 1
- 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 1
- JUNZLDGUJZIUCO-IHRRRGAJSA-N Cys-Pro-Tyr Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O JUNZLDGUJZIUCO-IHRRRGAJSA-N 0.000 description 1
- YWEHYKGJWHPGPY-XGEHTFHBSA-N Cys-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N)O YWEHYKGJWHPGPY-XGEHTFHBSA-N 0.000 description 1
- WVWRADGCZPIJJR-IHRRRGAJSA-N Cys-Val-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CS)N WVWRADGCZPIJJR-IHRRRGAJSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 101710095439 Erlin Proteins 0.000 description 1
- 238000011771 FVB mouse Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- INKFLNZBTSNFON-CIUDSAMLSA-N Gln-Ala-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O INKFLNZBTSNFON-CIUDSAMLSA-N 0.000 description 1
- XXLBHPPXDUWYAG-XQXXSGGOSA-N Gln-Ala-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XXLBHPPXDUWYAG-XQXXSGGOSA-N 0.000 description 1
- XEYMBRRKIFYQMF-GUBZILKMSA-N Gln-Asp-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O XEYMBRRKIFYQMF-GUBZILKMSA-N 0.000 description 1
- CGVWDTRDPLOMHZ-FXQIFTODSA-N Gln-Glu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CGVWDTRDPLOMHZ-FXQIFTODSA-N 0.000 description 1
- XJKAKYXMFHUIHT-AUTRQRHGSA-N Gln-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N XJKAKYXMFHUIHT-AUTRQRHGSA-N 0.000 description 1
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 1
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 1
- FTIJVMLAGRAYMJ-MNXVOIDGSA-N Gln-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(N)=O FTIJVMLAGRAYMJ-MNXVOIDGSA-N 0.000 description 1
- MWERYIXRDZDXOA-QEWYBTABSA-N Gln-Ile-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MWERYIXRDZDXOA-QEWYBTABSA-N 0.000 description 1
- ZNTDJIMJKNNSLR-RWRJDSDZSA-N Gln-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZNTDJIMJKNNSLR-RWRJDSDZSA-N 0.000 description 1
- CAXXTYYGFYTBPV-IUCAKERBSA-N Gln-Leu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CAXXTYYGFYTBPV-IUCAKERBSA-N 0.000 description 1
- IOFDDSNZJDIGPB-GVXVVHGQSA-N Gln-Leu-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IOFDDSNZJDIGPB-GVXVVHGQSA-N 0.000 description 1
- 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 1
- KFHASAPTUOASQN-JYJNAYRXSA-N Gln-Phe-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CCC(=O)N)N KFHASAPTUOASQN-JYJNAYRXSA-N 0.000 description 1
- RBSKVTZUFMIWFU-XEGUGMAKSA-N Gln-Trp-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O RBSKVTZUFMIWFU-XEGUGMAKSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- FHPXTPQBODWBIY-CIUDSAMLSA-N Glu-Ala-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHPXTPQBODWBIY-CIUDSAMLSA-N 0.000 description 1
- KBKGRMNVKPSQIF-XDTLVQLUSA-N Glu-Ala-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KBKGRMNVKPSQIF-XDTLVQLUSA-N 0.000 description 1
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 1
- OJGLIOXAKGFFDW-SRVKXCTJSA-N Glu-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)O)N OJGLIOXAKGFFDW-SRVKXCTJSA-N 0.000 description 1
- FLLRAEJOLZPSMN-CIUDSAMLSA-N Glu-Asn-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FLLRAEJOLZPSMN-CIUDSAMLSA-N 0.000 description 1
- RJONUNZIMUXUOI-GUBZILKMSA-N Glu-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N RJONUNZIMUXUOI-GUBZILKMSA-N 0.000 description 1
- LJLPOZGRPLORTF-CIUDSAMLSA-N Glu-Asn-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O LJLPOZGRPLORTF-CIUDSAMLSA-N 0.000 description 1
- ZJICFHQSPWFBKP-AVGNSLFASA-N Glu-Asn-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZJICFHQSPWFBKP-AVGNSLFASA-N 0.000 description 1
- SAEBUDRWKUXLOM-ACZMJKKPSA-N Glu-Cys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(O)=O SAEBUDRWKUXLOM-ACZMJKKPSA-N 0.000 description 1
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 1
- QQLBPVKLJBAXBS-FXQIFTODSA-N Glu-Glu-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QQLBPVKLJBAXBS-FXQIFTODSA-N 0.000 description 1
- MTAOBYXRYJZRGQ-WDSKDSINSA-N Glu-Gly-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MTAOBYXRYJZRGQ-WDSKDSINSA-N 0.000 description 1
- CUPSDFQZTVVTSK-GUBZILKMSA-N Glu-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O CUPSDFQZTVVTSK-GUBZILKMSA-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
- LKOAAMXDJGEYMS-ZPFDUUQYSA-N Glu-Met-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LKOAAMXDJGEYMS-ZPFDUUQYSA-N 0.000 description 1
- GTFYQOVVVJASOA-ACZMJKKPSA-N Glu-Ser-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N GTFYQOVVVJASOA-ACZMJKKPSA-N 0.000 description 1
- GMVCSRBOSIUTFC-FXQIFTODSA-N Glu-Ser-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMVCSRBOSIUTFC-FXQIFTODSA-N 0.000 description 1
- DTLLNDVORUEOTM-WDCWCFNPSA-N Glu-Thr-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DTLLNDVORUEOTM-WDCWCFNPSA-N 0.000 description 1
- CQGBSALYGOXQPE-HTUGSXCWSA-N Glu-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O CQGBSALYGOXQPE-HTUGSXCWSA-N 0.000 description 1
- MXJYXYDREQWUMS-XKBZYTNZSA-N Glu-Thr-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O MXJYXYDREQWUMS-XKBZYTNZSA-N 0.000 description 1
- HQTDNEZTGZUWSY-XVKPBYJWSA-N Glu-Val-Gly Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)NCC(O)=O HQTDNEZTGZUWSY-XVKPBYJWSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MZZSCEANQDPJER-ONGXEEELSA-N Gly-Ala-Phe Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MZZSCEANQDPJER-ONGXEEELSA-N 0.000 description 1
- VXKCPBPQEKKERH-IUCAKERBSA-N Gly-Arg-Pro Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(O)=O VXKCPBPQEKKERH-IUCAKERBSA-N 0.000 description 1
- FUTAPPOITCCWTH-WHFBIAKZSA-N Gly-Asp-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O FUTAPPOITCCWTH-WHFBIAKZSA-N 0.000 description 1
- NMROINAYXCACKF-WHFBIAKZSA-N Gly-Cys-Cys Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O NMROINAYXCACKF-WHFBIAKZSA-N 0.000 description 1
- HQRHFUYMGCHHJS-LURJTMIESA-N Gly-Gly-Arg Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N HQRHFUYMGCHHJS-LURJTMIESA-N 0.000 description 1
- LPCKHUXOGVNZRS-YUMQZZPRSA-N Gly-His-Ser Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O LPCKHUXOGVNZRS-YUMQZZPRSA-N 0.000 description 1
- SXJHOPPTOJACOA-QXEWZRGKSA-N Gly-Ile-Arg Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N SXJHOPPTOJACOA-QXEWZRGKSA-N 0.000 description 1
- HKSNHPVETYYJBK-LAEOZQHASA-N Gly-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)CN HKSNHPVETYYJBK-LAEOZQHASA-N 0.000 description 1
- PAWIVEIWWYGBAM-YUMQZZPRSA-N Gly-Leu-Ala Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O PAWIVEIWWYGBAM-YUMQZZPRSA-N 0.000 description 1
- IUZGUFAJDBHQQV-YUMQZZPRSA-N Gly-Leu-Asn Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IUZGUFAJDBHQQV-YUMQZZPRSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- JPAACTMBBBGAAR-HOTGVXAUSA-N Gly-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)CN)CC(C)C)C(O)=O)=CNC2=C1 JPAACTMBBBGAAR-HOTGVXAUSA-N 0.000 description 1
- QGDOOCIPHSSADO-STQMWFEESA-N Gly-Met-Phe Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGDOOCIPHSSADO-STQMWFEESA-N 0.000 description 1
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 1
- IGOYNRWLWHWAQO-JTQLQIEISA-N Gly-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IGOYNRWLWHWAQO-JTQLQIEISA-N 0.000 description 1
- JPVGHHQGKPQYIL-KBPBESRZSA-N Gly-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 JPVGHHQGKPQYIL-KBPBESRZSA-N 0.000 description 1
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 1
- ISSDODCYBOWWIP-GJZGRUSLSA-N Gly-Pro-Trp Chemical compound [H]NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ISSDODCYBOWWIP-GJZGRUSLSA-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
- YOBGUCWZPXJHTN-BQBZGAKWSA-N Gly-Ser-Arg Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YOBGUCWZPXJHTN-BQBZGAKWSA-N 0.000 description 1
- 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 1
- MYXNLWDWWOTERK-BHNWBGBOSA-N Gly-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN)O MYXNLWDWWOTERK-BHNWBGBOSA-N 0.000 description 1
- SFOXOSKVTLDEDM-HOTGVXAUSA-N Gly-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CN)=CNC2=C1 SFOXOSKVTLDEDM-HOTGVXAUSA-N 0.000 description 1
- YJDALMUYJIENAG-QWRGUYRKSA-N Gly-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN)O YJDALMUYJIENAG-QWRGUYRKSA-N 0.000 description 1
- GNNJKUYDWFIBTK-QWRGUYRKSA-N Gly-Tyr-Asp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O GNNJKUYDWFIBTK-QWRGUYRKSA-N 0.000 description 1
- DUAWRXXTOQOECJ-JSGCOSHPSA-N Gly-Tyr-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O DUAWRXXTOQOECJ-JSGCOSHPSA-N 0.000 description 1
- GWCJMBNBFYBQCV-XPUUQOCRSA-N Gly-Val-Ala Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O GWCJMBNBFYBQCV-XPUUQOCRSA-N 0.000 description 1
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 1
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 1
- 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
- HXKZJLWGSWQKEA-LSJOCFKGSA-N His-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CN=CN1 HXKZJLWGSWQKEA-LSJOCFKGSA-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
- BSVLMPMIXPQNKC-KBPBESRZSA-N His-Phe-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O BSVLMPMIXPQNKC-KBPBESRZSA-N 0.000 description 1
- CUEQQFOGARVNHU-VGDYDELISA-N His-Ser-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CUEQQFOGARVNHU-VGDYDELISA-N 0.000 description 1
- UOYGZBIPZYKGSH-SRVKXCTJSA-N His-Ser-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N UOYGZBIPZYKGSH-SRVKXCTJSA-N 0.000 description 1
- VIJMRAIWYWRXSR-CIUDSAMLSA-N His-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CN=CN1 VIJMRAIWYWRXSR-CIUDSAMLSA-N 0.000 description 1
- DEMIXZCKUXVEBO-BWAGICSOSA-N His-Thr-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O DEMIXZCKUXVEBO-BWAGICSOSA-N 0.000 description 1
- KFQDSSNYWKZFOO-LSJOCFKGSA-N His-Val-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KFQDSSNYWKZFOO-LSJOCFKGSA-N 0.000 description 1
- 101000764625 Homo sapiens Transmembrane inner ear expressed protein Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- HERITAGIPLEJMT-GVARAGBVSA-N Ile-Ala-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HERITAGIPLEJMT-GVARAGBVSA-N 0.000 description 1
- YKRIXHPEIZUDDY-GMOBBJLQSA-N Ile-Asn-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YKRIXHPEIZUDDY-GMOBBJLQSA-N 0.000 description 1
- KMBPQYKVZBMRMH-PEFMBERDSA-N Ile-Gln-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O KMBPQYKVZBMRMH-PEFMBERDSA-N 0.000 description 1
- HOLOYAZCIHDQNS-YVNDNENWSA-N Ile-Gln-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N HOLOYAZCIHDQNS-YVNDNENWSA-N 0.000 description 1
- UBHUJPVCJHPSEU-GRLWGSQLSA-N Ile-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N UBHUJPVCJHPSEU-GRLWGSQLSA-N 0.000 description 1
- ZXIGYKICRDFISM-DJFWLOJKSA-N Ile-His-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ZXIGYKICRDFISM-DJFWLOJKSA-N 0.000 description 1
- QZZIBQZLWBOOJH-PEDHHIEDSA-N Ile-Ile-Val Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)O QZZIBQZLWBOOJH-PEDHHIEDSA-N 0.000 description 1
- 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
- FFJQAEYLAQMGDL-MGHWNKPDSA-N Ile-Lys-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FFJQAEYLAQMGDL-MGHWNKPDSA-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
- SVZFKLBRCYCIIY-CYDGBPFRSA-N Ile-Pro-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SVZFKLBRCYCIIY-CYDGBPFRSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- PELCGFMHLZXWBQ-BJDJZHNGSA-N Ile-Ser-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)O)N PELCGFMHLZXWBQ-BJDJZHNGSA-N 0.000 description 1
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 1
- JNLSTRPWUXOORL-MMWGEVLESA-N Ile-Ser-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N JNLSTRPWUXOORL-MMWGEVLESA-N 0.000 description 1
- HXIDVIFHRYRXLZ-NAKRPEOUSA-N Ile-Ser-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)O)N HXIDVIFHRYRXLZ-NAKRPEOUSA-N 0.000 description 1
- BLFXHAFTNYZEQE-VKOGCVSHSA-N Ile-Trp-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N BLFXHAFTNYZEQE-VKOGCVSHSA-N 0.000 description 1
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 101710203526 Integrase Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 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
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- GRZSCTXVCDUIPO-SRVKXCTJSA-N Leu-Arg-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRZSCTXVCDUIPO-SRVKXCTJSA-N 0.000 description 1
- FJUKMPUELVROGK-IHRRRGAJSA-N Leu-Arg-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N FJUKMPUELVROGK-IHRRRGAJSA-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
- KTFHTMHHKXUYPW-ZPFDUUQYSA-N Leu-Asp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KTFHTMHHKXUYPW-ZPFDUUQYSA-N 0.000 description 1
- GBDMISNMNXVTNV-XIRDDKMYSA-N Leu-Asp-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O GBDMISNMNXVTNV-XIRDDKMYSA-N 0.000 description 1
- DKEZVKFLETVJFY-CIUDSAMLSA-N Leu-Cys-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N DKEZVKFLETVJFY-CIUDSAMLSA-N 0.000 description 1
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 1
- 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 1
- DZQMXBALGUHGJT-GUBZILKMSA-N Leu-Glu-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O DZQMXBALGUHGJT-GUBZILKMSA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- KGCLIYGPQXUNLO-IUCAKERBSA-N Leu-Gly-Glu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O KGCLIYGPQXUNLO-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
- ORWTWZXGDBYVCP-BJDJZHNGSA-N Leu-Ile-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(C)C ORWTWZXGDBYVCP-BJDJZHNGSA-N 0.000 description 1
- SEMUSFOBZGKBGW-YTFOTSKYSA-N Leu-Ile-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SEMUSFOBZGKBGW-YTFOTSKYSA-N 0.000 description 1
- PPQRKXHCLYCBSP-IHRRRGAJSA-N Leu-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N PPQRKXHCLYCBSP-IHRRRGAJSA-N 0.000 description 1
- WXZOHBVPVKABQN-DCAQKATOSA-N Leu-Met-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N WXZOHBVPVKABQN-DCAQKATOSA-N 0.000 description 1
- UCXQIIIFOOGYEM-ULQDDVLXSA-N Leu-Pro-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UCXQIIIFOOGYEM-ULQDDVLXSA-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
- ZDJQVSIPFLMNOX-RHYQMDGZSA-N Leu-Thr-Arg 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)CCCN=C(N)N ZDJQVSIPFLMNOX-RHYQMDGZSA-N 0.000 description 1
- 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 1
- 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 1
- FPFOYSCDUWTZBF-IHPCNDPISA-N Leu-Trp-Leu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H]([NH3+])CC(C)C)C(=O)N[C@@H](CC(C)C)C([O-])=O)=CNC2=C1 FPFOYSCDUWTZBF-IHPCNDPISA-N 0.000 description 1
- NQCJGQHHYZNUDK-DCAQKATOSA-N Lys-Arg-Ser Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CCCN=C(N)N NQCJGQHHYZNUDK-DCAQKATOSA-N 0.000 description 1
- RDIILCRAWOSDOQ-CIUDSAMLSA-N Lys-Cys-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N RDIILCRAWOSDOQ-CIUDSAMLSA-N 0.000 description 1
- WTZUSCUIVPVCRH-SRVKXCTJSA-N Lys-Gln-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N WTZUSCUIVPVCRH-SRVKXCTJSA-N 0.000 description 1
- GGNOBVSOZPHLCE-GUBZILKMSA-N Lys-Gln-Asp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GGNOBVSOZPHLCE-GUBZILKMSA-N 0.000 description 1
- RZHLIPMZXOEJTL-AVGNSLFASA-N Lys-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)N RZHLIPMZXOEJTL-AVGNSLFASA-N 0.000 description 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
- DCRWPTBMWMGADO-AVGNSLFASA-N Lys-Glu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DCRWPTBMWMGADO-AVGNSLFASA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- 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 1
- ZXFRGTAIIZHNHG-AJNGGQMLSA-N Lys-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N ZXFRGTAIIZHNHG-AJNGGQMLSA-N 0.000 description 1
- XREQQOATSMMAJP-MGHWNKPDSA-N Lys-Ile-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XREQQOATSMMAJP-MGHWNKPDSA-N 0.000 description 1
- WAIHHELKYSFIQN-XUXIUFHCSA-N Lys-Ile-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O WAIHHELKYSFIQN-XUXIUFHCSA-N 0.000 description 1
- OVAOHZIOUBEQCJ-IHRRRGAJSA-N Lys-Leu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OVAOHZIOUBEQCJ-IHRRRGAJSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- ZCWWVXAXWUAEPZ-SRVKXCTJSA-N Lys-Met-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZCWWVXAXWUAEPZ-SRVKXCTJSA-N 0.000 description 1
- WGILOYIKJVQUPT-DCAQKATOSA-N Lys-Pro-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O WGILOYIKJVQUPT-DCAQKATOSA-N 0.000 description 1
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- QVTDVTONTRSQMF-WDCWCFNPSA-N Lys-Thr-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CCCCN QVTDVTONTRSQMF-WDCWCFNPSA-N 0.000 description 1
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 1
- VHTOGMKQXXJOHG-RHYQMDGZSA-N Lys-Thr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VHTOGMKQXXJOHG-RHYQMDGZSA-N 0.000 description 1
- CNXOBMMOYZPPGS-NUTKFTJISA-N Lys-Trp-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O CNXOBMMOYZPPGS-NUTKFTJISA-N 0.000 description 1
- KXYLFJIQDIMURW-IHPCNDPISA-N Lys-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CCCCN)=CNC2=C1 KXYLFJIQDIMURW-IHPCNDPISA-N 0.000 description 1
- PPNCMJARTHYNEC-MEYUZBJRSA-N Lys-Tyr-Thr Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)CC1=CC=C(O)C=C1 PPNCMJARTHYNEC-MEYUZBJRSA-N 0.000 description 1
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VHGIWFGJIHTASW-FXQIFTODSA-N Met-Ala-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O VHGIWFGJIHTASW-FXQIFTODSA-N 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
- FBQMBZLJHOQAIH-GUBZILKMSA-N Met-Asp-Met Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O FBQMBZLJHOQAIH-GUBZILKMSA-N 0.000 description 1
- DNDVVILEHVMWIS-LPEHRKFASA-N Met-Asp-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N DNDVVILEHVMWIS-LPEHRKFASA-N 0.000 description 1
- PNDCUTDWYVKBHX-IHRRRGAJSA-N Met-Asp-Tyr Chemical compound CSCC[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 PNDCUTDWYVKBHX-IHRRRGAJSA-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
- 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
- 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
- GVIVXNFKJQFTCE-YUMQZZPRSA-N Met-Gly-Gln Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O GVIVXNFKJQFTCE-YUMQZZPRSA-N 0.000 description 1
- HSJIGJRZYUADSS-IHRRRGAJSA-N Met-Lys-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HSJIGJRZYUADSS-IHRRRGAJSA-N 0.000 description 1
- WTHGNAAQXISJHP-AVGNSLFASA-N Met-Lys-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O WTHGNAAQXISJHP-AVGNSLFASA-N 0.000 description 1
- XOFDBXYPKZUAAM-GUBZILKMSA-N Met-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N XOFDBXYPKZUAAM-GUBZILKMSA-N 0.000 description 1
- ILKCLLLOGPDNIP-RCWTZXSCSA-N Met-Met-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ILKCLLLOGPDNIP-RCWTZXSCSA-N 0.000 description 1
- NTYQUVLERIHPMU-HRCADAONSA-N Met-Phe-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N NTYQUVLERIHPMU-HRCADAONSA-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
- 101001134212 Mus musculus Otoferlin Proteins 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
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000701945 Parvoviridae Species 0.000 description 1
- JVTMTFMMMHAPCR-UBHSHLNASA-N Phe-Ala-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 JVTMTFMMMHAPCR-UBHSHLNASA-N 0.000 description 1
- JEGFCFLCRSJCMA-IHRRRGAJSA-N Phe-Arg-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N JEGFCFLCRSJCMA-IHRRRGAJSA-N 0.000 description 1
- HTKNPQZCMLBOTQ-XVSYOHENSA-N Phe-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O HTKNPQZCMLBOTQ-XVSYOHENSA-N 0.000 description 1
- WIVCOAKLPICYGY-KKUMJFAQSA-N Phe-Asp-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N WIVCOAKLPICYGY-KKUMJFAQSA-N 0.000 description 1
- DJPXNKUDJKGQEE-BZSNNMDCSA-N Phe-Asp-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DJPXNKUDJKGQEE-BZSNNMDCSA-N 0.000 description 1
- OJUMUUXGSXUZJZ-SRVKXCTJSA-N Phe-Asp-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O OJUMUUXGSXUZJZ-SRVKXCTJSA-N 0.000 description 1
- HQVPQHLNOVTLDD-IHRRRGAJSA-N Phe-Cys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N HQVPQHLNOVTLDD-IHRRRGAJSA-N 0.000 description 1
- UNLYPPYNDXHGDG-IHRRRGAJSA-N Phe-Gln-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 UNLYPPYNDXHGDG-IHRRRGAJSA-N 0.000 description 1
- MPFGIYLYWUCSJG-AVGNSLFASA-N Phe-Glu-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MPFGIYLYWUCSJG-AVGNSLFASA-N 0.000 description 1
- LWPMGKSZPKFKJD-DZKIICNBSA-N Phe-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O LWPMGKSZPKFKJD-DZKIICNBSA-N 0.000 description 1
- RFEXGCASCQGGHZ-STQMWFEESA-N Phe-Gly-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O RFEXGCASCQGGHZ-STQMWFEESA-N 0.000 description 1
- ZLGQEBCCANLYRA-RYUDHWBXSA-N Phe-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O ZLGQEBCCANLYRA-RYUDHWBXSA-N 0.000 description 1
- MJQFZGOIVBDIMZ-WHOFXGATSA-N Phe-Ile-Gly Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)O MJQFZGOIVBDIMZ-WHOFXGATSA-N 0.000 description 1
- KXUZHWXENMYOHC-QEJZJMRPSA-N Phe-Leu-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O KXUZHWXENMYOHC-QEJZJMRPSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- HQPWNHXERZCIHP-PMVMPFDFSA-N Phe-Leu-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 HQPWNHXERZCIHP-PMVMPFDFSA-N 0.000 description 1
- FENSZYFJQOFSQR-FIRPJDEBSA-N Phe-Phe-Ile Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FENSZYFJQOFSQR-FIRPJDEBSA-N 0.000 description 1
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 1
- 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 1
- XBCOOBCTVMMQSC-BVSLBCMMSA-N Phe-Val-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 XBCOOBCTVMMQSC-BVSLBCMMSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- APKRGYLBSCWJJP-FXQIFTODSA-N Pro-Ala-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O APKRGYLBSCWJJP-FXQIFTODSA-N 0.000 description 1
- 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 1
- ONPFOYPPPOHMNH-UVBJJODRSA-N Pro-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@@H]3CCCN3 ONPFOYPPPOHMNH-UVBJJODRSA-N 0.000 description 1
- KDIIENQUNVNWHR-JYJNAYRXSA-N Pro-Arg-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KDIIENQUNVNWHR-JYJNAYRXSA-N 0.000 description 1
- WPQKSRHDTMRSJM-CIUDSAMLSA-N Pro-Asp-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 WPQKSRHDTMRSJM-CIUDSAMLSA-N 0.000 description 1
- GDXZRWYXJSGWIV-GMOBBJLQSA-N Pro-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1 GDXZRWYXJSGWIV-GMOBBJLQSA-N 0.000 description 1
- SZZBUDVXWZZPDH-BQBZGAKWSA-N Pro-Cys-Gly Chemical compound OC(=O)CNC(=O)[C@H](CS)NC(=O)[C@@H]1CCCN1 SZZBUDVXWZZPDH-BQBZGAKWSA-N 0.000 description 1
- GQLOZEMWEBDEAY-NAKRPEOUSA-N Pro-Cys-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GQLOZEMWEBDEAY-NAKRPEOUSA-N 0.000 description 1
- 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 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- ULIWFCCJIOEHMU-BQBZGAKWSA-N Pro-Gly-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 ULIWFCCJIOEHMU-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
- VWXGFAIZUQBBBG-UWVGGRQHSA-N Pro-His-Gly Chemical compound C([C@@H](C(=O)NCC(=O)[O-])NC(=O)[C@H]1[NH2+]CCC1)C1=CN=CN1 VWXGFAIZUQBBBG-UWVGGRQHSA-N 0.000 description 1
- CFVRJNZJQHDQPP-CYDGBPFRSA-N Pro-Ile-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 CFVRJNZJQHDQPP-CYDGBPFRSA-N 0.000 description 1
- KLSOMAFWRISSNI-OSUNSFLBSA-N Pro-Ile-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 KLSOMAFWRISSNI-OSUNSFLBSA-N 0.000 description 1
- CLJLVCYFABNTHP-DCAQKATOSA-N Pro-Leu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O CLJLVCYFABNTHP-DCAQKATOSA-N 0.000 description 1
- SRBFGSGDNNQABI-FHWLQOOXSA-N Pro-Leu-Trp Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C(=O)[C@@H]1CCCN1 SRBFGSGDNNQABI-FHWLQOOXSA-N 0.000 description 1
- NTXFLJULRHQMDC-GUBZILKMSA-N Pro-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 NTXFLJULRHQMDC-GUBZILKMSA-N 0.000 description 1
- FYKUEXMZYFIZKA-DCAQKATOSA-N Pro-Pro-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FYKUEXMZYFIZKA-DCAQKATOSA-N 0.000 description 1
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 1
- CGSOWZUPLOKYOR-AVGNSLFASA-N Pro-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 CGSOWZUPLOKYOR-AVGNSLFASA-N 0.000 description 1
- POQFNPILEQEODH-FXQIFTODSA-N Pro-Ser-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O POQFNPILEQEODH-FXQIFTODSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- ITUDDXVFGFEKPD-NAKRPEOUSA-N Pro-Ser-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ITUDDXVFGFEKPD-NAKRPEOUSA-N 0.000 description 1
- KWMZPPWYBVZIER-XGEHTFHBSA-N Pro-Ser-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWMZPPWYBVZIER-XGEHTFHBSA-N 0.000 description 1
- VVAWNPIOYXAMAL-KJEVXHAQSA-N Pro-Thr-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VVAWNPIOYXAMAL-KJEVXHAQSA-N 0.000 description 1
- BXHRXLMCYSZSIY-STECZYCISA-N Pro-Tyr-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1)C(O)=O BXHRXLMCYSZSIY-STECZYCISA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- IIRBTQHFVNGPMQ-AVGNSLFASA-N Pro-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 IIRBTQHFVNGPMQ-AVGNSLFASA-N 0.000 description 1
- ZMLRZBWCXPQADC-TUAOUCFPSA-N Pro-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 ZMLRZBWCXPQADC-TUAOUCFPSA-N 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 238000012181 QIAquick gel extraction kit Methods 0.000 description 1
- 108010003201 RGH 0205 Proteins 0.000 description 1
- FIXILCYTSAUERA-FXQIFTODSA-N Ser-Ala-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FIXILCYTSAUERA-FXQIFTODSA-N 0.000 description 1
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 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
- GHPQVUYZQQGEDA-BIIVOSGPSA-N Ser-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N)C(=O)O GHPQVUYZQQGEDA-BIIVOSGPSA-N 0.000 description 1
- UCOYFSCEIWQYNL-FXQIFTODSA-N Ser-Cys-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(O)=O UCOYFSCEIWQYNL-FXQIFTODSA-N 0.000 description 1
- 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 1
- YPUSXTWURJANKF-KBIXCLLPSA-N Ser-Gln-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YPUSXTWURJANKF-KBIXCLLPSA-N 0.000 description 1
- 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
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- WSTIOCFMWXNOCX-YUMQZZPRSA-N Ser-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CO)N WSTIOCFMWXNOCX-YUMQZZPRSA-N 0.000 description 1
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 1
- FYUIFUJFNCLUIX-XVYDVKMFSA-N Ser-His-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O FYUIFUJFNCLUIX-XVYDVKMFSA-N 0.000 description 1
- BEAFYHFQTOTVFS-VGDYDELISA-N Ser-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N BEAFYHFQTOTVFS-VGDYDELISA-N 0.000 description 1
- JIPVNVNKXJLFJF-BJDJZHNGSA-N Ser-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N JIPVNVNKXJLFJF-BJDJZHNGSA-N 0.000 description 1
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 1
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 1
- XXNYYSXNXCJYKX-DCAQKATOSA-N Ser-Leu-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O XXNYYSXNXCJYKX-DCAQKATOSA-N 0.000 description 1
- GVMUJUPXFQFBBZ-GUBZILKMSA-N Ser-Lys-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GVMUJUPXFQFBBZ-GUBZILKMSA-N 0.000 description 1
- JUTGONBTALQWMK-NAKRPEOUSA-N Ser-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)N JUTGONBTALQWMK-NAKRPEOUSA-N 0.000 description 1
- IFLVBVIYADZIQO-DCAQKATOSA-N Ser-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N IFLVBVIYADZIQO-DCAQKATOSA-N 0.000 description 1
- NUEHQDHDLDXCRU-GUBZILKMSA-N Ser-Pro-Arg Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NUEHQDHDLDXCRU-GUBZILKMSA-N 0.000 description 1
- SQHKXWODKJDZRC-LKXGYXEUSA-N Ser-Thr-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQHKXWODKJDZRC-LKXGYXEUSA-N 0.000 description 1
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 1
- QNBVFKZSSRYNFX-CUJWVEQBSA-N Ser-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N)O QNBVFKZSSRYNFX-CUJWVEQBSA-N 0.000 description 1
- ZSDXEKUKQAKZFE-XAVMHZPKSA-N Ser-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N)O ZSDXEKUKQAKZFE-XAVMHZPKSA-N 0.000 description 1
- TYIHBQYLIPJSIV-NYVOZVTQSA-N Ser-Trp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)NC(=O)[C@H](CO)N TYIHBQYLIPJSIV-NYVOZVTQSA-N 0.000 description 1
- QYBRQMLZDDJBSW-AVGNSLFASA-N Ser-Tyr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYBRQMLZDDJBSW-AVGNSLFASA-N 0.000 description 1
- KIEIJCFVGZCUAS-MELADBBJSA-N Ser-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N)C(=O)O KIEIJCFVGZCUAS-MELADBBJSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 101150086693 Slc17a8 gene Proteins 0.000 description 1
- BSNZTJXVDOINSR-JXUBOQSCSA-N Thr-Ala-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BSNZTJXVDOINSR-JXUBOQSCSA-N 0.000 description 1
- KEGBFULVYKYJRD-LFSVMHDDSA-N Thr-Ala-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KEGBFULVYKYJRD-LFSVMHDDSA-N 0.000 description 1
- JMZKMSTYXHFYAK-VEVYYDQMSA-N Thr-Arg-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O JMZKMSTYXHFYAK-VEVYYDQMSA-N 0.000 description 1
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 1
- IOWJRKAVLALBQB-IWGUZYHVSA-N Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O IOWJRKAVLALBQB-IWGUZYHVSA-N 0.000 description 1
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 1
- JEDIEMIJYSRUBB-FOHZUACHSA-N Thr-Asp-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O JEDIEMIJYSRUBB-FOHZUACHSA-N 0.000 description 1
- GKMYGVQDGVYCPC-IUKAMOBKSA-N Thr-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]([C@@H](C)O)N GKMYGVQDGVYCPC-IUKAMOBKSA-N 0.000 description 1
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 1
- KCRQEJSKXAIULJ-FJXKBIBVSA-N Thr-Gly-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O KCRQEJSKXAIULJ-FJXKBIBVSA-N 0.000 description 1
- MSIYNSBKKVMGFO-BHNWBGBOSA-N Thr-Gly-Pro Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N1CCC[C@@H]1C(=O)O)N)O MSIYNSBKKVMGFO-BHNWBGBOSA-N 0.000 description 1
- UDNVOQMPQBEITB-MEYUZBJRSA-N Thr-His-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UDNVOQMPQBEITB-MEYUZBJRSA-N 0.000 description 1
- 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 1
- URPSJRMWHQTARR-MBLNEYKQSA-N Thr-Ile-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O URPSJRMWHQTARR-MBLNEYKQSA-N 0.000 description 1
- RFKVQLIXNVEOMB-WEDXCCLWSA-N Thr-Leu-Gly Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N)O RFKVQLIXNVEOMB-WEDXCCLWSA-N 0.000 description 1
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 1
- KDGBLMDAPJTQIW-RHYQMDGZSA-N Thr-Met-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)O)N)O KDGBLMDAPJTQIW-RHYQMDGZSA-N 0.000 description 1
- KZURUCDWKDEAFZ-XVSYOHENSA-N Thr-Phe-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O KZURUCDWKDEAFZ-XVSYOHENSA-N 0.000 description 1
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-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
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- DVIIYMVCSUQOJG-QEJZJMRPSA-N Trp-Glu-Asp Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DVIIYMVCSUQOJG-QEJZJMRPSA-N 0.000 description 1
- NOBINHCGDUHOBV-NAZCDGGXSA-N Trp-His-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NOBINHCGDUHOBV-NAZCDGGXSA-N 0.000 description 1
- IQXWAJUIAQLZNX-IHPCNDPISA-N Trp-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=CNC3=CC=CC=C32)N IQXWAJUIAQLZNX-IHPCNDPISA-N 0.000 description 1
- WSMVEHPVOYXPAQ-XIRDDKMYSA-N Trp-Ser-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N WSMVEHPVOYXPAQ-XIRDDKMYSA-N 0.000 description 1
- STKZKWFOKOCSLW-UMPQAUOISA-N Trp-Thr-Val Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)[C@@H](C)O)=CNC2=C1 STKZKWFOKOCSLW-UMPQAUOISA-N 0.000 description 1
- YCEHCFIOIYNQTR-NYVOZVTQSA-N Trp-Trp-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)N[C@@H](CO)C(=O)O)N YCEHCFIOIYNQTR-NYVOZVTQSA-N 0.000 description 1
- RKISDJMICOREEL-QRTARXTBSA-N Trp-Val-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N RKISDJMICOREEL-QRTARXTBSA-N 0.000 description 1
- AKXBNSZMYAOGLS-STQMWFEESA-N Tyr-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AKXBNSZMYAOGLS-STQMWFEESA-N 0.000 description 1
- YLHFIMLKNPJRGY-BVSLBCMMSA-N Tyr-Arg-Trp 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](CC1=CNC2=C1C=CC=C2)C(O)=O YLHFIMLKNPJRGY-BVSLBCMMSA-N 0.000 description 1
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 1
- PEVVXUGSAKEPEN-AVGNSLFASA-N Tyr-Asn-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PEVVXUGSAKEPEN-AVGNSLFASA-N 0.000 description 1
- IXTQGBGHWQEEDE-AVGNSLFASA-N Tyr-Asp-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 IXTQGBGHWQEEDE-AVGNSLFASA-N 0.000 description 1
- UXUFNBVCPAWACG-SIUGBPQLSA-N Tyr-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N UXUFNBVCPAWACG-SIUGBPQLSA-N 0.000 description 1
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 1
- WSFXJLFSJSXGMQ-MGHWNKPDSA-N Tyr-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N WSFXJLFSJSXGMQ-MGHWNKPDSA-N 0.000 description 1
- QHLIUFUEUDFAOT-MGHWNKPDSA-N Tyr-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=CC=C(C=C1)O)N QHLIUFUEUDFAOT-MGHWNKPDSA-N 0.000 description 1
- CDKZJGMPZHPAJC-ULQDDVLXSA-N Tyr-Leu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDKZJGMPZHPAJC-ULQDDVLXSA-N 0.000 description 1
- ZOBLBMGJKVJVEV-BZSNNMDCSA-N Tyr-Lys-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O ZOBLBMGJKVJVEV-BZSNNMDCSA-N 0.000 description 1
- VUVVMFSDLYKHPA-PMVMPFDFSA-N Tyr-Lys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC3=CC=C(C=C3)O)N VUVVMFSDLYKHPA-PMVMPFDFSA-N 0.000 description 1
- KHUVIWRRFMPVHD-JYJNAYRXSA-N Tyr-Met-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O KHUVIWRRFMPVHD-JYJNAYRXSA-N 0.000 description 1
- WTTRJMAZPDHPGS-KKXDTOCCSA-N Tyr-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(O)=O WTTRJMAZPDHPGS-KKXDTOCCSA-N 0.000 description 1
- ZMKDQRJLMRZHRI-ACRUOGEOSA-N Tyr-Phe-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N ZMKDQRJLMRZHRI-ACRUOGEOSA-N 0.000 description 1
- SCZJKZLFSSPJDP-ACRUOGEOSA-N Tyr-Phe-Leu 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](CC(C)C)C(O)=O SCZJKZLFSSPJDP-ACRUOGEOSA-N 0.000 description 1
- FGVFBDZSGQTYQX-UFYCRDLUSA-N Tyr-Phe-Val 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](C(C)C)C(O)=O FGVFBDZSGQTYQX-UFYCRDLUSA-N 0.000 description 1
- IEWKKXZRJLTIOV-AVGNSLFASA-N Tyr-Ser-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O IEWKKXZRJLTIOV-AVGNSLFASA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- TYFLVOUZHQUBGM-IHRRRGAJSA-N Tyr-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 TYFLVOUZHQUBGM-IHRRRGAJSA-N 0.000 description 1
- 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 1
- PFNZJEPSCBAVGX-CYDGBPFRSA-N Val-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N PFNZJEPSCBAVGX-CYDGBPFRSA-N 0.000 description 1
- AUMNPAUHKUNHHN-BYULHYEWSA-N Val-Asn-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N AUMNPAUHKUNHHN-BYULHYEWSA-N 0.000 description 1
- NWDOPHYLSORNEX-QXEWZRGKSA-N Val-Asn-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N NWDOPHYLSORNEX-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
- XLDYBRXERHITNH-QSFUFRPTSA-N Val-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)C(C)C XLDYBRXERHITNH-QSFUFRPTSA-N 0.000 description 1
- XJFXZQKJQGYFMM-GUBZILKMSA-N Val-Cys-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)O)N XJFXZQKJQGYFMM-GUBZILKMSA-N 0.000 description 1
- UZDHNIJRRTUKKC-DLOVCJGASA-N Val-Gln-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N UZDHNIJRRTUKKC-DLOVCJGASA-N 0.000 description 1
- 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 1
- XWYUBUYQMOUFRQ-IFFSRLJSSA-N Val-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N)O XWYUBUYQMOUFRQ-IFFSRLJSSA-N 0.000 description 1
- OXGVAUFVTOPFFA-XPUUQOCRSA-N Val-Gly-Cys Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N OXGVAUFVTOPFFA-XPUUQOCRSA-N 0.000 description 1
- PMDOQZFYGWZSTK-LSJOCFKGSA-N Val-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C PMDOQZFYGWZSTK-LSJOCFKGSA-N 0.000 description 1
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 1
- KVRLNEILGGVBJX-IHRRRGAJSA-N Val-His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CN=CN1 KVRLNEILGGVBJX-IHRRRGAJSA-N 0.000 description 1
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 1
- RWOGENDAOGMHLX-DCAQKATOSA-N Val-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N RWOGENDAOGMHLX-DCAQKATOSA-N 0.000 description 1
- 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 1
- SJRUJQFQVLMZFW-WPRPVWTQSA-N Val-Pro-Gly Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SJRUJQFQVLMZFW-WPRPVWTQSA-N 0.000 description 1
- WANVRBAZGSICCP-SRVKXCTJSA-N Val-Pro-Met Chemical compound CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)C(O)=O WANVRBAZGSICCP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- QZKVWWIUSQGWMY-IHRRRGAJSA-N Val-Ser-Phe Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QZKVWWIUSQGWMY-IHRRRGAJSA-N 0.000 description 1
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 1
- LNWSJGJCLFUNTN-ZOBUZTSGSA-N Val-Trp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)N)C(=O)O)N LNWSJGJCLFUNTN-ZOBUZTSGSA-N 0.000 description 1
- LZRWTJSPTJSWDN-FKBYEOEOSA-N Val-Trp-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O)N LZRWTJSPTJSWDN-FKBYEOEOSA-N 0.000 description 1
- PMKQKNBISAOSRI-XHSDSOJGSA-N Val-Tyr-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N PMKQKNBISAOSRI-XHSDSOJGSA-N 0.000 description 1
- 102100038033 Vesicular glutamate transporter 3 Human genes 0.000 description 1
- 101710107968 Vesicular glutamate transporter 3 Proteins 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
- 229960005054 acepromazine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010011559 alanylphenylalanine Proteins 0.000 description 1
- 230000037005 anaesthesia Effects 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
- 230000006907 apoptotic process Effects 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 1
- 108010038850 arginyl-isoleucyl-tyrosine Proteins 0.000 description 1
- 208000002982 auditory neuropathy Diseases 0.000 description 1
- 210000003984 auditory pathway Anatomy 0.000 description 1
- 201000006197 autosomal recessive nonsyndromic deafness 6 Diseases 0.000 description 1
- 208000032441 autosomal recessive nonsyndromic hearing loss 6 Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000000238 cell of claudius Anatomy 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- -1 coatings Substances 0.000 description 1
- 210000000262 cochlear duct Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000015155 detection of stimulus involved in sensory perception Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000000959 ear middle Anatomy 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000001062 endolymphatic sac Anatomy 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000003976 gap junction Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 108010042598 glutamyl-aspartyl-glycine Proteins 0.000 description 1
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 1
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 238000012074 hearing test Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 102000052168 human OTOF Human genes 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004879 molecular function Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 238000007474 nonparametric Mann- Whitney U test Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- ZLIBICFPKPWGIZ-UHFFFAOYSA-N pyrimethanil Chemical compound CC1=CC(C)=NC(NC=2C=CC=CC=2)=N1 ZLIBICFPKPWGIZ-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 102220001997 rs151045328 Human genes 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000001079 scala tympani Anatomy 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 210000002480 semicircular canal Anatomy 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000000697 sensory organ Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000002205 spiral ligament of cochlea Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000002504 synaptic vesicle Anatomy 0.000 description 1
- 108060008004 synaptotagmin Proteins 0.000 description 1
- 102000003137 synaptotagmin Human genes 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 210000003454 tympanic membrane Anatomy 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960004175 xylazine hydrochloride Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knock-out vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/054—Animals comprising random inserted nucleic acids (transgenic) inducing loss of function
- A01K2217/056—Animals comprising random inserted nucleic acids (transgenic) inducing loss of function due to mutation of coding region of the transgene (dominant negative)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/07—Animals genetically altered by homologous recombination
- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/20—Animal model comprising regulated expression system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14144—Chimeric viral vector comprising heterologous viral elements for production of another viral vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14171—Demonstrated in vivo effect
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biotechnology (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Virology (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Marine Sciences & Fisheries (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
본 발명자는 본원에서, DFNB9 마우스 모델(OTOF 녹-아웃 마우스)에서, 이중-AAV 벡터 접근법을 통한 단편화된 cDNA의 달팽이관 전달이 이러한 마우스의 청각 시스템이 성숙된 후(P30) 잘 투여되는 경우 이러한 마우스의 명백한 청각장애 표현형을 효과적으로 및 장기-지속적으로 교정할 수 있다는 최초의 원리검증을 보고한다. 따라서, 본 발명은 DFNB9 청각장애를 앓고 있는 환자를 치료하거나 DFNB9 돌연변이를 갖는 환자에서 DFNB9 청각장애를 예방하는데 사용하기 위한, 내부 모 세포내에서, 전체 길이의 오토페를린 폴리펩타이드, 또는 이의 기능성 단편의 발현을 허용하는 벡터 시스템에 관한 것이며, 여기서 상기 환자는 발달한 및 성숙한 청각 시스템을 가진 사람, 예를 들면, 출생아, 영아, 유아, 십대 또는 성인이다.
Description
발명의 배경
무증상의 심각한 선천성 청각장애(congenital deafness)의 경우 중 1/2 이상은 유전적 원인을 가지고 있으며, 대부분(~ 80%)은 상염색체 열성(DFNB) 형태이다(Duman D. & Tekin M, Front Biosci (Landmark Ed) 17:2213-2236 (2012)). 청각장애의 유전적 진단은 달팽이관 유전자 치료요법에 대한 필수 정보를 제공하며, 급속한 진전이 지난 몇년 내에 유전적 시험에 대한 정확성 및 접근용이성 둘 다에서 이루어져 왔다. 증상성 청각장애 유전자내 돌연변이의 확인은 환자에게서 증상이 발현하기 수년 전에 이루어져서 질환 관리를 계획하기 위한 시간이 주어질 수 있었다.
청각장애 유전자는 감각 기관의 발달, 모 세포(hair cell)의 부동섬모내 소리 변환, 달팽이관내 전위(endocochlear potential)(EP) 및 고 농도의 세포외 칼륨, 및 모 세포와 나선상 신경절 뉴우런(spiral ganglion neuron)(SGN) 사이의 시냅스 신경전달의 발달과 같은, 달팽이관 기능화를 위한 광범위한 분자 기능을 지닌 단백질을 암호화한다. 청각장애 유전자로부터 제조되는 주요 단백질은 이온 채널 및 수송인자(transporter), 갭 결합(gap junction) 및 강력한 결합(tight junction), 세포골격 및 분자 운동내 단백질 소단위(subunit), 및 달팽이관 발달시 일시적으로 발현된 전사 인자를 포함한다. 돌연변이가 조기 달팽이관 발달에 영향을 미쳐 유의적인 세포 변성을 초래하는지의 여부는 "치료 시간 윈도우(treatment time window)"를 결정하는데 있어서 주요 인자이며, 이는 치료학적 분야에서 중요한 문제이다.
인공 달팽이관 이식(Prosthetic cochlear implant)은 현재 원상 회복을 위해 사용되고 있으나(Kral A & O'Donoghue GM N Engl J Med 363(15):1438-1450 (2010)), 특히 소음이 있는 환경에서 대화 또는 음악의 지각의 경우에는, 채널간 전기 간섭에 의해 부여되는 것으로서 이의 고유의 주파수 분해능의 제한으로 인하여 청력 회복이 완벽하지 않다.
생물학적 치료를 개발하는데 있어서 주요 동기는 어떠한 인공 장치의 이식없이 청력을 회복하고, 달팽이관 이식체를 사용하여 현재 달성가능한 것보다 훨씬 우수한 음질 분해 및 단위 비용을 달성하는 것이다. 특히, 국소 아데노-관련 바이러스(Adeno-associated virus)(AAV)-매개된 유전자 치료요법을 사용한 유전자 치료요법이 청각장애의 사람 형태를 치료하기 위해 이미 제안되었다(Zhang et al, Frontiers in Molecular Neuroscience, vol.11, Art.221, 2018).
어셔 형 C 질환을 연구하기 위한 Ush1c c.216G>A 녹-인 마우스(knock-in mouse)를 사용하여, 문헌: Pan et al. Nature biotechnology; 35(3):264-272 (2017)에서는 달팽이관 유전자 치료요법이 모 세포를 표적화하여 청각장애 표현형을 교정하는데 사용될 수 있는지의 여부를 시험하였다. 신규의 합성 AAV인, Anc80L65는 모 세포의 >90%을 형질도입시킬 수 있었다. 이러한 치료는 달팽이관내 형태학적 보존을 입증하고, 재조합 바이러스 벡터를 P0-P1(즉, 마우스가 출생한 날 또는 다음날, 이는 "출생 후 0일 또는 1일"로 불린다)에 주사한 경우 처리되지 않은 귀와 비교하여 청각 역치(auditory threshold)를 60 내지 70 dB로 개선시켰음을 입증한다. P10-P12(즉, 출생 10일 또는 12일 후, 청력이 발병하기 직전 - 이는 당해 종에서 대략 P12에 발생한다)에서 수행된 동일한 주사는 어떠한 치료 효과도 생성하지 않았다(Pan et al. Nature biotechnology; 35(3):264-272 (2017).
문헌: Akil et al. Neuron 75:283-293 (2012)에서는 AAV2/1을 사용하여 소낭 글루타메이트 수송인자(vesicular glutamate transporter) 3(Vglut3) cDNA를 신생아(즉, 출생한지 1 내지 12일 후) KO 마우스에게 전달하여 내부 모 세포의 시냅스 전달 장애를 치료하였다. 청성 뇌간 반응(auditory brainstem response)(ABR) 및 청각 놀람 반사(acoustic startle reflex)로부터의 데이타를 기반으로, 이들은 주사맞은 귀에서 청각 기능이 2주 내에 회복되었음을 입증하였다.
이러한 2개의 연구는 재조합 바이러스 벡터를 조기 출생 후 단계에서, 즉, 마우스 모 세포의 돌연변이 전에 주사한 경우 달팽이관내 세포 변성의 유의적인 완화를 입증한다.
지금까지, 마우스에서 내이(inner ear) 치료요법을 평가한 모든 유전자 치료요법은 이러한 치료요법이 성체 동물에서는 효과적이지 않다고 결론지었다. 따라서, 유전자 치료요법이 청각 보호 또는 회복에 효과적일 중요한 기간이 존재하고 치료 기회의 윈도우(window of opportunity)가 배아 또는 출생 후 초기 단계, 즉, 청력 발병이 일어나기 전에만 존재한다는 합의가 존재한다(Ahmed et al, JARO 18:649-670 (2017).
마우스 내이가 출생시 여전히 구조적으로 및 기능적으로 미성숙되어 있고, 청력 발병이 당해 동물 종에서 출생후 12일(P12)에 발생하여 출생 후 대략 20일(P20)에 종결됨은 잘 알려져 있다(Shnerson and Willott, J. Comp. Physiol. Psychol. 94, 36-40 (1980)). 그러나, 청력 발병 및 성숙은 사람에서 시기가 완전히 상이하다. 실제로, 사람 내이는 자궁내에서 4.5개월로 일찍 청각 기능을 가질 수 있고 출생시 종결된다(참고: 도 6 및 Hepper PG & Shahidullah BS Arch Dis Child71(2):F81-87 (1994)).
이는 청력 발병 전 또는 달팽이관 성숙 종료 전 청각 기능을 회복하는 것을 목표로 하는 선행 기술의 실험이 사람에 대한 시험으로 바뀌는 경우 자궁내에서 수행되어야 함을 의미한다(도 6). 그러나, 출생 후 단계 또는 유아기에서 청력을 회복하는 것(즉, 청각 시스템이 전적으로 성숙되어 기능성인 경우)은 불가능한 것으로 고려되었기 때문에, 아직까지 모 세포 유전자 치료요법을 사용하여 치료된 사람은 없었다.
그럼에도 불구하고, 달팽이관 유전자 치료요법에 대한 궁극적인 목표는 잠재적인 유전적으로 유도된 청각장애가 검출 또는 진단될 수 있게 된 후, 즉, 출생 후 대부분의 시기에, 사람에서 일반적인 유전적 청각장애의 치료이다.
실제로, 달팽이관 내로의 치료제의 자궁내 전달에 관련된 유전자 치료요법 프로토콜을 개발하는 것은, 이러한 외과적 수술이 다수의 부작용, 이중에서도 최종적인 청력 상실을 유도할 가능성이 있기 때문에, 가능하지 않다(Zhang et al, Frontiers in Molecular Neuroscience, vol.11, Art.221, 2018). 더욱이, DFNB 청각장애는 신생아 기간, 즉, 출생 후 0 내지 4개월 동안 사람에서 전형적으로 진단되는 것으로 잘 알려져 있다.
따라서, 사람에게 수송가능하게 되기 위해서, 유전자 치료요법 접근법이 시험되어야 하고 예를 들어, 출생 후 > P20(젊은 또는 성인 사람에 상응함)인 마우스에게 투여되는 경우, 성숙한 청각 시스템에 영향을 미치는 확립된 청각장애 표현형을 역전시키는데 효율적이어야 한다.
이는 치료제가 청각 시스템이 완료된, 출생 후, 유아 및 성인 사람에서 투여될 수 있으므로, 이의 시간 윈도우(time window)가 사람 윤리 및 복지와 부합하는 치료제를 확인하는 유일한 방법이 될 것이다.
발명의 상세한 설명
본 발명자는 청각 시스템, 특히 달팽이관이 성숙한 대상체, 특히 사람에서, 배아 유전자 전달에 아직 관련되지 않고, 청력 상실을 효율적으로 예방하거나 역전시키는 실현가능한 기회를 갖는 치료를 확인하기 위한 대안적인 연구를 개발하였다. 당해 맥락에서, 이들은 내이 세포내 오토페를린 단백질(otoferlin protein)의 재조합 발현이 출생 후 > P20(젊거나 성인 사람에 상응함)에서 치료된 모델 마우스에서 청각을 회복시킬 수 있음을 입증할 수 있었다.
오토페를린은 달팽이관의 감각 내부 모 세포(sensory inner hair cell)(IHC)에서 풍부하게 발현된다. 이는 또한 중추 신경계의 다른 세포내에서 발현된다. 이는 달팽이관 모 세포 시냅스에서 구심성 나선상 신경절 뉴우런과의 시냅스 소포 융합의 최종 단계에서 중요한 역활을 한다. 보다 상세하게는, 이는 청각 리본 시냅스(auditory ribbon synapse)에서 세포외유출(exocytosis)에 중요하다(Roux et al, Cell 127(2):277-89, 2006).
사람에서, 오토페를린(OTOFERLIN) 유전자("OTOF 유전자")에 영향을 미치는 돌연변이는 출생 후 그러나 언어 습득 전에 발생하는 중증의 무증상 양쪽 청각 상실(non-syndromic bilateral loss)을 초래한다. 이들 중 일부는 또한 온도-민감성 무증상 청각 신경병증(non-syndromic auditory neuropathy)을 초래하며, 이는 체온이 중요하게 상승하는 경우(예를 들면, 열이 나는 경우, 참고: Marlin S. et al, Biochemical and Biophysical Research Communications, 394 (2010) 737-742 및 Varga R. et al, J. Med. Genet 2006; 43:576-581)에 개시(trigger)된다. 적어도 60개의 돌연변이가 지금까지 확인되었고(참고: 도 7), 이중에서 5개는 열민감성인 것으로 알려져 있다(문헌: Pangrsic T. et al, Trends in Neurosciences, 2012, col.35, No.11에 기술된 바와 같은, P.Q994VfsX6, P.I515T, p.G541S, PR1607W, p.E1804del).
이러한 2개의 청각장애 표현형(구성적 및 유도성)은 모두 전세계적으로 발견되며 "청각장애, 상염색체 열성 9" 또는 "DFNB9" 청각장애로 알려져 있다.
DFNB9 청각장애는 일부 서양 집단에서 상염색체 열성 무증상 청력 상실의 8% 이하를 차지함으로써 여전히 치료학적 개입을 필요로 하는 유전적 청력 장애의 상위 5개 내에 위치한다.
본 발명자는 본원에서, DFNB9 마우스 모델(OTOF 녹-아웃 마우스)에서, 이중-AAV 벡터 접근법을 통한 단편화된 cDNA의 달팽이관 전달이 마우스의 청각 시스템이 성숙된 후(P30) 잘 투여되는 경우 이러한 마우스의 명백한 청각장애 표현형을 효과적으로 및 장기-지속적으로 교정할 수 있다는 최초의 원리검증(proof-of-principle)을 보고한다. 이러한 결과는 DFNB9로 인하여 선천성 청각장애를 지닌 환자에서 국소 유전자 전달을 위한 치료학적 윈도우가 실제로 초기 예측한 것보다 더 길다는 것을 시사한다.
실제로, 각각 OTOF 유전자의 일부을 제공하고 출생 후 마지막 날짜(P30)에 OTOF 녹-아웃 마우스의 형질감염된 내부 모 세포내에서 완전한 길이의 OTOF 단백질의 발현이 가능한, 본 발명의 벡터의 투여는 보다 어린 마우스를 시험한 경우 보다 우수한 결과를 이끈다.
다수의 연구에서 유전적 청각장애를 앓고 있는 마우스에서 국소 유전자 전달에 대한 치료학적 윈도우는 배아 또는 출생 후 이른 날짜 이내라는 것이 교시되었음을 고려할 때 매우 놀라운 것이다(Ahmed et al, JARO 18:649-670 (2017); Zhang et al, Frontiers in Molecular Neuroscience, vol.11, Art.221, 2018).
마우스에서, 반응 빈도의 전체 범위가 P14(즉, 출생 후 14일째)까지 관찰될 수 있음이 알려져 있다. 반응 잠복기(Response latency) 및 피크간 간격(interpeak interval)은 출생 후 2 내지 3주 동안에 걸쳐 급격하게 성숙하고 P18에 성인과 유사한 특성을 달성한다(Song L. et al, J Acoust Soc Am 119(4):2242-2257 (2006)). 따라서, P30에서, 마우스의 청각 시스템은 완전히 성숙된다. 이는 유아 또는 성인 사람의 청각 시스템에 상응한다(참고: 도 6).
따라서, 본 발명자에 의해 수득된 결과는 본 발명에 사용된 유전자 치료요법이 출생 전 시간 윈도우뿐만 아니라 선천성 DFNB9 청각장애를 앓을 것으로 진단된 유아 환자에서, 또는 예를 들면, OTOF 유전자에 열민감성 돌연변이를 수반하기 때문에, 나중에 진단된 성인 환자에서 효율적일 수 있음을 시사한다.
제1 양태에서, 본 발명은 DFNB9 청각장애를 앓고 있는 환자를 치료하는데 사용하기 위한, 내부 모 세포내에서, 전체 길이의 오토페를린 폴리펩타이드, 또는 이의 기능성 단편의 발현을 허용하는 벡터 시스템에 관한 것이고, 여기서 상기 환자는 바람직하게는 영아(toddler), 영아(infant), 십대 또는 성인 사람이다.
본원에 사용된 바와 같은, 용어 "오토페를린"은 오토페를린 폴리펩타이드를 나타낸다. 이는 본원에서 "OTOF"로 약술된다. 이러한 폴리펩타이드는 또한 "AUNB1"; "DFNB6"; "DFNB9"; "NSRD9" 및 "FER1L2"로 알려져 있다.
야생형 사람 오토페를린 폴리펩타이드의 동형 1의 전체 길이는 서열 번호: 1(진뱅크(Genbank) 번호 AF183185.1에 상응)에 나타낸다. 이러한 폴리펩타이드는 막관통 단백질(transmembrane protein)의 페를린 계열의 구성원이고, 이는 시냅토타그민(synaptotagmin)으로서 C2 도메인, PKC 및 PLC를 갖는다. 이러한 긴 형태는 6개의 C2 도메인을 함유한다. 상기 언급한 바와 같이, 이는 달팽이관 모 세포와 구심성 나선상 신경절 뉴우런 사이에 시냅스 소포 융합(synaptic vesicle fusion)에 관련되어 있다(Roux et al, Cell 127(2):277-89, 2006; Michalski et al, Elife, 2017 Nov 7;6 e31013).
용어 "오토페를린 폴리펩타이드"는 본 문맥에서 목적한 오토페를린 폴리펩타이드의 적어도 하나의 생물학적 기능을 보유한 서열 번호: 1의 오토페를린 폴리펩타이드 및 이의 동족 서열을 나타낸다. 예를 들면, 이러한 생물학적 기능은 1차 청각 뉴우런을 활성화시키는 달팽이관 내부 모 세포 리본 시냅스(cochlear inner hair cell ribbon synapse)에서 소포 융합의 조절과 관련되어 있다(Roux et al 2006; Michalski et al, Elife, 2017 Nov 7;6 e31013). 이러한 조절은 전통적인 생체외(ex vivo) 전기생리학적 척도로 평가될 수 있었다.
바람직한 구현예에서, 본 발명의 벡터 시스템은 이의 아미노산 서열이 서열 번호: 1과 적어도 70% 동일성 및/또는 유사성을 공유하는 상동성 폴리펩타이드의 발현을 허용한다. 상기 상동성 서열은 보다 바람직하게는 서열 번호: 1과 적어도 75%, 및 심지어 보다 바람직하게는 적어도 80%, 또는 적어도 90% 동일성 및/또는 유사성을 공유한다. 상동성 폴리펩타이드가 서열 번호: 1보다 훨씬 더 짧은 경우, 국소 정렬이 고려될 수 있다.
상기 상동성 폴리펩타이드는 예를 들면, 서열 번호: 5(진뱅크 번호 NP_001274418에 상응)로 나타낸 아미노산 서열을 가질 수 있다. 상기 서열은 야생형 사람 오토페를린 폴리펩타이드의 동형 e(변이체 5)를 특성화한다. 이러한 동형 e는 서열 번호: 22를 갖는 cDNA 변이체에 의해 암호화된다. 이러한 변이체는 3' 암호화 영역내에서 대안적 프레임내(in-frame) 엑손을 결여하고 있으며 서열 번호: 1과 비교하여 하류 정지 코돈을 사용한다. 이는 서열 번호: 1과 비교하여 명백한 C-말단을 암호화한다(그러나 이의 N-말단 부위는 동일하다).
상기 상동성 폴리펩타이드는 각각 짧은 동형 b 및 c(변이체 2 및 3)에 상응하는 서열 번호: 6(진뱅크 번호 NP_004793.2에 상응함)으로 나타낸 아미노산 서열 또는 서열 번호: 24(진뱅크 번호 NP_919303.1에 상응함)로 나타낸 아미노산 서열을 가질 수 있다. 보다 구체적으로, 서열 번호: 6은 보다 짧은 N-말단을 가지고 서열 번호: 1과 비교하여 분절(segment)을 결여한 동형 b(변이체 2, 또한 '짧은 형태 1'로 불림)를 나타낸다. 다른 한편, 서열 번호: 24는 동형 c(변이체 3, "짧은 형티 2"로 불림)를 나타내고, 이는 서열 번호: 1과 비교하여 보다 짧고 명백한 C-말단을 가지기 때문에 변이체 1(서열 번호: 1)과 비교하여 5' UTR 및 암호화 서열에서 상이하다.
상기 상동성 서열은 또한 예를 들면, 다른 동물 종의 오토펠르린 폴리펩타이드, 예를 들면, 오토페를린 폴리펩타이드의 마우스 전체 길이 동형 1(진뱅크 번호 NP_001093865.1에 상응함)이다. 이러한 동형은 서열 번호: 16(NM_1100395)의 cDNA에 의해 암호화된다.
본 발명의 문맥에서, 상기 2개의 상동성 서열 사이에 동일성 퍼센트는 이의 전체에서 서열의 전반적인 정렬에 의해 확인할 수 있는 경우(예를 들면, 서열이 대략 동일한 크기인 경우), 이러한 정렬은 기술자에게 잘 공지된 알고리즘의 수단, 예를 들면, 문헌: Needleman and Wunsch (1970)에 개시된 것으로 수행할 수 있다. 따라서, 2개의 아미노산 서열 또는 2개의 뉴클레오타이드 서열 사이의 서열 비교는 예를 들면, 기술자에게 공지된 임의의 소프트웨어, 예를 들면, 10의 "갭 오픈(Gap open)" 매개변수, 0.5의 "갭 연장(Gap extend)" 매개변수 및 "블로섬(Blosum) 62" 매트릭스를 사용한 "니들(needle)" 소프트웨어를 사용하여 수행할 수 있다.
서열의 국소 정렬이 고려되는 경우(예컨대, 본 발명의 서열보다 더 작은 크기를 갖는 동족체의 경우에), 이후에 상기 정렬은 통상의 알고리즘의 수단, 예를 들면, 문헌: Smith and Waterman (J. Mol. Evol. 1981; 18(1) 38-46)에 개시된 것으로 수행할 수 있다.
본 발명은 서열 번호: 1 또는 서열 번호: 5 또는 서열 번호: 6 또는 서열 번호: 24와 "유사한" 상동성 아미노산 서열을 암호화하는 시스템을 제공한다. 2개의 표적화된 아미노산 서열의 "유사성"은 2개의 아미노산 서열에 대한 유사성 점수를 계산함으로써 측정할 수 있다. 본원에 사용된 바와 같은, "유사성 점수"는 2개의 서열이 최적으로 정렬된 경우, BLOSUM62 아미노산 치환 매트릭스, 11의 갭 존재 패널티(gap existence penalty), 및 1의 갭 연장 패널티를 사용하여 2개의 서열에 대해 생성된 점수를 지칭한다. 2개의 서열이 정렬되어 서열의 이러한 쌍에 대해 최대의 가능한 점수를 생산하는 경우 "최적으로 정렬"되며, 이는 이러한 최대 점수를 달성하기 위한 서열 중 하나 또는 둘 다내에서 갭의 도입을 필요로 할 수 있다. 2개의 아미노산 서열은 이의 유사성 점수가 특정의 역치 값(threshold value)을 초과하는 경우 실질적으로 유사하다. 역치 값은 특수한 참고 서열(예컨대, 서열 번호: 1)에 대해 적어도 1190 내지 최대의 가능한 점수 범위의 임의의 정수일 수 있다. 예를 들면, 역치 유사성 점수는 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500 이상일 수 있다. 본 발명의 특수한 구현예에서, 역치 점수는, 예를 들면, 1300에서 설정되고 참고 서열이 서열 번호: 1이면, 서열 번호: 1과 최적으로 정렬되어 1300을 초과하는 유사성 점수를 생성할 수 있는 임의의 아미노산 서열은 서열 번호: 1과 "유사"하다. 아미노산 치환 매트릭스 및 2개의 서열 사이에 유사성을 정량화하는데 있어서 이의 용도는 당해 분야에 잘 공지되어 있고, 예컨대, 문헌: Dayhoff et al. (1978), "A model of evolutionary change in proteins", "Atlas of Protein 서열 and Structure," Vol. 5, Suppl. 3 (ed. M. O. Dayhoff), pp. 345-352. Natl. Biomed. Res. Found., Washington, D.C. and in Henikoff et al. (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919에 기술되어 있다. 최적의 정렬 및 점수매김은 수동으로 달성될 수 있지만, 이러한 공정은 컴퓨터-시행된 정렬 알고리즘, 예컨대, 문헌: Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402에 기술되고, 국립 생물공학 정보 센터(National Center for Biotechnology Information) 웹사이트에서 공공으로 이용가능하게 제조된 갭이 있는(gapped) BLAST 2.0의 사용에 의해 촉진된다. NCBI BLAST를 사용하여 정밀한 유사성 점수를 생성하기 위해, 임의의 필터링, 예컨대, 저 복잡성 필터링을 끄고(turn off), 조성 기반한 통계학의 사용을 무력화시키는 것이 중요하다. 또한 정확한 치환 매트릭스 및 갭 패널티를 사용하는 것을 확인하여야 한다. 최적의 정렬, 예를 들어, 다수의 정렬을 예컨대, NCBI 인터넷 사이트를 통해 이용가능하고 문헌: Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402에 기술된 PSI-BLAST를 사용하여 제조할 수 있다.
다른 구현예에서, 본 발명의 벡터 시스템은 오토페를린 폴리펩타이드의 기능성 단편의 발현을 허용할 수 있다. 본원에서 용어 "기능성 단편"은 사람 오토페를린 폴리펩타이드의 임의의 단편 또는 상기 정의된 바와 같은 상동성 서열을 갖는 폴리펩타이드의 임의의 단편을 나타내고, 여기서 상기 단편은 본 문맥에서 목적한 오토페를린 폴리펩타이드의 적어도 하나의 생물학적 기능을 보유한다. 예를 들면, 이러한 생물학적 기능은 일차 청각 뉴우런을 활성화시키는 달팽이관 내부 모 세포 리본 시냅스에서 소포 융합의 조절에 관한 것이다 (Roux et al 2006; Michalski et al, Elife, 2017 Nov 7;6 e31013). 이러한 조절은 전통적인 생체외 전기생리학적 척도로 평가할 수 있었다.
예를 들면, 상기 기능적 단편은 서열 번호: 6(진 뱅크 번호 NP_004793.2를 갖는 동형 b에 상응함) 또는 서열 번호: 24(진뱅크 번호 NP_919303.1를 갖는 동형 c에 상응함)로 나타낸 아미노산 서열을 가질 수 있다. 상기 서열은 단지 3개의 C2 도메인을 포함하는, 야생형 오토페를린 폴리펩타이드의 짧은 동형을 특성화한다.
본 발명의 당해 양태에서, 본 발명의 벡터 시스템은 DFNB9 청각장애를 앓는 환자에게 투여된다. "DFNB9 청각장애를 앓는 환자"라는 용어는, 본원에서 구성적 오토페를린 유전자내 돌연변이를 갖는 것으로 고려된(또는 갖는 것으로 진단된) 환자, 특히 사람 환자를 의미하며, 상기 돌연변이는 오토페를린 단백질의 비정상적인 발현, 기능 또는 둘 다를 개시한다. 특수한 구현예에서, 상기 돌연변이는 열-민감성일 수 있다.
지금까지, 60개 이상의 발병성 돌연변이(pathogenic mutation)가 오토페를린에서 보고되었다(참고: 도 7). 이들 중에는 열(fever)에 의해 조건화된 에피소드 청각장애(episodic deafness)를 앓는 환자에서 확인된 적어도 5개의 열민감성 돌연변이(P.Q994VfsX6, P.I515T, p.G541S, PR1607W, p.E1804del)가 존재한다.
이러한 환자는 숙련된 의사에 의해, 예컨대, 청각 뇌간 반응(auditory brain stem response)(ABR)의 전기생리학적 시험 및/또는 OTOF 유전자내 돌연변이를 확인하기 위한 유전 시험의 조합을 사용하여, 확인할 수 있다. 일부 구현예에서, 환자는 OTOF 유전자내 다음의 넌센스(nonsense) 또는 미스센스(missense) 돌연변이 중 하나 이상을 갖는다: TYR730TER, GLN829TER, PR01825ALA, PRO50ARG, LEU1011PRO, ILE515THR, ARG1939GLN, 또는 GLY541SER. 일부 구현예에서, 환자는 인트론(intron) 8/엑손(exon) 9 연결부에서 A-대-G 전이(IVS8-2A-G) 또는 +1 위치, 즉, 엑손 5의 스플라이스(splice) 공여체 부위에서 첫번째 인트론성 뉴클레오타이드에서 G-대-A 전이 또는 인트론 39의 공여체 스플라이스 부위내 G-C 전환(transversion)을 갖는다. 일부 구현예에서, 환자는 엑손 16내에 하나의 염기쌍 결실(1778G)을 가짐으로써, 정지 코돈을 이끌고, 6141G-A 변화를 가짐으로써 엑손 48에서 ARG-대-GLN 치환을 생성한다.
본 발명의 벡터 시스템이 투여된 환자는 청각 시스템, 특히 달팽이관이 이미 발달하여 성숙한 환자, 특히 사람 환자이다. 따라서, 이러한 환자, 특히 사람 환자는 투여가 자궁내에서 수행될 의도가 아니므로, 사람 배아 또는 태아가 아니다. 도 7에 따라서, DFNB9 청각장애가 이러한 어린이에게 진단된 경우, 본 발명에 의해 표적화된 환자는 바람직하게는 사람 신생아, 전형적으로 6개월 이상의 어린이, 또는 심지어 3개월 이상의 어린이이다. 이러한 사람 아기는 보다 바람직하게는 3개월 내지 1세이다.
참고로, 전체로서 사람 달팽이관은 임신 17 내지 19주째에 성인 크기를 획득하며 30 내지 36주(마우스에서 출생 후 12일에 상응함)에서 완전히 형태학적으로 성숙한다. 내부 모 세포 리본 시냅스의 기능적 성숙은 ABR 기록의 I 파(wave I)를 모니터링함으로써 평가할 수 있으며, 이는 사람에서 약 임신 28주째에 기록될 수 있다. ABR I파의 기록 및 분석(일차 청각 뉴우런과의 내부 모 세포 시냅스의 기능을 반영함)은 출생시(마우스에서 출생 후 20일에 상응함) 사람 아기에서 완전한 기능적 성숙을 나타내었다. 이는 당해 분야에 잘 공지되어 있다(참고: 예를 들면, Pujol et Lavigne-Rebillard, Acta oto-laryngologica. Supplementum·February 1991).
따라서, 더 나이가 많은 사람 환자, 예를 들면, 영아(2 내지 6세), 유아(6 내지 12세), 10대(12 내지 18세) 또는 성인 사람(18세 이상)에게 본 발명의 벡터 시스템을 투여하는 것이 또한 가능하다.
이와 함께, 따라서 본 발명의 벡터 시스템을 3개월 내지 25세 연령의 사람 환자에게 투여하는 것이 바람직하다.
본 발명의 환자는 특히 언어 습득 후 DFNB9 청각장애에 걸린 것으로 진단된 사람 유아이다.
다른 특수한 구현예에서, 본 발명의 환자는 6세 이상인 사람인데, 즉, 치료제의 투여는 중추 신경계가 완전히 성숙된 경우 일어난다(참고: 도 7).
특수한 구현예에서, 본 발명의 벡터 시스템은 열 민감성 돌연변이에 의해 유도된 DFNB9 청각장애를 앓는 사람 환자, 바람직하게는 상기 언급한 오토페를린 열민감성 돌연변이 중 적어도 하나를 수반하는 십대 또는 성인 사람에게 투여된다.
본원에 사용된 바와 같은, 용어 "치료하는"은 DFNB9 청각장애를 앓는 환자에서 청력을 부분적으로 또는 완전히 회복하기 위하여, 치료학적 유효량의 본 발명의 벡터 시스템 중 하나를 상기 환자에게 투여하는 것을 의미하는 것으로 의도된다. 상기 회복은 전기생리학적 장치를 사용한 청각 뇌간 반응(ABR)을 시험함으로써 평가할 수 있다. "DFNB9 청각장애의 치료"는 특히 관련된 세포 메카니즘과 상관없이 청력 기능의 완전한 회복을 나타내는 것으로 의도된다.
열-민감성 돌연변이를 수반하는 환자의 경우, 본 발명의 벡터 시스템은 또한 체온 조절로부터 유도된 청력의 상실을 예방하기 위해 투여될 수 있다. 본 발명의 문맥에서, 용어 "예방하는"은 가청 주파수 범위(audible frequency range)내 청력 상실을 손상시키거나 지연시킴을 나타낸다.
이러한 및 다른 DFNB9 환자에서, 본 발명의 벡터 시스템은 이것이 발생하기 전에 청력의 상실을 예방하고, 청력 상실이 이미 발생한 경우 청력 능력을 회복하는 것 둘 다를 위해 투여될 수 있다.
내이(inner ear)로의 다수의 전달 경로가 탐구되었다. 이는 정원 창막(round window membrane)(RWM)을 통한 및 난원창(oval window)을 통한 외림프 공간(perilymphatic space) 내로의 주사 또는 코클레오스토미(cochleostomy)를 통한 고실계(scala tympani) 또는 전정계(scala vestibule) 내로의 주사를 포함한다. 외림프 공간 전체의 분포는 모든 이러한 전달 경로에 대해 입증되었다. 또한, 달팽이관 및 전정 기관을 통한 이류 유동(advection flow)은 주사 부위로부터 내이의 보다 근접한 영역까지 치료제의 분포를 촉진시킬 수 있다. 내림프 공간(endolymphatic space)내로의 전달이 또한 중간계(scala media) 내로의 코클레오스토미를 통해, 카날로스토미(canalostomy)를 통해 및 내림프낭(endolymphatic sac)내로의 주사에 의해 탐구되었다. 이러한 접근법은 또한 광범위한 분포를 생성하였지만 높은 칼륨 내림프와 외림프 사이에 장벽을 깨는 추가의 도전(challenge)에 직면해 있다. 장벽의 파괴는 2개의 잠재적인 문제를 지닌다. 첫째로, 모세포 및 뉴우런의 기저외측 표면을 덮고 있는 외림프 공간내로의 높은 칼륨의 유출은 이러한 세포를 만성적으로 탈분극시켜 세포 사멸을 초래할 수 있다. 둘째로, 내림프와 외림프 사이에 강력한 연결의 파괴는 일반적으로 +80 내지 +120 mV 사이의 범위인 내달팽이관 전위의 소진을 초래할 수 있다. 내달팽이관 전위의 소진은 모 세포내 감각 변환을 위한 추진력을 감소시키므로 달팽이관 민감성을 감소시키고 청각 역치를 상승시킨다. 이러한 합병증을 피하는 것은 성인 달팽이관에서 특히 도전적이다. 그러나, 내림프 잠재능은 가지고 있지 않지만, 달팽이관 내림프 공간과 연속적인 전정계내 내림프 공간을 표적화함으로써, 이러한 교란 문제를 최소화시키면서 여전히 달팽이관내에 충분한 분포를 제공할 수 있다(Ahmed et al, JARO 18:649-670 (2017)).
달팽이관은 고도로 구획화되어 있고 혈액-달팽이관 장벽(BCB)에 의해 신체의 나머지로부터 분리되어 있으며, 이는 치료 주사 용적 및 신체의 일반적인 순환계내로의 누출을 최소화함으로써 달팽이관 면역 특권을 보호하고 전신 면역 부작용의 변화를 감소시킨다. 달팽이관내 모 세포와 지지 세포는 일반적으로 분열하지 않으므로, 달팽이관내 세포는 안정하에 남아있으므로, 지속적인 이식유전자 발현을 위해 비통합성 바이러스 벡터(예컨대, AAV)를 사용하는 것이 가능하다.
후 반고리뼈관(posterior semi-circular canal)은 사람에서 접근가능한 것으로 나타나므로 반-원형 접근법(semi-circular approach)이 사람 시험에서 추가의 달팽이관 유전자 치료요법을 위한 촉망되는 주사 경로로 시사되었다(Suzuki et al., Sci. Rep. 7:45524 (2017); Yoshimura et al., Sci. Rep. 8:2980 (2018).
본 발명의 바람직한 구현예에서, 본 발명의 벡터 시스템은 임상 이과 수술 실시(clinical otologic surgical practice)에서 통상적으로 사용된 2개의 일반적이고 잘-확립된 기술 중 하나를 통해 사람 귀에 투여된다. 보다 정밀하게는, 이러한 접근법은 외림프 공간을 표적화하기 위해 채택될 것이다. 이러한 목적으로, 마이크로-카테터(micro-catheter)를 사용한 주사는 레이저 등골절개술(laser stapedotomy) (경-등골(trans-stapes))을 사용한 난원창(oval window) 또는 유양돌기(transmastoid)/트랜스-둥근 창(trans-round window)을 통해 수행될 것이다(Dai C. et al, JARO, 18:601-617, 2017).
정맥내 주사 또는 주입에 의한 전신계 투여가 또한 가능하다.
본 발명의 벡터 시스템은 내부 모 세포내에서, 전체 길이의 오토페를린 폴리펩타이드, 또는 이의 기능적 단편의 발현을 개시할 수 있는 적어도 하나의 폴리누클레오타이드 벡터를 함유한다. 바람직하게는, 상기 폴리뉴클레오타이드 벡터는 상기 폴리펩타이드, 또는 이의 기능성 단편을 암호화하는 암호화 서열을 함유하며, 이는 구체적으로 상기 세포내 유전자의 발현이 가능하도록 하는 프로모터와 작동적으로 연결된다.
상기 암호화 서열은 예를 들면, 사람 야생형 오토페를린 유전자(NM_194248.2 = 가장 긴 동형인, 동형 a 또는 변이체 1)의 동형 1의 cDNA 서열에 상응하는, 서열 번호: 2의 사람 오토페를린 유전자이다.
상기 암호화 서열은 또한 서열 번호: 22의 보다 짧은 cDNA 서열 NM_001287489.1(동형 e 또는 변이체 5), cDNA 서열 NM_004802.3(동형 b 또는 변이체 2), cDNA 서열 NM_194322.2(동형 c 또는 변이체 3), 또는 cDNA 서열 NM_194323.2(동형 d 또는 변이체 4)일 수 있다.
다수의 바이러스 및 비바이러스 벡터가 다양한 조직 및 기관에서 유전 물질의 전달을 위해 개발되었다. 대부분의 경우에, 이러한 벡터는 복제 불능성이고 바이러스-유도된 질환의 위협이 거의 없다. 오히려, 바이러스 게놈은 부분적으로 또는 완전히 제거되어, 바이러스 캡시드 내에 치료학적 DNA 화물(cargo)의 혼입을 허용한다. 일부 벡터는 단일-가닥 DNA를 포함하지만, 다른 것은 이중-가닥 DNA를 포함한다. 본 발명의 문맥에서 특히 바람직한 벡터는 문헌: Ahmed et al, JARO 18:649-670 (2017)에 개시된 바와 같은 렌티바이러스 벡터, 아데노바일스 벡터, 아데노-관련 바이러스(AAV)이다.
구체적으로, AAV는 파르보비리다에(Parvoviridae) 계열로부터의 작은 복제-결핍성 아데노바이러스-의존성 바이러스이다. 이는 직경이 20 내지 25 nm이고 2개의 역위된 말단 반복체(inverted terminal repeat)(ITR)에 의해 플랭킹된(flanked) 4.8 kb의 게놈의 이코사에드랄 캡시드(icosaedrical capsid)를 갖는다. 숙주 세포내에서 탈코팅(uncoating)된 후, AAV 게놈은 고 분자량 헤드-대-테일 환형 콘카타머(head-to-tail circular concatamer)를 형성함으로써 안정한 에피솜 상태로 지속될 수 있거나 숙주 세포 게놈내로 통합될 수 있다. 시나리오 둘 다는 장기간 및 고 수준 이식유전자 발현을 제공한다.
AAV는 눈 유전자 치료요법의 사람 시험에서 수득된 결과를 기반으로 한 달팽이관 유전자 치료요법에 대해 촉망되는 바이러스인 것으로 여겨진다. 사람 눈 유전자 치료요법에서 AAV의 성공 이유는: (1) 안전성 프로파일의 입증(다수의 사람 시험은 AAV가 병원성을 결여하고 매우 낮은 면역원성을 지님을 나타낸다), (2) 비-분열 세포에서 오래 지속되는 이식유전자 발현, (3) 세포 장벽을 가로질러 표적화된 세포에 도달하기 위한 확산을 돕는 작은 크기의 AAV(약 20 nm, 이는 아데노바이러스보다 5배 더 작다)(Zhang et al, Frontiers in Molecular Neuroscience, vol.11, Art.221, 2018)를 포함한다.
바람직한 구현예에서, 본 발명의 벡터 시스템은 상술한 바와 같은, 전체 길이의 오토페를린 폴리펩타이드 또는 이의 기능성 단편을 암호화하는 폴리뉴클레오타이드를 포함하는 적어도 하나의 AAV 입자를 포함한다.
다른 바람직한 구현예에서, 본 발명의 벡터 시스템은 적어도 2개의 AAV 입자를 포함하며, 이들 각각은 i) 하나에 대한 오토페를린 폴리펩타이드, 또는 이의 기능성 단편의 N-말단 부위, 및 ii) 다른 것에 대한 오토페를린 폴리펩타이드, 또는 이의 기능성 단편의 C-말단 부위를 암호화하는 부분 암호화 서열을 포함하는 폴리뉴클레오타이드를 포함한다.
사람 AAV의 12개의 천연적으로 존재하는 혈청형이 지금까지 특성화되었다. 이러한 혈청형은 근육, 폐, 간, 뇌, 망막, 및 맥관구조에서 상이한 고유의 향성(tropism) 및 형질도입 효능(transduction efficiency)을 갖는다. AAV 슈도타이핑(pseudotyping) 및 캡시드 가공의 다수의 시도는 형질도입의 향성 및 효능의 고려할만한 개선을 야기하였다. 내이의 세포의 경우, AAV1-4, 7, 및 8이 생체내에서 나선 연(spiral limbus), 나선 인대(spiral ligament), 및 나선 신경절 세포(spiral ganglion cell)를 감염시키는 것으로 밝혀졌다. IHC의 감염은 또한 AAV1-3, 5, 6, 및 8에 대해 밝혀졌다. AAV1은 가장 효과적이고 가끔 감염된 OHC 및 지지 세포이었다. 또한, AAV5는 클라우디우스(Claudius) 세포, 나선 신경절, 및 내부 고랑 세포(inner sulcus cell)에 효과적인 것으로 밝혀졌다. 슈도형 벡터 중에서, AAV2/1은 마우스 달팽이관에서 IHC 및 OHC를 발생시키는 전구 세포(progenitor cell)를 효율적으로 형질도입시키고, AAV2/2는 기니아 피그(guinea pig) 달팽이관의 IHC에 대해 최적인 것으로 밝혀졌다(Ahmed et al, JARO 18:649-670 (2017)).
따라서, 바람직한 구현예에서, 본 발명의 벡터 시스템은 AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, 및 AAV10으로 이루어진 그룹에서 선택된 AAV 벡터를 함유한다.
보다 바람직한 구현예에서, 상기 벡터의 혈청형은 AAV2, AAV8, AAV5, 또는 AAV1이다. 심지어 보다 바람직한 구현예에서, 상기 벡터의 혈청형은 AAV2 또는 AAV8이다. 본 발명의 문맥에서 가장 바람직한 혈청형인, AAV8은 현재 생체내에서 시험 중이다.
유전자 발현 효능을 증가시키고, 바이러스의 의도치않는 확산을 방지하기 위하여, AAV의 유전적 변형이 수행될 수 있다. 이러한 유전적 변형은 시스-작용의 역위 말단 반복체 및 패키징 신호(packaging signal)를 제외하고는, E1 영역의 결실, E1 영역의 결실과 함께 E2 또는 E4 영역의 결실, 또는 전체 아데노바이러스 게놈의 결실을 포함한다. 이러한 벡터는 본 발명에 유리하게 포함된다.
더욱이, 돌연변이된 캡시드 단백질을 가진 유전적으로 변형된 AAV를 사용하여 특수한 조직 유형, 예컨대, 청각 세포로의 유전자 발현을 지시할 수 있다. 이러한 목표를 위해, 바이러스 엔벨로프(envelope)내 타이로신 잔기가 알라닌 잔기에 대해 치환된 변형된 혈청형-2 및 -8 AAV 벡터를 사용할 수 있다. 타이로신 돌연변이체 혈청형-2의 경우에, 타이로신 444는 알라닌(AAV2-Y444A)으로 치환될 수 있다. 혈청형 8의 경우에, 타이로신 733은 알라닌 잔기(AAV8-Y733A)로 치환될 수 있다. AAV2-Y444A 또는 AAV8-Y733A를 사용함으로써, 유전자 전달을 10,000배까지 증가시키고, 달팽이관의 감각 모 세포를 감염시키는데 필요한 AAV의 양을 감소시키는 것이 가능하다.
바람직한 구현예에서, 오토페를린 폴리펩타이드 또는 이의 유전자 또는 기능성 단편을 발현시키는 본 발명의 폴리뉴클레오타이드(들)는 재조합 AAV2 입자내에 함유되며, 여기서 모든 타이로신 잔기는 페닐알라닌 잔기로 대체되었다(문헌: Petrs-Silva H et al, Mol. Ther. 19, 293-301 (2011) 및 하기 실시예에 개시된 바와 같이, AAV2 (Y->F) 또는 Quad Y-F). 캡시드 단백질의 외부 표면에서 돌연변이된 타이로신 잔기는 예를 들면, Tyr252의 Phe252로의(Y252F), Tyr272의 Phe272로의(Y272F), Tyr444의 Phe444로의(Y444F), Tyr500의 Phe500으로의(Y500F), Tyr700의 Phe700으로의(Y700F), Tyr704의 Phe704로의(Y704F), Tyr730의 Phe730으로의(Y730F) 및 Tyr733의 Phe733으로의(Y733F) 돌연변이를 포함하나, 이에 한정되지 않는다. 이러한 변형된 벡터는 원형 윈도우 막을 가로지른 벡터의 침투를 촉진하며, 이는 달팽이관의 모 세포/나선형 신경절 뉴우런으로의 벡터의 비-침입성 전달을 허용한다. 이러한 돌연변이된 벡터는 프로테오솜에 의한 분해를 방지하고, 이의 형질도입 효율이 유의적으로 증가된다.
천연 혈청형 1-10으로부터 유도되는 다른 재조합 AAV 입자는 AAV2-AAV3 하이브리드, AAVrh.10, AAVhu.14, AAV3a/3b, AAVrh32.33, AAV-HSC15, AAV-HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15/17, AAVM41, AAV9.45, AAV6(Y445F/Y731F), AAV2.5T, AAV-HAE1/2, AAV 클론 32/83, AAVShH10, AAV8(Y733F), AAV2.15, AAV2.4, AAVM41, 및 AAVr3.45(Asokan A. et al, Mol. Therapy, vol.20 n°4, 699-708, 2012)를 포함한다.
지금까지 보고된 내이 모 세포의 형질도입을 위해 최고 효능을 갖는 것으로 밝혀진 합성 벡터 Anc80L65를 사용하는 것이 또한 가능하다(Suzuki et al., Sci. Rep. 7:45524 (2017)). Gyorgy et al, Mol. Ther. 25(2):379-391, 2017에 의해 제안된 엑소좀-관련 AAV를 사용하는 것이 또한 가능하다.
이의 캡시드가 이의 패키징 능력을 향상시키도록 변형된 오버로드된(overloaded) AAV/PHP.B 벡터를 사용하는 것이 또한 가능하다.
이종 폴리뉴클레오타이드 또는 작제물을 포함하는 바이러스 및 비리온(virion)을 제조하는 방법이 당해 분야에 공지되어 있다. AAV의 경우에, 세포는 아데노바이러스 또는 AAV 헬퍼 기능에 적합한 아데노바이러스 유전자를 포함하는 폴리뉴클레오타이드 작제물로 동시감염되거나 형질감염될 수 있다. 물질 및 방법의 예는 예를 들면, U.S. 8,137,962 및 6,967,018에 기술되어 있다.
기술자는 본 발명의 벡터(들)의 투여 전에, 필요할지의 여부를 용이하게 측정하여, 표적 세포에 따라, WO 2011/075838에서 제안된 바와 같이 둥근 창 막의 투과능을 향상시킬 수 있다.
심지어 AAV를 사용하는 경우, 본 발명의 시스템은 1-벡터 시스템일 수 있다. 이러한 경우, 변형된 캡시드가 사용될 수 있다(참고: AAV/PHP.B 벡터).
선택된 AAV 캡시드가 5 킬로염기(kilobase)의 제한된 패키징 능력을 갖는 경우, 예를 들면, 본원에 참고로 포함된, WO 2013/075008에 개시된 바와 같은 이중 벡터 시스템을 사용하는 것이 보다 양호하다.
본 발명자는 상기 이중-AAV 벡터 접근법을 사용하여 오토페를린 유전자의 2개의 1/2 부위를 내부 모 세포에 제공하였고, 여기서 동종 재조합이 일어나서 전체 길이의 단백질이 발현된다. 이의 결과는 2개의 명백한 AAV 벡터가 표적화된 내부 모 세포를 효율적으로 형질도입시킬 수 있고, 여기서 오토페를린 단백질은 장기 지속되는 방식으로 DFNB9 무효화에 기인한 선천성 청각장애를 앓는 마우스 OTOF KO의 극심한 청각장애 표현형을 생산하고 회복시킨다.
따라서, 본 발명의 벡터 시스템은 바람직하게는 적어도 2개의 AAV 입자를 포함하며, 상기 AAV 입자 각각은:
a) 상기 폴리뉴클레오타이드의 각각의 말단, 및, 상기 역위된 말단 반복체 사이에, 역위된 말단 반복체, 5'로부터 3'까지: 적합한 프로모터에 이어서 오토페를린 유전자의 N-말단 부분을 함유하는 부분 암호화 서열, 및 스플라이스 공여체 부위를 포함하는 제1의 폴리뉴클레오타이드, 또는
b) 상기 폴리뉴클레오타이드의 각각의 말단, 및, 상기 역위된 말단 반복체 사이에, 역위된 말단 반복체, 5'로부터 3'까지: 스플라이스 수용체 부위(splice acceptor site), 오토페를린 유전자의 C-말단 부분을 함유하는 부분 암호화 서열에 이어서 임의로 폴리아데닐화 서열을 포함하는 제2의 폴리뉴클레오타이드를 포함하고,
여기서 제1 및 제2 폴리뉴클레오타이드의 암호화 서열은 또한 상기 제1의 폴리뉴클레오타이드에서 스플라이스 공여체 부위 이후 및 상기 제2의 폴리뉴클레오타이드내 스플라이스 수용체 부위 앞에 위치하는 재조합유전성 서열을 함유하고,
여기서 제1 및 제2 폴리뉴클레오타이드내 암호화 서열은 조합되는 경우, 전체 길이의 오토페를린 폴리펩타이드를 암호화한다.
당해 바람직한 구현예는 "제1" 및 "제2" 폴리뉴클레오타이드를 사용한다. 그러나, "제1" 및 "제2"는 어딘가에 달리 표현하여 기술하지 않는 한, 특수한 순서 또는 중요도를 내포하는 것을 의미하지 않는 것으로 이해된다.
도 1 및 WO 2013/075008에 설명된 바와 같이, 당해 특수한 구현예에서 사용된 제1 및 제2 폴리뉴클레오타이드는 표적 세포내에서 오토페를린 단백질의 적절한 재조합 및 발현을 유도하기 위하여 특수한 유전적 구성성분을 함유하여야 한다.
이러한 특수한 구성성분은 다음과 같다:
· ITR
본 발명의 일부 구현예에서, OTOF 유전자의 부분 또는 전체 길이의 cDNA는 2개의 ITR-함유 플라스미드내로 삽입된다.
AAV 벡터(들)이 사용된 경우, 본원에 기술된 폴리뉴클레오타이드의 ITR 서열은 임의의 AAV 혈청형(예컨대, 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10)으로부터 유래되거나 하나 이상의 혈청형으로부터 유래될 수 있다. 본원에 제공된 폴리뉴클레오타이드의 일부 구현예에서, ITR 서열은 AAV2로부터 유래된다. ITR 서열 및 ITR 서열을 포함하는 플라스미드는 당해 분야에 공지되어 있고 상업적으로 이용가능하다.
발현 작제물의 5' 말단을 플랭킹하기 위한 예시적인 AAV2 ITR 서열은 서열 번호: 10의 서열을 포함한다. 발현 작제물의 3' 말단을 플랭킹하기 위한 예시적인 AAV2 ITR 서열은 서열 번호: 11의 서열을 포함한다.
이러한 ITR은 또한 본 발명의 폴리뉴클레오타이드가 단일 벡터 시스템인 경우 유리하게 사용될 수 있다.
· 적합한 프로모터
본 발명의 벡터 시스템에서 사용하기 위해 고려된 프로모터는 사이토메갈로바이러스(cytomegalovirus)(CMV) 프로모터, SV40 프로모터, 로우스 육종 바이러스(Rous sarcoma virus)(RSV) 프로모터, 키메라 CMV/닭 베타-액틴 프로모터(CBA) 및 CBA의 트렁케이트된 형태(truncated form)(smCBA)를 포함하나, 이에 한정되지 않는다(미국 특허 8,298,818). 구체적인 구현예에서, 프로모터는 CMV 및 베타-액틴 프로모터를 포함하는 키메라 프로모터이다.
바람직한 구현예에서, 본 발명의 벡터 시스템에 사용된 프로모터는 서열 번호: 8의 트렁케이트된 키메라 CMV β 액틴(smcBA) 프로모터 또는 서열 번호: 8과 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100%의 서열 동일성을 갖는 프로모터이다.
이러한 프로모터는 또한 본 발명의 폴리뉴클레오타이드가 단일 벡터 시스템인 경우 유리하게 사용될 수 있다.
프로모터는 당해 분야에 공지된 표준 기술을 사용하여 벡터내로 혼입할 수 있다. 프로모터 또는 다중 프로모터의 다중 카피를 본 발명의 벡터 시스템에 사용할 수 있다. 일 구현예에서, 프로모터는 이의 천연의 유전 환경내 전사 출발 부위로부터 존재하므로 전사 출발 부위로부터 거의 동일한 거리에 위치할 수 있다. 이러한 거리에서 일부 변화는 프로모터 활성의 실질적인 감소없이 허용된다. 전사 출발 부위는 전형적으로 벡터 내에 포함된다.
· OTOF 폴리펩타이드의 전체 암호화 서열을 생산하기 위해서, 생체내에서 cDNA의 1/2 2개의 동종 재조합 및 형질감염된 내부 모 세포내에서 이의 발현을 촉진하는 재조합유전성 서열.
일부 구현예에서, 본 발명의 2개의 폴리뉴클레오타이드(예컨대, 제1 및 제2 폴리뉴클레오타이드)는 일단 세포로 전달되면 2개의 폴리뉴클레오타이드 사이에 동종 재조합을 촉진시킬 수 있는 소위 "재조합유전성 영역"을 포함한다(참고: 예컨대, Ghosh et al. Hum Gene Ther. 2011 Jan;22(l):77-83).
이러한 재조합유전성 영역은 전형적으로 제2 폴리뉴클레오타이드내 동종 영역을 갖는 제1 폴리뉴클레오타이드의 제1 영역 또는 이의 역으로 전형적으로 이루어진다. 2개의 영역은 바람직하게는 상기 정의된 바와 같이, 서로 적어도 75%, 적어도 80%, 적어도 90%, 적어도 95%, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100% 동일성의 역치 수준을 갖는다.
이러한 재조합유전성 영역은 바람직하게는 50 내지 500, 50 내지 400, 50 내지 300, 100 내지 500, 100 내지 400, 100 내지 300, 200 내지 500, 200 내지 400, 또는 200 내지 300개 뉴클레오타이드를 포함하는 크기를 갖는다.
바람직한 구현예에서, 2개의 영역은 동일하고 200 내지 300개 뉴클레오타이드를 포함한 크기를 갖는다.
이러한 재조합유전성 서열은 표준 엄격한 조건(stringent condition) 및 표준 방법 하에서 서로 하이브리드화를 허용하기에 충분히 상동성인 서열을 갖는다.
본원에 사용된 바와 같은, 하이브리드화용 "엄격한" 조건은 하이브리드화가 밤새 20 내지 25℃에서 DNA 하이브리드의 용융 온도(Tm) 이하로 6x SSPE, 5x 덴하르트 용액(Denhardt's solution), 0.1% SDS, 0.1 mg/ml 변성된 DNA 속에서 수행되는 조건을 지칭한다. 용융 온도는 다음의 식으로 기술된다: Tm=81.5 C+16.6 Log[Na+]+0.41 (%G+C)-0.61(포름아미드 %)-600/염기쌍내 듀플렉스(duplex)의 길이.
세척은 통상적으로 다음과 같이 수행된다: (1) 실온에서 15분 동안 1x SSPE, 0.1 % SDS(낮은 엄격성(stringency) 세척) 속에서 2회. 2) Tm-20℃에서 15분 동안 0.2x SSPE, 0.1% SDS(중간 스트링전시 세척) 속에서 1회.
보다 바람직한 구현예에서, 2개의 영역은 동일하고 서열 번호: 9의 서열 또는 서열 번호: 9와 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100%의 서열 동일성을 갖는 서열을 갖는다.
·스플라이스 공여체 부위 및 스플라이스 수용체 부위
일단 생체내에서 재조합되면, 전체 길이의 cDNA는 재조합유전성 영역 밖의 스플라이싱(splicing)을 유발하는 스플라이스 공여체/스플라이스 수용체 쌍을 함유한다. 본 발명의 디중-벡터 시스템내에 포함된 폴리뉴클레오타이드는 스플라이스 공여체 또는 스플라이스 수용체 부위를 포함한다. 바람직한 구현에에서, 스플라이스 공여체 및/또는 스플라이스 수용체 부위는 스플라이스 컨센서스 서열(consensus sequence)을 함유한다. 보다 바람직한 구현예에서, 본 발명의 벡터 시스템내에 포함된 폴리뉴클레오타이드에 의해 수반된 스플라이스 공여체 및/또는 스플라이스 수용체 부위는 알칼린 포스파타제 효소로부터 유래된 스플라이스 컨센서스 서열을 함유한다.
바람직한 구현예에서, 본 발명의 이중-벡터 시스템내에 포함된 폴리뉴클레오타이드는 각각 스플라이스 공여체 및 수용체 부위로서 서열 번호: 12 및/또는 서열 번호: 13, 또는 서열 번호: 12 및/또는 서열 번호: 13과 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 96%, 적어도 97%, 적어도 98%, 적어도 99% 또는 100%의 서열 동일성을 포함하는 스플라이스 부위를 포함한다.
단일 또는 이중 벡터 시스템 내에 함유된, 본 발명의 폴리뉴클레오타이드 서열은 벡터가 발현될 내부 모 세포내에서 기능성인 다른 조절 구성성분을 함유할 수 있다. 당해 분야의 통상의 기술자는 사람 내부 모 세포에서 사용하기 위한 조절 성분을 선택할 수 있다. 조절 성분은, 예를 들면, 내부 리보소옴 도입 부위(internal ribosome entry site)(IRES), 전사 종결 서열, 해독 종결 서열, 인핸서(enhancer), 및 폴리아데닐화 성분을 포함한다.
전사 종결 영역은 전형적으로 진핵 또는 바이러스 유전자 서열의 3' 해독되지 않은 영역으로부터 수득될 수 있다. 전사 종결 서열은 암호화 서열의 하부에 위치함으로써 효율적인 종결을 제공할 수 있다. 신호 펩타이드 서열은 특이적인 세포기관 구획으로부터 단백질 작용 부위 및 세포외 환경까지의 범위의 광범위한 해독 후 세포 목적지까지 작동적으로 연결된 폴리펩타이드의 전좌에 관여하는 정보를 암호화하는 아미노 말단 서열이다. 인핸서는 유전자 전사를 증가시키고 또한 벡터 내에 포함될 수 있는 시스-작용 성분이다. 인핸서 성분은 당해 분야에 공지되어 있고, CaMV 35S 인핸서 성분, 사이토메갈로바이러스(CMV) 얼리(early) 프로모터 인핸서 성분, 및 SV40 인핸서 성분을 포함하나, 이에 한정되지 않는다.
구조 유전자에 의해 암호화된 mRNA의 폴리아데닐화를 지시하는 DNA 서열이 또한 벡터 내에 포함될 수 있다.
이중-벡터 접근법은 OTOF 유전자의 암호화 서열을 2개의 부분으로 분할하여, 제한된 패키징 능력을 갖는 비리온(virion) 내로 더 용이하게 패키징하는 것이 유리하다. AAV 캡시드가 사용된 경우, 5 킬로염기(kilobase) 이하, 4 킬로염기 이하, 및 심지어 보다 바람직하게는 3 킬로염기 이하를 함유하는 OTOF 암호화 서열을 함유하는 폴리뉴클레오타이드를 사용하는 것이 바람직하다.
사람 OTOF 유전자의 암호화 서열은 바람직하게는 천연 스플라이싱 부위에서 절단된다.
예를 들면, 서열 번호: 2의 사람 OTOF 유전자 동형 1은 서열 번호: 3으로 나타낸 바와 같은 뉴클레오타이드 서열(서열 번호: 2의 뉴클레오타이드 1 내지 2676번)을 갖는 N-말단 부분 및 서열 번호: 4로 나타낸 바와 같은 뉴클레오타이드 서열(서열 번호: 2의 뉴클레오타이드 2677 내지 5994번)을 갖는 C-말단 부분으로 분할될 수 있다. 그리고, 서열 번호:22를 갖는 사람 OTOF 유전자 동형 5는 서열 번호: 3의 N-말단 부분 및 서열 번호: 23의 C-말단 부분으로 분할될 수 있다.
본 발명의 벡터 시스템내 제1 및 제2 폴리뉴클레오타이드로서 사용될 수 있는 예시적인 폴리뉴클레오타이드는 예를 들면, 서열 번호: 19 및 서열 번호: 20 각각이다. 이러한 2개의 폴리뉴클레오타이드는 오토페를린 사람 단백질의 동형 1의 N-말단 및 C-말단 부분을 각각 암호화한다.
서열 번호: 19는 다음을 함유한다:
- 서열 번호: 10의 서열을 갖는 AAV2의 5 ITR 서열(nt 20-162)
- CMV 인핸서(nt 186-440), 닭 β-액틴 프로모터(nt 441 - 835), β-액틴 단백질의 엑손 1 및 키메라 인트론(nt 836-1130), 3개 모두는 서열 번호: 8의 서열에 상응하는 "smCBA"로 불린다,
- 서열 번호: 3의 서열을 갖는 서열을 암호화하는 사람 오토페를린 동형 1의 5' 부분(nt 1153-3558),
- 서열 번호: 12의 서열을 갖는 알칼린 포스파타제의 스플라이스 공여체 부위(nt 3559-3642),
- 서열 번호: 9의 서열을 갖는 재조합유전성 서열(nt 3649-3935), 및
서열 번호: 11의 서열을 갖는 AAV2의 3' ITR 서열을 함유한다.
다른 한편, 서열 번호: 20은:
- 서열 번호: 10의 서열을 갖는 AAV2의 5' ITR 서열(nt 20-162),
- 서열 번호: 9의 서열을 갖는 재조합유전성 서열(nt 207-493),
- 서열 번호: 13의 서열을 갖는 알칼린 포스파타제의 스플라이스 수용체 부위(nt 516-564),
- 서열 번호: 4의 서열을 갖는 사람 오토페를린 동형 1 암호화 서열의 3' 부분(nt 565-4152), 및
- 소(bovine) 성장 호르몬 폴리아데닐화 신호(nt 4190-4411), 및
서열 번호: 11의 서열을 갖는 AAV2의 3' ITR 서열을 포함한다.
본 발명의 벡터 시스템에서 제1 및 제2 폴리뉴클레오타이드로서 사용될 수 있는 폴리뉴클레오타이드는 예를 들면, 각각 서열 번호: 19 및 서열 번호: 21이다. 이러한 2개의 폴리뉴클레오타이드는 서열 번호: 22의 오토페를린 사람 유전자의 동형 5의 N-말단 및 C-말단 부분을 각각 암호화한다(동형 1 및 5의 N-말단 부분은 동일하므로, 2개의 동형의 발현을 유도하기 위하여 서열 번호: 19를 사용하는 것도 가능하다).
서열 번호: 21은:
- 서열 번호: 10의 서열을 갖는 AAV2의 5' ITR 서열(nt 20-162),
- 서열 번호: 9의 서열을 갖는 재조합유전성 서열(nt 207-493),
- 서열 번호: 13의 서열을 갖는 알칼린 포스파타제의 스플라이스 수용체 부위(nt 516-564),
- 서열 번호: 23의 서열을 갖는 사람 오토페를린 동형 5의 3' 부분(nt 565-4152),
및
- 소 성장 호르몬 폴리아데닐화 신호(nt 4190-4411), 및
- 서열 번호: 11의 서열을 갖는 AAV2의 3' ITR 서열을 함유한다.
본 발명의 약제학적 조성물
다른 양태에서, 본 발명은 성숙한 청각 시스템을 갖고, DFNB9 청각장애를 앓는 환자, 특히 사람 환자를 치료하거나, DFNB9 돌연변이를 갖는 환자에서 DFNB9 청각장애를 예방하기 위한, 상술된 바와 같이, 본 발명의 벡터 시스템(즉, 폴리뉴클레오타이드 또는 이를 함유하는 비리온)을 포함하는 약제학적 조성물을 표적화한다.
보다 일반적으로, 이러한 약제학적 조성물은 변경된 DFNB59 유전자 발현 또는 결핍증으로 인하여 선천성 청력 상실을 앓고 있는 사람 대상체에게 투여될 수 있다. 상기 결핍증은 예를 들면, 오토페를린이 정상 수준에서 발현되지만 기능성이 아닌 경우 관찰될 수 있다.
다시 말해서, 본 발명은 성숙한 청각 시스템을 갖고, 변경된 DFNB59 유전자 발현 또는 결핍증과 연관된 상기 인용된 장애를 앓는, 환자, 특히 사람을 예방 및/또는 치료하도록 의도된 약제학적 조성물의 제조를 위한, 상술한 바와 같은, 본 발명의 벡터 시스템의 용도에 관한 것이다.
본원에 사용된 바와 같은, "약제학적으로 허용되는 담체"는 생리학적으로 혼용성인 임의의 및 모든 용매, 분산 매질, 코팅, 항세균제 및 항진균제, 등장성 및 흡수 지연제 등을 포함한다. 약제학적으로 허용되는 담체의 예는 물, 염수, 인산염 완충된 염수, 덱스트로즈, 글리세롤, 에탄올 뿐만 아니라 이의 조합 중 하나 이상을 포함한다. 많은 경우에, 등장성 제제, 예를 들면, 당, 다가알코올, 예를 들면, 만니톨, 소르비톨, 또는 염화나트륨을 조성물 속에 포함시키는 것이 바람직할 수 있다. 약제학적으로 허용되는 담체는 또한 소량의 보조 물질, 예를 들면, 습윤제, 유화제, 방부제 또는 완충제를 추가로 포함할 수 있으며, 이는 항산화성 화합물 또는 이를 함유하는 약제학적 조성물의 유통기한 또는 효능을 향상시킨다.
본 발명의 약제학적 조성물은 다양한 형태로 존재할 수 있다. 이는 예를 들면, 액체, 반-고체 및 고체 투여량 형태, 예를 들면, 액체 용액(예컨대, 주사가능한 및 주입가능한 용액), 분산액 또는 현탁액, 정제, 환제, 분말, 리포좀 및 좌제를 포함한다. 사용된 형태는 의도된 투여 방식 및 치료학적 적용에 의존한다. 대표적인 조성물은 주사가능한 또는 주입가능한 용액의 형태이다.
약제학적 조성물은 전형적으로 제조 및 저장 조건 하에서 멸균성이고 안정하여야만 한다. 본 발명의 약제학적 조성물은 바람직하게는 용액, 미세유액, 분산액, 리포좀, 또는 고 약물 농도에 적합한 다른 주문형 구조로 제형화된다. 멸균 주사가능한 용액은 필요량의 본 발명의 벡터를 적절한 용매 속에 상기 열거한 성분 중 하나 또는 조합과 함께 혼입시킨 다음, 필요한 경우 여과된 멸균화에 의해 제조할 수 이다. 일반적으로, 분산제는 본 발명의 벡터를 기본 분산 매질 및 상기 열거된 것으로부터 필요한 다른 성분을 함유하는 멸균 비히클내로 혼입시켜 제조한다. 멸균 주사가능한 용액의 제조를 위한 멸균 동결건조된 분말의 경우에, 바람직한 제조 방법은 진공 건조 및 활성 성분의 분말 및 이의 이미 멸균-여과된 용액으로부터의 추가의 목적한 성분을 생성하는 진공 건조 및 분무-건조이다. 용액의 적절한 유동성은 예를 들면, 코팅, 예를 들면, 레시틴을 사용하고, 분산액의 경우에 필요한 입자 크기를 유지시키고 계면활성제를 사용함으로써 유지시킬 수 있다. 주사가능한 조성물의 연장된 흡수는 흡수를 지연시키는 제제, 예를 들면, 모노스테아레이트 염 및 젤라틴을 조성물 속에 포함시킴으로써 달성할 수 있다.
본 발명의 문맥에서, 본 발명의 조성물의 대표적인 투여 방식은 고실내(intratympanic)(중이 내), 달팽이관내(intracochlear), 또는 비경구(예컨대, 정맥내, 피하, 복강내, 근육내, 척추강내)이다. 하나의 예에서, 본 발명의 약제학적 조성물은 정맥내 주입 또는 주사에 의해 투여된다. 다른 예에서, 본 발명의 약제학적 조성물은 입체정적 전달(stereostatic delivery)을 사용하여 특정 위치에, 특히 고막 또는 유양 돌기를 통해 중이로 전달된다.
보다 상세하게는, 본 발명의 조성물을 레이저 등골절개술(laser stapedotomy)(경-등골)을 사용하여 난원창을 통해 또는 유돌경유(transmastoid)/경-둥근 창(trans-round window)을 통해 수행될 마이크로-카테터(micro-catheter)를 사용하여 투여할 수 있다(Dai C. et al, JARO, 18:601-617, 2017).
본 발명의 바람직한 구현예에서, 본 발명의 약제학적 조성물은 달팽이관내 투여를 통해, 보다 상세하게는 전정계내 내림프 공간을 표적화하거나 상기 언급한 반-원형 접근법(semi-circular approach)에 의해 사람 귀내에 투여된다.
본 발명의 약제학적 조성물은 전형적으로 본 발명의 벡터의 "치료학적 유효량" 또는 "예방학적 유효량"을 포함한다. "치료학적 유효량"은 허용되지 않는 독성 또는 바람직하지 않은 부작용없이 청력 상실의 예방 및 치료 둘 다를 위한 당해 경우에, 목적한 치료학적 결과를 달성하는데 필요한 투여량에서 및 기간 동안, 효과적인 본 발명의 벡터의 양을 지칭한다.
본 발명의 벡터의 치료학적 유효량은 대상체의 질환 상태, 연령, 성별, 및 체중과 같은 인자, 및 동일한 대상체에서 목적한 반응을 유발하는 상기 화합물의 능력에 따라 변할 수 있다. 치료학적 유효량은 청구된 화합물의 임의의 독성 또는 유해한 효과가 치료학적으로 유리한 효과보다 큰 것일 수 있다. "예방학적 유효량"은 목적한 예방학적 결과를 달성하는데 필요한 투여량 및 기간 동안 효과적인 본 발명의 벡터의 양을 지칭한다. 전형적으로, 예방학적 용량은 질환 전 또는 조기 단계에 대상체에서 사용될 수 있으므로, 예방학적 유효량은 일반적으로 치료학적 유효량 미만이다.
투여량 요법을 조절하여 최적의 목적한 반응(예컨대, 치료학적 또는 예방학적 반응)을 제공할 수 있다. 예를 들면, 단일 거환(bolus)을 투여할 수 있거나, 수회의 분할된 용량을 시간에 걸쳐 투여할 수 있거나 용량을 치료학적 상황의 위급상태에 의해 나타난 것으로서 예방학적으로 감소시키거나 증가시킬 수 있다. 본원에 사용된 투여량 단위형은 치료될 포유동물 대상체에 대한 일원화된 투여량으로서 적합한 생리학적으로 별개인 단위를 지칭하며; 각각의 단위는 필요한 약제학적 담체와 함께 목적한 치료학적 또는 예방학적 효과를 생산하기 위해 계산된 본 발명의 벡터 화합물의 예정된 양을 함유한다. 투여량 단위형에 대한 명세는 (a) 벡터(들)의 유일한 특성 및 달성될 특수한 치료학적 또는 예방학적 효과, 및 (b) 대상체에서 청력 상실을 치료 또는 예방하기 위한 이러한 벡터(들)를 제형화하는 분야에서 고유한 제한에 의해 영향받고 이에 직접 의존할 수 있다.
일부 구현예에서, 제1 및 제2 AAV 입자가 사용되어야 하는 경우, 제1 및 제2 AAV 폴리뉴클레오타이드/입자는 동일한 조성물 또는 상이한 조성물 내에 함유될 수 있고 함께 또는 별도로 투여될 수 있다.
일부 구현예에서, 본 발명의 조성물은 106 내지 1014개의 입자/mL 또는 1010 내지 1015개의 입자/mL, 또는 이러한 범위 중 어느 하나에 대해 이들 사이의 임의의 값, 예를 들면, 약 106, 107, 108, 109, 1010, 1011, 1012, 1013, 또는 1014개의 입자/mL를 함유한다. 일 구현예에서, 본 발명의 조성물은 1013개 이상의 AAV 입자/mL를 함유한다.
일부 구현예에서, 제1 폴리뉴클레오타이드를 포함하는 제1 AAV 입자 및 제2 폴리뉴클레오타이드를 포함하는 제2 AAV 입자를 투여하는 경우, 투여된 양은 입자 둘 다에 대해 동일하다.
본 발명은 또한 벡터 시스템 및 이를 함유하는 약제학적 조성물을 성숙한 청각 시스템을 갖고, DFNB9 청각장애를 앓는 환자, 특히 사람 환자에게 투여함을 포함하는 치료 방법에 관한 것이다. 상기 개시된 구현예 모두는 상기 치료 방법에 적용된다.
도 1은 이중 AAV-벡터 전달 후 HEK293 세포내에서의 오토페를린의 발현을 나타낸다.
A) 당해 연구에 사용된 재조합 AAV 벡터 쌍, 및 동시-감염된 세포에서 전체 길이의 단백질 오토페를린을 생산하는 재조합, 전사, 스플라이싱, 및 해독 공정의 개략도. 재조합 AAV-Otof NT 및 AAV-Otof CT 벡터는 오토페를린 cDNA의 5' 및 3' 부분을 각각 함유한다. 2개의 재조합 벡터 내에 존재한 재조합유전성 브릿징(bridging) 서열은 회색 구(sphere)로 나타낸다. 단배질 도해하의 적색 바아(red bar)는 오토페를린의 N-말단 및 C-말단 부분에 대해 항체를 생산하는데 사용된 2개의 펩타이드를 나타낸다. 약어: ITR, 역위된 말단 반복체; smCBA, 사이토메갈로바이러스 인터미디에이트 얼리(cytomegalovirus immediate early)/닭 β-액틴 키메라 프로모터; SA, 스플라이스 수용체 부위; SD, 스플라이스 공여체 부위; polyA, 폴리아데닐화 신호; C2, C2 도메인; TM, 막관통 도메인. B) HEK293 세포를 AAV-Otof NT 단독(상부 패널), AAV-Otof CT 단독(중간 패널), 또는 AAV-Otof NT 및 AAV-Otof CT를 함께(하부 패널)로 감염시켰다. 이들을 오토페를린(녹색)에 대해 단백질의 C-말단 부분에 대해 지시된 폴리클로날 항체로 48시간 후 오염시키고, 세포 핵을 DAPI(청색)로 표지하였다. 동시-감염된 세포 만이 오토페를린을 생산한다. 기준자(scale bar): 15 μm.
도 2는 P10 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법이 오토페를린 발현을 회복시키고 청각장애를 예방함을 나타낸다.
(a) 좌측 패널: P70(녹색)에서 오토페를린을 위해 면역염색된 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. IHC의 큰 부위는 오토페를린을 발현하나, 외부 모 세포(OHC)는 오토페를린을 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 사각형 부위의 보다 높은 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(ribeye)(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역(synaptic active zone)은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 좌측 패널: 이중 AAV 주사 4주 후, Otof -/- 마우스는 야생형 마우스의 것과 근접한 8 kHz, 16 kHz, 및 32 kHz(녹색 점, n = 8)의 주파수에서 클릭 또는 톤-버스트(tone-burst)에 대한 반응시 ABR 역치를 나타내었다(검은색 점, n = 8). 대조적으로, AAV-Otof NT(오렌지색 점, n = 3)를 제공받거나 주사되지 않은(청색 점, n = 6) Otof -/- 마우스는 86 dB SPL의 사운드 강도 수준까지 확인가능한 ABR 파동을 가지지 않았다. 우측 패널: P10에서 처리된 Otof -/- 마우스에서(화살표), 클릭 자극에 대한 청력 역치는 회복 후 적어도 6개월 동안 안정하였다. (c) 좌측 패널: 야생형 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스, Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 3주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(회색, n = 8) 및 야생형 마우스(흑색, n = 5)에서 ABR 파장 I의 잠복 및 표준화된 크기를 나타내는 막대 그래프.
도 3은 P17에서 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법은 오토페를린 발현 및 청력을 내구적으로 회복한다.
(a) 좌측 패널: P80에서 오토페를린(녹색)에 대해 면역염색된, 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. 대부분의 IHC는 오토페를린을 발현하나, 외부 모 세포(OHC)는 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 사각형 부위의 보다 큰 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 좌측 패널: 처리된 마우스에서 재조합 벡터 쌍의 달팽이관내 주사 4주 후 8 kHz, 16 kHz, 및 32 kHz의 주파수에서 클릭 또는 톤-버스트 자극에 대한 반응시 처리되지 않은 Otof -/- 마우스(청색, n=5), 처리된 Otof -/- 마우스(녹색, n=5), 및 야생형 마우스(검정색, n=5)의 ABR 역치. 우측 패널: P17에서 주사를 제공받은 Otof -/- 마우스의 청력 회복의 시간 과정(화살표), 거의 야생형 수준까지 청력 회복이 주사 후 적어도 20주 동안 유지되었다. (c) 좌측 패널: 야생형 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스(흑색), Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 2주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(회색, n = 5)에서 ABR 파장 I의 잠복이 야생형 마우스(n=5)에서와 유사하지만, 이의 표준화된 크기가 야생형 마우스의 약 1/2임을 나타내는 막대 그래프.
도 4는 P30에서 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법이 지속된 방식으로 오토페를린 발현 및 청력을 회복함을 나타낸다.
(a) 좌측 패널: P40에서 오토페를린(녹색)에 대해 면역염색된, 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. 대부분의 IHC는 오토페를린을 발현하나, 외부 모 세포(OHC)는 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 박스친 부위의 보다 큰 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(rebeye)(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 처리된 마우스에서 재조합 벡터 쌍의 달팽이관내 주사 후 3주(좌측 패널), 4주, 및 20주(우측 패널)째에, 8 kHz, 16 kHz, 및 32 kHz의 주파수에서 클릭 또는 톤-버스트 자극에 대한 반응시 처리되지 않은 Otof -/- 마우스(청색, n=3), 처리된 Otof -/- 마우스(녹색, n=3), 및 야생형 마우스(검정색, n=3)의 ABR 역치. 이러한 마우스에서 야생형 수준까지의 청력 회복이 주사 후 적어도 20주 동안 유지되었다. (c) 좌측 패널: 야생형 마우스 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스(흑색), Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 7주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(n = 3)에서 ABR 파장 I의 잠복이 야생형 마우스(n=3)에서와 유사하지만, 이의 표준화된 크기가 야생형 마우스의 약 1/2임을 나타내는 막대 그래프.
도 5는 Otof ts/ts 마우스에서 이중 AAV-매개된 유전자 치료요법이 오토페를린 정상 발현 및 청력을 회복시킴을 나타낸다. A) 오토페를린(녹색)에 대해 면역염색된, 야생형(Otof +/+ ) 마우스(좌측 패널), Otof ts/ts 마우스(중간 패널), 및 처리된 Otof ts/ts (우측 패널) 마우스로부터 중간-회전 달팽이관내 위치한 IHC(점선으로 윤곽을 나타냄)의 공초점 영상. 오토페를린은 비-처리된 Otof ts/ts 마우스에서 IHC 염기에서 비정상적인 응집을 나타내지만, 처리된 마우스의 IHC에서 이의 발현은 거의 정상이다. B) 야생형 마우스(검정색), Otof ts/ts 마우스(청색), 및 구조된 Otof ts/ts 마우스(녹색)에서, 치료제 주사 4주 후 기록된, ABR 파형은 야생형 및 구조된 마우스에서 유사한 파형을 나타내지만, ABR 파장은 치료되지 않은 돌연변이체에서 검출되지 않는다.
도 6에서 도해는 사람 및 마우스에스 청력 시스템의 차등적인 성숙을 개시하고 있다(Shnerson and Willott, J. Comp. Physiol. Psychol. 1980 Feb; 94(1):36-40).
도 7은 지금까지 확인된 DFNB9 유전자의 성숙의 일부를 기술한다. 이러한 성숙은 언어사용전 청각장애 DFNB9의 열성 형태의 기저가 된다.
도 8은 (A) Otof ts/ts 마우스의 내부 모 세포내 오토페를린의 단백질 응집 및 미스폴딩(misfolding) 및 (B) Otof +/ts , 및 Otof ts/ts 마우스에서 청각 뇌간 반응(ABR)을 나타낸다(또한 도 5 참고).
도 9는 Otof ts/ts 마우스에서 AAV-Otof NT 및 AAV-Otof CT 재조합 벡터 쌍의 단독 주사의 효과를 개시한다. 주사 5주 후, 3마리의 Otof ts/ts 마우스의 처리된 달팽이관의 감각 상피를 미세해부하고 오토페를린에 대해 면역표지하였다. 처리된 달팽이관의 IHC에서 오토페를린 발현을 측정하고 Otof ts/ts 처리되지 않은 마우스에서의 발현과 비교하였다(또한 도 5 참고).
도 10은 야생형, Otof ts/ts 및 Otof ts/ts 처리된 IHC에서 ICa(A) 및 상응하는 ΔCm 반응(B)의 전압-활성화 곡선을 개시한다. 세포막 커패시턴스(cell membrane capacitance)(ΔCm)에서의 변화를 사용하여 세포외유출 동안 시냅스 소낭의 융합을 모니터하였다.
A) 당해 연구에 사용된 재조합 AAV 벡터 쌍, 및 동시-감염된 세포에서 전체 길이의 단백질 오토페를린을 생산하는 재조합, 전사, 스플라이싱, 및 해독 공정의 개략도. 재조합 AAV-Otof NT 및 AAV-Otof CT 벡터는 오토페를린 cDNA의 5' 및 3' 부분을 각각 함유한다. 2개의 재조합 벡터 내에 존재한 재조합유전성 브릿징(bridging) 서열은 회색 구(sphere)로 나타낸다. 단배질 도해하의 적색 바아(red bar)는 오토페를린의 N-말단 및 C-말단 부분에 대해 항체를 생산하는데 사용된 2개의 펩타이드를 나타낸다. 약어: ITR, 역위된 말단 반복체; smCBA, 사이토메갈로바이러스 인터미디에이트 얼리(cytomegalovirus immediate early)/닭 β-액틴 키메라 프로모터; SA, 스플라이스 수용체 부위; SD, 스플라이스 공여체 부위; polyA, 폴리아데닐화 신호; C2, C2 도메인; TM, 막관통 도메인. B) HEK293 세포를 AAV-Otof NT 단독(상부 패널), AAV-Otof CT 단독(중간 패널), 또는 AAV-Otof NT 및 AAV-Otof CT를 함께(하부 패널)로 감염시켰다. 이들을 오토페를린(녹색)에 대해 단백질의 C-말단 부분에 대해 지시된 폴리클로날 항체로 48시간 후 오염시키고, 세포 핵을 DAPI(청색)로 표지하였다. 동시-감염된 세포 만이 오토페를린을 생산한다. 기준자(scale bar): 15 μm.
도 2는 P10 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법이 오토페를린 발현을 회복시키고 청각장애를 예방함을 나타낸다.
(a) 좌측 패널: P70(녹색)에서 오토페를린을 위해 면역염색된 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. IHC의 큰 부위는 오토페를린을 발현하나, 외부 모 세포(OHC)는 오토페를린을 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 사각형 부위의 보다 높은 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(ribeye)(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역(synaptic active zone)은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 좌측 패널: 이중 AAV 주사 4주 후, Otof -/- 마우스는 야생형 마우스의 것과 근접한 8 kHz, 16 kHz, 및 32 kHz(녹색 점, n = 8)의 주파수에서 클릭 또는 톤-버스트(tone-burst)에 대한 반응시 ABR 역치를 나타내었다(검은색 점, n = 8). 대조적으로, AAV-Otof NT(오렌지색 점, n = 3)를 제공받거나 주사되지 않은(청색 점, n = 6) Otof -/- 마우스는 86 dB SPL의 사운드 강도 수준까지 확인가능한 ABR 파동을 가지지 않았다. 우측 패널: P10에서 처리된 Otof -/- 마우스에서(화살표), 클릭 자극에 대한 청력 역치는 회복 후 적어도 6개월 동안 안정하였다. (c) 좌측 패널: 야생형 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스, Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 3주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(회색, n = 8) 및 야생형 마우스(흑색, n = 5)에서 ABR 파장 I의 잠복 및 표준화된 크기를 나타내는 막대 그래프.
도 3은 P17에서 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법은 오토페를린 발현 및 청력을 내구적으로 회복한다.
(a) 좌측 패널: P80에서 오토페를린(녹색)에 대해 면역염색된, 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. 대부분의 IHC는 오토페를린을 발현하나, 외부 모 세포(OHC)는 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 사각형 부위의 보다 큰 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 좌측 패널: 처리된 마우스에서 재조합 벡터 쌍의 달팽이관내 주사 4주 후 8 kHz, 16 kHz, 및 32 kHz의 주파수에서 클릭 또는 톤-버스트 자극에 대한 반응시 처리되지 않은 Otof -/- 마우스(청색, n=5), 처리된 Otof -/- 마우스(녹색, n=5), 및 야생형 마우스(검정색, n=5)의 ABR 역치. 우측 패널: P17에서 주사를 제공받은 Otof -/- 마우스의 청력 회복의 시간 과정(화살표), 거의 야생형 수준까지 청력 회복이 주사 후 적어도 20주 동안 유지되었다. (c) 좌측 패널: 야생형 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스(흑색), Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 2주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(회색, n = 5)에서 ABR 파장 I의 잠복이 야생형 마우스(n=5)에서와 유사하지만, 이의 표준화된 크기가 야생형 마우스의 약 1/2임을 나타내는 막대 그래프.
도 4는 P30에서 Otof -/- 마우스에서 이중 AAV-매개된 유전자 치료요법이 지속된 방식으로 오토페를린 발현 및 청력을 회복함을 나타낸다.
(a) 좌측 패널: P40에서 오토페를린(녹색)에 대해 면역염색된, 주사맞은 달팽이관의 중간 및 정점 회전의 모자이크 공초점 영상. 세포 핵을 DAPI(청색)로 염색한다. 대부분의 IHC는 오토페를린을 발현하나, 외부 모 세포(OHC)는 발현하지 않는다. 화살촉은 형질도입되지 않은 IHC를 나타낸다. 삽도: 박스친 부위의 보다 큰 확대. 기준자: 50 μm 및 10 μm(삽도). 우측 패널: 오토페를린(녹색), 리본 단백질 리베이(rebeye)(청색), 및 후-시냅스성 글루타메이트 수용체의 GluA2 소단위(적색)에 대해 동시-염색된 IHC의 영상. 시냅스 활성 구역은 오토페를린을 발현하는 형질도입된 IHC에서 정규 분포를 갖지만, 이들은 형질도입되지 않은 IHC(점선으로 나타냄)에서 클러스터(화살촉)를 형성하는 경향이 있다. 기준자: 5 μm. (b) 처리된 마우스에서 재조합 벡터 쌍의 달팽이관내 주사 후 3주(좌측 패널), 4주, 및 20주(우측 패널)째에, 8 kHz, 16 kHz, 및 32 kHz의 주파수에서 클릭 또는 톤-버스트 자극에 대한 반응시 처리되지 않은 Otof -/- 마우스(청색, n=3), 처리된 Otof -/- 마우스(녹색, n=3), 및 야생형 마우스(검정색, n=3)의 ABR 역치. 이러한 마우스에서 야생형 수준까지의 청력 회복이 주사 후 적어도 20주 동안 유지되었다. (c) 좌측 패널: 야생형 마우스 및 구조된 마우스에서 유사한 파형을 나타내는, 야생형 마우스(흑색), Otof -/- 마우스(Otof -/-), 및 구조된 Otof -/- 마우스(Otof -/- 주사됨)에서 치료제 주사 후 7주째에 기록한 ABR 추적. 우측 패널: 구조된 Otof -/- 마우스(n = 3)에서 ABR 파장 I의 잠복이 야생형 마우스(n=3)에서와 유사하지만, 이의 표준화된 크기가 야생형 마우스의 약 1/2임을 나타내는 막대 그래프.
도 5는 Otof ts/ts 마우스에서 이중 AAV-매개된 유전자 치료요법이 오토페를린 정상 발현 및 청력을 회복시킴을 나타낸다. A) 오토페를린(녹색)에 대해 면역염색된, 야생형(Otof +/+ ) 마우스(좌측 패널), Otof ts/ts 마우스(중간 패널), 및 처리된 Otof ts/ts (우측 패널) 마우스로부터 중간-회전 달팽이관내 위치한 IHC(점선으로 윤곽을 나타냄)의 공초점 영상. 오토페를린은 비-처리된 Otof ts/ts 마우스에서 IHC 염기에서 비정상적인 응집을 나타내지만, 처리된 마우스의 IHC에서 이의 발현은 거의 정상이다. B) 야생형 마우스(검정색), Otof ts/ts 마우스(청색), 및 구조된 Otof ts/ts 마우스(녹색)에서, 치료제 주사 4주 후 기록된, ABR 파형은 야생형 및 구조된 마우스에서 유사한 파형을 나타내지만, ABR 파장은 치료되지 않은 돌연변이체에서 검출되지 않는다.
도 6에서 도해는 사람 및 마우스에스 청력 시스템의 차등적인 성숙을 개시하고 있다(Shnerson and Willott, J. Comp. Physiol. Psychol. 1980 Feb; 94(1):36-40).
도 7은 지금까지 확인된 DFNB9 유전자의 성숙의 일부를 기술한다. 이러한 성숙은 언어사용전 청각장애 DFNB9의 열성 형태의 기저가 된다.
도 8은 (A) Otof ts/ts 마우스의 내부 모 세포내 오토페를린의 단백질 응집 및 미스폴딩(misfolding) 및 (B) Otof +/ts , 및 Otof ts/ts 마우스에서 청각 뇌간 반응(ABR)을 나타낸다(또한 도 5 참고).
도 9는 Otof ts/ts 마우스에서 AAV-Otof NT 및 AAV-Otof CT 재조합 벡터 쌍의 단독 주사의 효과를 개시한다. 주사 5주 후, 3마리의 Otof ts/ts 마우스의 처리된 달팽이관의 감각 상피를 미세해부하고 오토페를린에 대해 면역표지하였다. 처리된 달팽이관의 IHC에서 오토페를린 발현을 측정하고 Otof ts/ts 처리되지 않은 마우스에서의 발현과 비교하였다(또한 도 5 참고).
도 10은 야생형, Otof ts/ts 및 Otof ts/ts 처리된 IHC에서 ICa(A) 및 상응하는 ΔCm 반응(B)의 전압-활성화 곡선을 개시한다. 세포막 커패시턴스(cell membrane capacitance)(ΔCm)에서의 변화를 사용하여 세포외유출 동안 시냅스 소낭의 융합을 모니터하였다.
실시예
I. 물질 및 방법
동물
C57BL/6 균주(Roux I. et al, Cell, 127, 277-289 (2006)로 생산된 오토페를린 녹아웃(Otof -/-) 마우스를 10세대 이상 동안 FVB 마우스와 역교배하여, 처음 10개월의 생애에서 안정한 청력 역치와 관련된, C57BL/6 배경과는 달리, 당해 배경으로서 균질한 FVB 유전적 배경을 수득하였다(Kommareddi, P., et al. J Assoc Res Otolaryngol 16, 695-712 (2015)). 재조합 AAV2 벡터를 FVB 유전적 배경인 Otof -/- 마우스에 전달하였다. 모든 과정 및 동물 취급은 Institut National de la Sante et de la Recherche Medicale, 파스퇴르 연구소(Institut Pasteur), 및 NIH 복지 지침에 부합하였고, 샌프란시스코 소재의 캘리포니아대(University of California)에서 프로토콜 요건을 승인받았다. 수술 전에, 마우스에게 케타민 하이드로클로라이드(Ketaset, 100 mg/kg), 크살라진 하이드로클로라이드(Xyla-ject, 10 mg/kg), 및 아세프로마진(2 mg/kg)의 혼합물을 복강내 주사함으로써 마취시켰다. 마취의 깊이를 발가락 핀치(toe pinch)에 대한 심부 조직 반응을 모니터링함으로써 점검하였다. 수술 전 및 수술 후 24시간 마다 1주 동안, 마우스에게 카르프로펜(2 mg/kg)을 피하 주사로 공급하여 염증 및 통증을 경감시켰다. 동물을 수술 후 고통 및 비정상적인 체중 감소에 대해 모니터링하였다.
C2F 도메인 내에 열민감성 돌연변이를 수반하는 마우스 모델(Otof ts/ts ) (p.E1804del)을 생성시켰다. Otof ts/ts 마우스는 중증 청각 장애이다. 도 8에 나타낸 결과는 이러한 마우스의 IHC내 오토페를린의 분포가 비정상적으로/강하게 교란되어 있음을 강조한다. 더욱이, 청각 뇌간 반응(ABR)을 Otof +/ts , 및 Otof ts/ts 마우스 내에 기록하여 일차 청각 뉴우런의 전기 반응 및 클릭 자극에 대한 중심 청각 경로의 연속적인 뉴우런 릴레이(neuronal relay)를 모니터링하는 경우, 1개월령에서, ABR 특징적인 파형이 시험한 다양한 강도(40-86 dB)에서 Otof +/ts 마우스에 대해 관찰되지만, 심지어 100 dB에서도 Otof ts/ts 마우스에서는 반응이 나타나지 않음이 관찰된다.
재조합 AAV2 벡터 작제물 및 패키징
쥐 오토페를린 cDNA(Otof1 동형 1;NM_001100395.1)의 전체 길이의 암호화 서열을 5' 단편(뉴클레오타이드 1-2448) 및 3' 단편(뉴클레오타이드 2449-5979)으로 분할하고, 당해 단편을 합성하였다(Genscript, 뉴저지주 피스카타웨이 소재). 5" 작제물은 Otof1 cDNA(아미노산 1-816을 암호화함, 이는 단백질의 C2A, C2B, 및 C2C 도메인을 포함한다) 및 스플라이스 공여체(SD) 부위를 함유하였고, 3' 작제물은 Otof1 cDNA(아미노산 817- 1992를 암호화함, 이는 단백질의 C2D, C2E, C2F 및 막관통 도메인을 포함한다), 스플라이스 수용체 부위(SA)를 함유하였다. 또한, 작제물 둘 다는 알칼린 포스파타제 재조합유전성 브릿징 서열 서열을 함유한다[Lay Y et al, Hum Gene Ther 17, 1036-1042 (2006); Ghosh A. et al, Hum Gene Ther 22, 77-83 (2011); Dyka F.M. et al, Hum Gene Ther Methods 25, 166-177 (2014)]. NotI/NheI 및 MfeI/KpnI 제한 엔도뉴클레아제에 대한 인식 부위를 이러한 작제물에 가한 다음, AAV pTR22 벡터내로 앞서 기술한 바와 같이 삽입하여[Lay Y et al, Hum Gene Ther 17, 1036-1042 (2006); Ghosh A. et al, Hum Gene Ther 22, 77-83 (2011); Dyka F.M. et al, Hum Gene Ther Methods 25, 166-177 (2014)], AAV-Otof NT 및 AAV-Otof CT로 지칭된 재조합 벡터의 쌍을 생산하였다. 녹색 형광성 단백질(GFP) cDNA를 함유하는 추가의 재조합 벡터를 가공하여 세포 형질도입의 양성 대조군으로서 제공하였다. 재조합 벡터를 AAV2 quadY-F 캡시드내에 패키징하고(Petrs-Silva H. et al, Molecular therapy: the journal of the American Society of Gene Therapy 19, 293-301 (2011), 재조합 바이러스를 정제하고 플로리다대 눈 유전자 치료요법 코어(University of Florida Ocular Gene Therapy Core)에서 앞서 기술한 바와 같이 적정하였다[Zolotukhin S. et al, Methods 28, 158-167 (2002); Jacobson SG et al., Molecular therapy : the journal of the American Society of Gene Therapy 13, 1074-1084 (2006)].
형질감염된 HEK293 세포에서 이식유전자 발현
HEK293 세포를 6-웰 플레이트 속에서 폴리라이신-코팅된 커버슬립 상에서 1x 비-필수 아미노산 및 10% 소 태아 혈청(Gibco), 및 페니실린-스트렙토마이신(Pen/Strep, Invitrogen)이 보충된 둘베코 변형 이글 배지(Eagle's medium) 속에서 성장시켰다. 다음날, 세포를 앞서 기술한 바와 같이 감염시켰다(Lopes V.S. et al, Gene Ther 20, 824-833 (2013). 요약하면, 75% 합치(confluence)의 세포를 지닌 커버슬립을 AAV2-Otof 재조합 바이러스(10000개의 게놈-함유 입자/각각의 벡터용 세포) 중 하나 또는 둘 다를 함유하는 200 μl의 혈청-유리된 배지 속에서 37℃에서 4시간 동안 5% CO2와 함께 항온처리하였다. 2시간 후, 1 ml의 완전 배지를 가하였다. 다음날 배지를 교환하고, 세포를 추가로 48시간 동안 항온처리하였다. 세포를 0.1 M 인산염 완충된 염수(PBS), pH 7.4 중 4% 파라포름알데하이드로 4℃에서 2시간 동안 고정시키고, PBS로 3회 세정하고, PBS 중 0.25% 트리톤 X-100 및 5% 정상의 염소 혈청과 함께 실온에서 1시간 동안 항온처리하였다. 이후에, 세포를 앞서 특성화된 토끼 폴리클로날 항체인, 오토페를린의 N-말단 부분(아미노산 196-211) 및 C-말단 부분(아미노산 1848-1978) 각각(Roux I. et al, Cell, 127, 277-289 (2006)(희석 1:200)에 대해 지시된 14cc 및 C19와 함께 4℃에서 밤새 항온처리하였다. 샘플을 PBS로 2회 세척하고, PBS 중 Cy3-접합된 염소 항-토끼 IgG 2차 항체(Life Technologies, dilution 1:2000)와 함께 실온에서 2시간 동안 항온처리하였다. 이후에, 샘플을 PBS로 2회 세정하고, 4',6-디아미디노-2-페닐인돌(DAPI)로 염색하여 세포 핵을 가시화하고, Fluorsave 배지(Biochem Laboratories, 프랑스) 1방울이 있는 유리 슬라이드 위에 놓고 Olympus 공초점 면역형광 현미경(confocal immunofluorescence microscope)으로 관찰하였다.
달팽이관으로 벡터 전달
바이러스를 앞서 기술한 바와 같이 좌측 달팽이관으로 전달하였다(Akil O. et al, Neuron 75, 283-293 (2012)). P10, P17, 또는 P30에서 마취된 Otof -/- 마우스에게 AAV2-Otof 벡터 쌍의 주사를 둥근 창 막을 통해 달팽이관의 고실계내로 제공하였다. 귀를 등쪽 절개(dorsal incision)를 통해 접근하였다(Duan M et al, Gene Ther 11 Suppl 1, S51-56 (2004). 18G 침(needle)을 사용하여 수포(bullar)에 작은 구멍을 만들고 핀셋으로 확장시켰다. 둥근 창 막을 붕규산 모세관 유리 피펫으로 부드럽게 구멍을 내고, 이를 이후 제거하였다. 외림프 유출이 중단되면, AAV2-Otof NT(6.3 x 1012 vg/ml) 및 AAV2-Otof CT(4.5 x 1012 vg/ml) 벡터 쌍을 함유하는 고정된 용적(2 μl)을 미세 유리 마이크로피펫(10 μm의 외부 팁 직경)을 사용하여 고실계내로 1분의 기간에 걸쳐 주사하였다. 피펫을 빼내고, 틈새를 근막과 지방 조직으로 신속하게 밀봉하였다. 상처를 6-0 흡수가능한 크롬 봉합사(Ethicon)를 사용하여 층으로 봉합하였다.
청각 시험
청각 시험을 마취된 Otof +/+ 마우스, Otof -/- 마우스, 및 구조된 Otof -/- 마우스에서 상이한 시점에, 방음실(sound-proof chamber)에서, 앞서 기술한 바와 같이 수행하였다(Akil O. et al, Neuron 75, 283-293 (2012). 마우스를 케타민 하이드로클로라이드(Ketaset, 100 mg/ml) 및 크실라진 하이드로클로라이드(Xyla-ject, 10 mg/ml)의 혼합물의 복강내 주사와, 필요한 경우 초기 용량의 1/5의 후속적인 주사로 마취시켰다. 체온을 가열 패드로 유지시키고 기록 전체에서 직장 프로브(rectal probe)로 모니터링하였다. 청각 뇌간 반응(ABR)을 TDT BioSig III 시스템(Tucker Davis Technologies)에서 기록하고 3개의 피하 침 전극을 마우스 두피에 위치시켰다: 하나는 정점에, 하나는 좌측 귀의 귓바퀴 아래에(참고 전극), 및 하나는 반대쪽 귀 아래에(접지 전극). 소리 자극은 클릭(5 ms 기간, 31 Hz) 및 8, 16, 및 32 kHz에서 톤 핍(tone pip)(10 ms 기간, 코사인 제곱 성형(cosine squared shaping), 21 Hz)이었다. 이를 좌측 귀로부터 기록하는 단청 반응 기록(우측 귀는 기록 동안 차단하였다)과 함께 자유-장 조건(free-field condition)에서 전달하였다. 각각의 소리 자극에 대해, 뇌파계(electroencephalographic)(EEG) 활성을 20 ms 동안 25 kHz의 샘플링 속도에서, 필터링(0.3-3 kHz)과 함께 기록하였다. 512개 자극 및 1000개 자극에 대한 EEG 파형을 클린 및 톤 버스트(tone burst) 각각의 범위에 대해 평균내었다. 소리 자극 강도는 시험된 최대 강도(86 dB SPL)로부터 5 dB 음압 수준(sound pressure level)(SPL) 간격으로 감소하였다. 청력 역치는 파장 I-V에 대한 ABR 피크가 명확하고 가시적 관측시 반복적으로 나타나는 최저 자극 수준으로 정의하였다. 이러한 역치 평가는 저장된 파형의 오프라인 분석으로 확인하였다. ABR 파장 I의 잠복기를 클릭 자극과 파장 I의 피크 진폭 사이의 시간 간격으로 측정하였다. 또한, 구조된 Otof-/- 마우스와 야생형 마우스 사이의 비교를 위해 ABR 트레이스의 파장 I 피크 강도의 값을 대조군 야생형 마우스(100%로서 취함)에서 평균 값에 대해 표준화하였다.
내부 모 세포 및 시냅스 리본 수(synaptic ribbon count)
마우스 달팽이관에 0.1 M PBS(pH 7.4) 중 4% 파라포름알데하이드를 주입하고 동일한 고정액 속에서 4℃로 2시간 동안 항온처리하였다. 달팽이관을 PBS로 3회 세척하고, 0.1M PBS 중 5% 에틸렌디아민 테트라-아세트산(EDTA)과 함께 4℃에서 2시간 동안 항온처리하여 석회질을 제거하였다. 달팽이관 감각 상피(코르티(Corti)의 기관)을 표면 제제로 미세절개하여, PBS(차단 완충액) 중 0.25% 트리톤 X-100 및 5% 정상 염소 혈청과 함께 실온에서 1시간 동안 항온처리하고, 일차 항체와 함께 4℃에서 밤새 항온처리하였다. 다음의 항체를 사용하였다: 토끼 항오토페를린 C-말단 부분(C19, 1:250 희석) 1, 마우스(IgG1) 항-CtBP2/리베이, 마우스(IgG2a) 항-글루타메이트 수용체 소단위 A2(Millipore, 1:200 희석), 및 토끼 항-GFP(Invitrogen, A11122; 1:250 희석). 샘플을 PBS 속에서 3회 세정하고, 적절한 제2 항체: Alexa Fluor 488-접합된 항-마우스 IgG1, Alexa Fluor 568-접합된 항-마우스 IgG2a(Life Technologies, 1:1000 희석), 또는 Atto Fluor 647-접합된 항-토끼 IgG(Sigma, 1:200 희석)과 함께 항온처리하였다. 샘플을 PBS 속에서 3회 세척하고, 유리 슬라이드 위의 Fluorsave 1방울 속에, DAPI와 함께 두어, 세포 핵을 염색하였다. 코르티의 기관의 형광성 공초점 z-스택(fluorescence confocal z-stack)을 고-해상도 대물렌즈(1.4의 개구수(numerical aperture), 60 x 오일-침지 대물렌즈)가 장착된 LSM 700 공초점 현미경(Zeiss, 독일 오베르코첸 소재)을 사용하여 수득하였다. 영상을 512 × 512 또는 1024 × 1024 래스터(raster)(픽셀 크기 = x 및 y 축으로 0.036 μm)에서 0.2 μm z 단계로 획득하였다. 오르페를린 및 시냅스 리본을 생산하는 내부 모 세포(IHC)를 20개 이하의 공초점 영상의 z-스택의 3D 렌더링(rendering)으로 계수하였다. 오토페를린 이식유전자를 발현하는 IHC의 비율을 계산하기 위하여, 본 발명자는 오토페를린을 생산하는 IHC의 총 수를 이의 DAPI-염색된 세포 핵으로 확인된 IHC의 총 수로 나누었다(최소 150개의 연속 분석).
리버스 트랜스크립타제-폴리머라제 쇄 반응(RT-PCR)
총 mRNA를 P10에서 구조한 6마리의 Otof +/+ 마우스 및 6마리의 0tof -/- 마우스의 좌측 달팽이관으로부터 추출(트리아졸, Invitrogen)하였다. 역 전사(RT)를 oligodT 프라이머 및 superscript II RNase H-(Invitrogen)를 사용하여 42℃에서 50분 동안 수행하였다. 2 마이크로리터의 RT 반응 생성물을 35 주기(94℃에서 30초, 60℃에서 45초, 72℃에서 60초)와 72℃에서 10분의 최종 연장으로 이루어진 폴리머라제 쇄 반응(PCR; Taq DNA 폴리머라제, Invitrogen)에 대해 사용하였다. PCR 프라이머 쌍(전방향 프라이머 TGTCTCAGAGCTCCGAGGCA(서열 번호: 14) 및 역방향 프라이머 ATCGTGGAGGAGGAACTGGGCA(서열 번호: 15)를 설계하여 AAV-Otof NT와 AAV-Otof CT 삽입체 사이에 연결부를 포함하는 오토페를린 cDNA (GenBank 수탁 번호 NM_001100395.1)의 2676 bp의 중간 단편(intermediate fragment)(뉴클레오타이드 27 내지 2702)을 증폭시켰다. PCR 생성물을 0.5 mg/ml 에티디움 브로마이드(Qiaquick 겔 추출 키트, QIAGEN)를 함유하는 2% 아가로즈 겔 상에서 전기영동으로 정제하고, 서열분석하고(Elim Biopharmaceuticals), 오토페를린 cDNA 서열에 대한 서열 동일성에 대해 점검하였다.
통계적 분석
데이타는 평균 ± 표준 편차(SD)로 나타낸다. 모든 통계적 분석을 비-매개변수 만-휘트니 U 시험(Mann-Whitney U test)으로 수행하였다. 통계적 유의성은 다음과 같이 도에 나타낸다: n.s., 유의적이지 않음; *, p < 0.05; **, p < 0.01; ***, p < 0.001.
II. 결과
AAV2-기반 벡터를 가공하여 키메라 CMV-닭 β-액틴 프로모터의 제어 하에 녹색 형광성 단백질(gfp) 유전자를 발현시켰다. 당해 발현 카세트를 AAV2 quadY-F 캡시드 내에 패키징하였으며 여기서 AAV2 캡시드의 4개의 표면 타이로신(Y) 잔기를 페닐알라닌(F) 잔기로 대체시키고, 이는 망막내 유전자 전달의 효능을 증가시키는 것으로 밝혀졌다(Petrs-Silva H. et al, Molecular therapy : the journal of the American Society of Gene Therapy 19(2):293-301 (2011)). P2에 재조합 바이러스를 둥근 창 막을 통해 5마리의 야생형 마우스의 좌측 달팽이관내로 주사하였다. 주사 3주 후 감각 상피의 GFP 면역 염색은 IHC를 포함하는 다양한 세포 유형의 형질도입을 나타내었다. IHC에 대한 형질도입률은 78 ± 6%(평균 ± SD)이었으며, 이는 치료학적 유전자를 이러한 세포로 전달하는 당해 AAV 혈청형의 적합성을 입증한다(나타내지 않음). 쥐 오토페를린 cDNA의 암호화 서열을 5' 단편(Otof NT, 뉴클레오타이드 1-2448) 및 3' 단편(Otof CT, 뉴클레오타이드 2449-5979)으로 분할하고, 이들 각각을 재조합유전성 브릿징 서열을 수반하는 AAV 벡터내로 삽입하였다(Ghosh A. et al, Hum Gene Ther 22(1):77-83 (2011); Dyka FM et al, Hum Gene Ther Methods 25(2):166-177 (2014)). AAV-Otof NT 재조합 벡터는 cDNA의 5' 부분에 이어 스플라이스 공여체 부위를 수반하며, AAV-Otof CT 재조합 벡터는 스플라이스 수용체 부위에 이어서 cDNA의 3' 부분을 수반한다(참고: 방법 및 도 1). 이러한 재조합 벡터 각각을 AAV2 quadY-F 캡시드내로 패키징하였다. HEK293 세포를 AAV-Otof NT, AAV Otof CT, 또는 재조합 바이러스 둘 다로 감염시키고, 48시간 후에 오토페를린 48에 대해 면역염색하였다. 2개의 상이한 항체를 사용하여, 단백질의 C-말단 부분 또는 N-말단 부분에 대해 지시하고(Roux I, et al, Cell 127:277-289 (2006)), 동일한 결과를 수득하였다. 오토페를린은 바이러스 둘 다로 동시 감염된 세포내에서만 검출되었으므로, 2개의 벡터가 재조합하여 이의 역위된 말단 반복체를 통해, 단백질을 생성하기 위한 수득되는 전사체의 정확한 스플라이싱과 함께 콘카타머(concatemer)를 생성할 수 있음을 나타낸다(도 1).
AAV-Otof NT 및 AAV-Otof CT 재조합 벡터 쌍의 단일 단독 주사를 청력 발병(hearing onset) 전(P10) 또는 후에, 둥근 창 막을 통해 좌측 달팽이관내로 Otof -/- 마우스에게 투여하였다. IHC 리본 시냅스의 성숙은 여전히 P17에 진행중이지만, 달팽이관은 P30에 성숙(Song L. et al, J Acoust Soc Am 119(4):2242-2257 (2006))되므로, 청력 발병 후 주사를 2개의 상이한 시점, P17 및 P30 중 하나에서 수행하였다(Kros CJ et al, Nature 394(6690):281-284 (1998); Wong AB et al, EMBO J 33(3):247-264 (2014)). P10에 재조합 벡터 쌍의 주사 후 8주째에, 3마리의 Otof -/- 마우스의 처리된 달팽이관의 감각 상피를 미세절개하고 오토페를린에 대해 면역표지하여(단백질의 C-말단에 대해 지시된 항체 사용) IHC 형질도입률을 평가하였다. 단백질은 IHC의 60% 이상(64 ± 6%, 평균 ± SD, n = 3개의 달팽이관)에서 검출되었지만, 다른 세포형에서는 검출되지 않았다(도 2a, 좌측 패널). 이러한 결과는 생체내에서 재조합 AAV-벡터 쌍의 국소 전달시, 세포의 많은 부분에 의한 단백질의 지속적이고, 광범위한 생산과 함께, 큰 cDNA가 달팽이관 감각 세포내에서 효과적으로 재구성될 수 있다는 증거를 제공한다. 형질도입된 세포내에서 전-mRNA 스플라이싱 공정의 정확도는 RT-PCR로 점검하고 Otof NT와 Otof CT cDNA 사이의 연결부(나타내지 않음)를 포함하는 오토페를린 전사체의 큰 단편의 분석을 이루었다.
p10 주사 후 4주째에 마우스에서 청각 뇌간 반응(ABR) 기록은 모든 처리된 마우스(n=8)에서 클릭 및 톤-버스트 자극(8, 16, 및 32 kHz)에 대한 반응시 청력 역치가 실질적으로 회복하였지만, AAV-Otof NT 또는 AAV-Otof CT 단독을 제공받은 Otof -/- 마우스(n = 각각 3), 또는 주사맞지 않은 마우스(n = 6)에서 회복하지 않았음을 입증하였다(도 2b,2c). 처리된 마우스에서 클릭 및 톤-버스트 자극에 대한 ABR 역치는 대조군 야생형 마우스(n = 8; 만-휘트니 U 시험(Mann-Whitney U test), 모든 비교에 대해 p >0.15)의 것과는 유의적으로 상이하지 않았다. 유전자 치료요법의 장기간 효능은 1 내지 30주 사이에 수회의 주사 후 시점에서 클릭에 대한 반응시 ABR 기록을 수행함으로써 평가하였다. 4주째부터, 처리된 마우스의 ABR 역치는 야생형 마우스의 것과 유의적으로 상이하지 않았다(만-휘트니 U 시험, 모든 단계에서 비교를 위한 p > 0.05)(도 2b). 그러나, 소리 자극에 대한 일차 청각 뉴우런의 전기적 반응을 반형하는, ABR I 파의 진폭은 야생형 마우스에 대한 평균 값의 39 ± 7%(평균 ± SD)인 반면(만-휘트니 U 시험, p = 0.002), I파 잠복성(1.15 ± 0.09 ms)은 야생형 마우스의 것과 유사하였다(1.27 ± 0.05 ms; 만-휘트니 U 시험, p = 0.06)(도 2c).
주사 30주 후, p10에서 주사를 제공받은 8마리 마우스 중 6마리가 야생형 마우스의 것의 10 dB 이내인 청력 역치를 가졌다. 따라서, 청력 발병 전 유전자 치료요법은 Otof -/- 마우스에서 청각장애를 예방한다. 본 발명자는 IHC 리본의 약 1/2이 Otof -/- 마우스에서 악화됨을 이미 밝혔다(Roux I, et al, Cell 127:277-289 (2006)). 전시냅스 리본(후시냅스 글루타메이트 수용체와 함께)의 수를 면역형광성 및 3D 공초점 현미경 영상화(도 2a, 우측 패널)에 의해, P10에서 주사 후 8주째에 처리된 IHC 및 처리된 Otof -/- 달팽이관의 비형질도입된 IHC에서 분석하였다(도 2a, 우측 패널). 형질도입된 세포에서 IHC 당 리본의 수(12.5 ± 1.8, 평균 ± SD, n = 3마리의 마우스로부터 48개 세포)는 형질도입되지 않은 세포에서 보다 거의 2배 더 높았지만(6.9 ± 1.3, n = 3마리의 마우스로부터 48개의 세포; 만-휘트니 U 시험, p < 10-4), 야생형 IHC에서보다 더 낮게 남았고(16 ± 1.3, n = 3마리의 마우스로부터 48개 세포; 만-휘트니 U 시험, p < 10-4), 이는 ABR 기록에서 I파 진폭의 불완전한 회복을 잠재적으로 설명한다.
P17 또는 P30 Otof -/- 마우스의 달팽이관내로 재조합 벡터 쌍의 주사 후, 오토페를린은 처리된 달팽이관 전체에서 IHC에서 검출되었지만, 반대쪽 달팽이관의 IHC에서는 검출되지 않았다(나타내지 않음). IHC 형질도입률은 마우스의 2개 그룹에서 유사하였고(P17 및 P30 각각에 처리된 n = 5 및 n = 3의 달팽이관에 대해 82 ± 9% 및 85 ± 7%), P10에 주사를 제공받은 마우스에서의 것보다 더 높았다(만-휘트니 U 시험, 비교 둘 다에 대한 p < 0.05)(도 3a 및 4a). 주사 4주 후 ABR 기록은 P17에 주사를 제공받은 마우스 모두(n=5)에서 청력 회복을 나타내었고, 클릭 또는 톤-버스트 자극에 대한 반응시 ABR 역치는 야생형 마우스에서의 것과 현저히 유사하였음(n = 5; 만-휘트니 U 시험, 모든 비교에 대해 p > 0.2)을 나타내었다. 클릭에 대한 반응시 청력 역치는 주사 후 20주 동안 변하지 않고 유지되었으며, 이는 야행셩 마우스에서의 것의 약 1/2(47 ± 10%)인 평균 ABR I파 진폭에도 불구하고 이러한 마우스에서 청력의 지속적인 회복을 입증하였다(도 3b,c).
유사하게, p30에 주사를 제공받은 Otof-/- 마우스는 주사 후 3주와 같이 조기에 청력의 유사한 회복을 나타내었고, 클릭 또는 톤-버스트 자극에 대한 반응시 ABR 역치는 야생형 마우스에서의 것의 약 1/2(55 ± 10%)인 ABR I파 진폭에도 불구하고, 주사 후 20주 동안 야생형 수준에서 지속되었다(n = 3, 만-휘트니 U 시험, 모든 단게에서 비교에 대해 p > 0.5). 전시냅스 리본(후시냅스 글루타메이트 수용체와 함께)의 수를 면역형광성 및 3D 공초접 현미경 영상화에 의해, P17 및 P30에서 처리된 Otof -/- 달팽이관의 형질도입된 IHC 및 형질도입되지 않는 IHC에서 분석하였다(도 3a 및 4a). 형질도입된 세포에서 IHC당 리본의 수(10.0 ± 1.3, 평균 ± SD, P17에서 처리되고 P80에서 분석된 3마리의 마우스로부터 n = 48개 세포, 및 8.9 ± 2.3, p30에서 처리되고 P40에서 분석된 3마리의 마우스로부터 n = 48개 세포)는 동일한 달팽이관으로부터의 비-형질도입된 세포보다 더 높았지만(각각 6.2 ± 1.3, n = 48개 세포, 및 5.8 ± 0.7, n = 48개 세포; 만-휘트니 U 시험, 비교 둘 다에 대해 p < 10-4), 이들은 10주령의 야생형 마우스의 IHC에서보다 더 낮았다(16 ± 1.3, 3마리의 마우스로부터 n = 48개 세포; 만-휘트니 U 시험, 비교 둘 다에 대해 p < 10-4). IHC당 리본의 수는 P15에 분석된 처리되지 않은 Otof -/- 마우스에서 이미 현저히 감소하였고(8.2 ± 1.0, 3마리의 마우스로부터 n = 48개 세포), 이후 단계에서 처리된 마우스의 형질도입되지 않은 IHC에서 예측불가능하게 안정하게 유지되었고(상기 P40, P70, 및 P80의 값 참고), Otof -/- 마우스의 IHC에서 유전자 치료요법은 이의 변성을 방지하기보다는 이의 생산을 촉진함으로써 리본의 수를 증가시켰음이 유추될 수 있다.
동물에서 p30에 투여된, 상기 개시된 이중 AAV 유전자 치료요법을 사용하여, 오토페를린의 정상 분포 및 이의 DFNB9 유전자에서 사람 열민감성 돌연변이를 수반하는 거의 정상의 ABR 역치까지 청력 기능 둘 다를 회복시키는 것이 또한 가능하였다(Otof ts/ts 마우스, 도 5).
보다 상세하게는, 이중 바이러스 유전자 치료요법이 상기 DFNB9 마우스 모델에서 사람 열민감성 돌연변이로 인하여 오토페를린 응집체를 덮어쓰는 것으로 밝혀졌다(도 9). 본 실험에서, 청력 발병이 p30에서 수행된 후, AAV-Otof NT 및 AAV-Otof CT 재조합 벡터 쌍을 둥근창 막을 통해 좌측 달팽이관내로 Otofts/ts 마우스에 단일 일방적으로 투여하였다. 주사 5주 후, 3마리의 Otof ts/ts 마우스의 처리된 달팽이관의 감각 상피를 미세절개하고 오토페를린에 대해 면역표지하였다(참고: 도 9). 처리된 달팽이관의 IHC(점선)에서 오토페를린 발현은 Otof ts/ts 마우스(화살표)의 처리되지 않은 달팽이관내 오토페를린 응집체와 비교하는 경우 거의 정상인 것으로 밝혀졌다.
상기 이중 바이러스 유전자 치료요법은, 도 10에 나타낸 바와 같이, 당해 동물 모델에서 IHC의 칼슘 전류 및 세포외유출을 회복시키는 것으로 궁극적으로 밝혀졌다.
SEQUENCE LISTING
<110> INSTITUT PASTEUR
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)
INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)
<120> AAV-MEDIATED GENE THERAPY RESTORING THE OTOFERLIN GENE
<130> IP20214020FR
<150> EP19305071.3
<151> 2019-01-18
<160> 24
<170> KopatentIn 2.0
<210> 1
<211> 1997
<212> PRT
<213> homo sapiens
<400> 1
Met Ala Leu Leu Ile His Leu Lys Thr Val Ser Glu Leu Arg Gly Arg
1 5 10 15
Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser
20 25 30
Arg Val Leu Glu Asn Cys Glu Asp Val Ala Asp Phe Asp Glu Thr Phe
35 40 45
Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Met Leu Glu Ile
50 55 60
Gln Val Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr
65 70 75 80
Phe Arg Met Val Leu Gln Lys Val Val Glu Glu Ser His Val Glu Val
85 90 95
Thr Asp Thr Leu Ile Asp Asp Asn Asn Ala Ile Ile Lys Thr Ser Leu
100 105 110
Cys Val Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Ser Trp
115 120 125
Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Glu Lys
130 135 140
Asp Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Ser
145 150 155 160
Arg Pro Pro Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe
165 170 175
Ser Ala Met Lys Leu Gly Lys Asn Arg Ser His Lys Glu Glu Pro Gln
180 185 190
Arg Pro Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu
195 200 205
Ala Ile Arg Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala
210 215 220
Ser Val Thr Ala Leu Thr Thr Asn Val Ser Asn Lys Arg Ser Lys Pro
225 230 235 240
Asp Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val
245 250 255
Ser Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp
260 265 270
Pro Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met
275 280 285
Lys Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp
290 295 300
Phe His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser
305 310 315 320
Val Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser
325 330 335
Phe Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe
340 345 350
His His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ser Gly
355 360 365
Leu Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp
370 375 380
Asn Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile
385 390 395 400
Glu Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp
405 410 415
Ala Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met
420 425 430
Asn Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn
435 440 445
Lys Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys
450 455 460
Gly Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu
465 470 475 480
Gln Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys
485 490 495
Val Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr
500 505 510
His Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe
515 520 525
Leu Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg
530 535 540
Asn Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly
545 550 555 560
Glu Gly Val Ser Phe Arg Ala Arg Leu Leu Leu Gly Leu Ala Val Glu
565 570 575
Ile Val Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln
580 585 590
Val Glu Gln Ala Thr Pro Ile Ser Glu Ser Cys Ala Gly Lys Met Glu
595 600 605
Glu Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg
610 615 620
Arg Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr
625 630 635 640
Gly Asn Glu Val Asp Gly Leu Ser Arg Pro Gln Arg Pro Arg Pro Arg
645 650 655
Lys Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ala Ser
660 665 670
Asp Asp Glu Ala Gly Asp Ala Gly Asp Leu Ala Ser Val Ser Ser Thr
675 680 685
Pro Pro Met Arg Pro Gln Val Thr Asp Arg Asn Tyr Phe His Leu Pro
690 695 700
Tyr Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp
705 710 715 720
Gln Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp
725 730 735
Lys Leu Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu
740 745 750
Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser
755 760 765
Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His
770 775 780
Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg
785 790 795 800
Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val
805 810 815
Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu
820 825 830
Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp
835 840 845
Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg
850 855 860
Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly
865 870 875 880
Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys
885 890 895
Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu
900 905 910
Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly
915 920 925
Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu
930 935 940
His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe
945 950 955 960
Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp
965 970 975
Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln
980 985 990
Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp
995 1000 1005
Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His
1010 1015 1020
Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp
1025 1030 1035
Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala
1040 1045 1050
Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg
1055 1060 1065
Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala
1070 1075 1080
Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly
1085 1090 1095
Pro Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp
1100 1105 1110
Val Asp Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro
1115 1120 1125
Val Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg
1130 1135 1140
Asp Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val
1145 1150 1155
Asp Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His
1160 1165 1170
Asn Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe
1175 1180 1185
Glu Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn
1190 1195 1200
Ile Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val
1205 1210 1215
Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro
1220 1225 1230
Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu
1235 1240 1245
Arg Arg Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser
1250 1255 1260
Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys
1265 1270 1275
Lys Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val
1280 1285 1290
Val Lys Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys
1295 1300 1305
Lys Lys Gly Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu
1310 1315 1320
Ser Met Leu Asp Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr
1325 1330 1335
Met Lys Glu Gln Leu Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu
1340 1345 1350
Glu Glu Lys Glu Glu Val Asp Asn Thr Glu Gly Leu Lys Gly Ser
1355 1360 1365
Met Lys Gly Lys Glu Lys Ala Arg Ala Ala Lys Glu Glu Lys Lys
1370 1375 1380
Lys Lys Thr Gln Ser Ser Gly Ser Gly Gln Gly Ser Glu Ala Pro
1385 1390 1395
Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys
1400 1405 1410
Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu Asp Trp Leu His Thr
1415 1420 1425
Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser
1430 1435 1440
Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys
1445 1450 1455
Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly
1460 1465 1470
Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp
1475 1480 1485
Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp
1490 1495 1500
Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala
1505 1510 1515
Ile Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile
1520 1525 1530
Ser Lys Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu
1535 1540 1545
Ala Ser Phe Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp
1550 1555 1560
Trp Asp Leu Val Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile
1565 1570 1575
Asp Leu Glu Asn Arg Phe Tyr Ser Lys His Arg Ala Thr Cys Gly
1580 1585 1590
Ile Ala Gln Thr Tyr Ser Thr His Gly Tyr Asn Ile Trp Arg Asp
1595 1600 1605
Pro Met Lys Pro Ser Gln Ile Leu Thr Arg Leu Cys Lys Asp Gly
1610 1615 1620
Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly Arg Val Lys Val
1625 1630 1635
Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn
1640 1645 1650
Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Leu Ala Leu
1655 1660 1665
Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val Pro
1670 1675 1680
Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly
1685 1690 1695
Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met
1700 1705 1710
Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys
1715 1720 1725
Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu
1730 1735 1740
Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser
1745 1750 1755
Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys
1760 1765 1770
Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn
1775 1780 1785
Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu
1790 1795 1800
Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp
1805 1810 1815
Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp
1820 1825 1830
Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu
1835 1840 1845
Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln
1850 1855 1860
Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val
1865 1870 1875
Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu
1880 1885 1890
Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu
1895 1900 1905
Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro
1910 1915 1920
Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn
1925 1930 1935
Arg Pro Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser
1940 1945 1950
Ala Arg Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys
1955 1960 1965
Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Ala Leu Phe Leu
1970 1975 1980
Tyr Ser Val Pro Gly Tyr Leu Val Lys Lys Ile Leu Gly Ala
1985 1990 1995
<210> 2
<211> 7171
<212> DNA
<213> homo sapiens
<400> 2
atcggagggg ggtcgggagg aggaggagga ggcagcggca gagaagagag aggcgtgtga 60
gccgtgctcc accggctagc tccttcccgc tgctcctgcc tggcagtgcc aggcagccca 120
caccagcatg gccttgctca tccacctcaa gacagtctcg gagctgcggg gcaggggcga 180
ccggatcgcc aaagtgactt tccgagggca atccttctac tctcgggtcc tggagaactg 240
tgaggatgtg gctgactttg atgagacatt tcggtggccg gtggccagca gcatcgacag 300
aaatgagatg ctggagattc aggttttcaa ctacagcaaa gtcttcagca acaagctcat 360
cgggaccttc cgcatggtgc tgcagaaggt ggtagaggag agccatgtgg aggtgactga 420
cacgctgatt gatgacaaca atgctatcat caagaccagc ctgtgcgtgg aggtccggta 480
tcaggccact gacggcacag tgggctcctg ggacgatggg gacttcctgg gagatgagtc 540
tcttcaagag gaagagaagg acagccaaga gacggatgga ctgctcccag gctcccggcc 600
cagctcccgg cccccaggag agaagagctt ccggagagcc gggaggagcg tgttctccgc 660
catgaagctc ggcaaaaacc ggtctcacaa ggaggagccc caaagaccag atgaaccggc 720
ggtgctggag atggaagacc ttgaccatct ggccattcgg ctaggagatg gactggatcc 780
cgactcggtg tctctagcct cagtcacagc tctcaccact aatgtctcca acaagcgatc 840
taagccagac attaagatgg agccaagtgc tgggcggccc atggattacc aggtcagcat 900
cacggtgatc gaggcccggc agctggtggg cttgaacatg gaccctgtgg tgtgcgtgga 960
ggtgggtgac gacaagaagt acacatccat gaaggagtcc actaactgcc cctattacaa 1020
cgagtacttc gtcttcgact tccatgtctc tccggatgtc atgtttgaca agatcatcaa 1080
gatttcggtg attcactcca agaacctgct gcgcagtggc accctggtgg gctccttcaa 1140
aatggacgtg ggaaccgtgt actcgcagcc agagcaccag ttccatcaca agtgggccat 1200
cctgtctgac cccgatgaca tctcctcggg gctgaagggc tacgtgaagt gtgacgttgc 1260
cgtggtgggc aaaggggaca acatcaagac gccccacaag gccaatgaga ccgacgaaga 1320
tgacattgag gggaacttgc tgctccccga gggggtgccc cccgaacgcc agtgggcccg 1380
gttctatgtg aaaatttacc gagcagaggg gctgccccgt atgaacacaa gcctcatggc 1440
caatgtaaag aaggctttca tcggtgaaaa caaggacctc gtggacccct acgtgcaagt 1500
cttctttgct ggccagaagg gcaagacttc agtgcagaag agcagctatg agcccctgtg 1560
gaatgagcag gtcgtcttta cagacctctt ccccccactc tgcaaacgca tgaaggtgca 1620
gatccgagac tcggacaagg tcaacgacgt ggccatcggc acccacttca ttgacctgcg 1680
caagatttct aatgacggag acaaaggctt cctgcccaca ctgggcccag cctgggtgaa 1740
catgtacggc tccacacgta actacacgct gctggatgag catcaggacc tgaacgaggg 1800
cctgggggag ggtgtgtcct tccgggcccg gctcctgctg ggcctggctg tggagatcgt 1860
agacacctcc aaccctgagc tcaccagctc cacagaggtg caggtggagc aggccacgcc 1920
catctcggag agctgtgcag gtaaaatgga agaattcttt ctctttggag ccttcctgga 1980
ggcctcaatg atcgaccgga gaaacggaga caagcccatc acctttgagg tcaccatagg 2040
caactatggg aacgaagttg atggcctgtc ccggccccag cggcctcggc cccggaagga 2100
gccgggggat gaggaagaag tagacctgat tcagaacgca agtgatgacg aggccggtga 2160
tgccggggac ctggcctcag tctcctccac tccaccaatg cggccccagg tcaccgacag 2220
gaactacttc catctgccct acctggagcg aaagccctgc atctacatca agagctggtg 2280
gccggaccag cgccgccgcc tctacaatgc caacatcatg gaccacattg ccgacaagct 2340
ggaagaaggc ctgaacgaca tacaggagat gatcaaaacg gagaagtcct accctgagcg 2400
tcgcctgcgg ggcgtcctgg aggagctgag ctgtggctgc tgccgcttcc tctccctcgc 2460
tgacaaggac cagggccact catcccgcac caggcttgac cgggagcgcc tcaagtcctg 2520
catgagggag ctggaaaaca tggggcagca ggccaggatg ctgcgggccc aggtgaagcg 2580
gcacacggtg cgggacaagc tgaggctgtg ccagaacttc ctgcagaagc tgcgcttcct 2640
ggcggacgag ccccagcaca gcattcccga catcttcatc tggatgatga gcaacaacaa 2700
gcgtgtcgcc tatgcccgtg tgccctccaa ggacctgctc ttctccatcg tggaggagga 2760
gactggcaag gactgcgcca aggtcaagac gctcttcctt aagctgccag ggaagcgggg 2820
cttcggctcg gcaggctgga cagtgcaggc caaggtggag ctgtacctgt ggctgggcct 2880
cagcaaacag cgcaaggagt tcctgtgcgg cctgccctgt ggcttccagg aggtcaaggc 2940
agcccagggc ctgggcctgc atgccttccc acccgtcagc ctggtctaca ccaagaagca 3000
ggcgttccag ctccgagcgc acatgtacca ggcccgcagc ctctttgccg ccgacagcag 3060
cggactctca gacccctttg cccgcgtctt cttcatcaat cagagtcagt gcacagaggt 3120
gctgaatgag accctgtgtc ccacctggga ccagatgctg gtgttcgaca acctggagct 3180
ctatggtgaa gctcatgagc tgagggacga tccgcccatc attgtcattg aaatctatga 3240
ccaggattcc atgggcaaag ctgacttcat gggccggacc ttcgccaaac ccctggtgaa 3300
gatggcagac gaggcgtact gcccaccccg cttcccacct cagctcgagt actaccagat 3360
ctaccgtggc aacgccacag ctggagacct gctggcggcc ttcgagctgc tgcagattgg 3420
accagcaggg aaggctgacc tgccccccat caatggcccg gtggacgtgg accgaggtcc 3480
catcatgccc gtgcccatgg gcatccggcc cgtgctcagc aagtaccgag tggaggtgct 3540
gttctggggc ctacgggacc taaagcgggt gaacctggcc caggtggacc ggccacgggt 3600
ggacatcgag tgtgcaggga agggggtgca gtcgtccctg atccacaatt ataagaagaa 3660
ccccaacttc aacaccctcg tcaagtggtt tgaagtggac ctcccagaga acgagctgct 3720
gcacccgccc ttgaacatcc gtgtggtgga ctgccgggcc ttcggtcgct acacactggt 3780
gggctcccat gccgtcagct ccctgcgacg cttcatctac cggcccccag accgctcggc 3840
ccccagctgg aacaccacgg tcaggcttct ccggcgctgc cgtgtgctgt gcaatggggg 3900
ctcctcctct cactccacag gggaggttgt ggtgactatg gagccagagg tacccatcaa 3960
gaaactggag accatggtga agctggacgc gacttctgaa gctgttgtca aggtggatgt 4020
ggctgaggag gagaaggaga agaagaagaa gaagaagggc actgcggagg agccagagga 4080
ggaggagcca gacgagagca tgctggactg gtggtccaag tactttgcct ccattgacac 4140
catgaaggag caacttcgac aacaagagcc ctctggaatt gacttggagg agaaggagga 4200
agtggacaat accgagggcc tgaaggggtc aatgaagggc aaggagaagg caagggctgc 4260
caaagaggag aagaagaaga aaactcagag ctctggctct ggccaggggt ccgaggcccc 4320
cgagaagaag aaacccaaga ttgatgagct taaggtatac cccaaagagc tggagtccga 4380
gtttgataac tttgaggact ggctgcacac tttcaacttg cttcggggca agaccgggga 4440
tgatgaggat ggctccaccg aggaggagcg cattgtggga cgcttcaagg gctccctctg 4500
cgtgtacaaa gtgccactcc cagaggacgt gtcccgggaa gccggctacg actccaccta 4560
cggcatgttc cagggcatcc cgagcaatga ccccatcaat gtgctggtcc gagtctatgt 4620
ggtccgggcc acggacctgc accctgctga catcaacggc aaagctgacc cctacatcgc 4680
catccggcta ggcaagactg acatccgcga caaggagaac tacatctcca agcagctcaa 4740
ccctgtcttt gggaagtcct ttgacatcga ggcctccttc cccatggaat ccatgctgac 4800
ggtggctgtg tatgactggg acctggtggg cactgatgac ctcattgggg aaaccaagat 4860
cgacctggag aaccgcttct acagcaagca ccgcgccacc tgcggcatcg cccagaccta 4920
ctccacacat ggctacaata tctggcggga ccccatgaag cccagccaga tcctgacccg 4980
cctctgcaaa gacggcaaag tggacggccc ccactttggg ccccctggga gagtgaaggt 5040
ggccaaccgc gtcttcactg ggccctctga gattgaggac gagaacggtc agaggaagcc 5100
cacagacgag catgtggcgc tgttggccct gaggcactgg gaggacatcc cccgcgcagg 5160
ctgccgcctg gtgccagagc atgtggagac gaggccgctg ctcaaccccg acaagccggg 5220
catcgagcag ggccgcctgg agctgtgggt ggacatgttc cccatggaca tgccagcccc 5280
tgggacgcct ctggacatct cacctcggaa gcccaagaag tacgagctgc gggtcatcat 5340
ctggaacaca gatgaggtgg tcttggagga cgacgacttc ttcacagggg agaagtccag 5400
tgacatcttc gtgagggggt ggctgaaggg ccagcaggag gacaagcagg acacagacgt 5460
ccactaccac tccctcactg gcgagggcaa cttcaactgg cgctacctgt tccccttcga 5520
ctacctggcg gcggaggaga agatcgtcat ctccaagaag gagtccatgt tctcctggga 5580
cgagaccgag tacaagatcc ccgcgcggct caccctgcag atctgggatg cggaccactt 5640
ctccgctgac gacttcctgg gggccatcga gctggacctg aaccggttcc cgcggggcgc 5700
aaagacagcc aagcagtgca ccatggagat ggccaccggg gaggtggacg tgcccctcgt 5760
gtccatcttc aagcaaaagc gcgtcaaagg ctggtggccc ctcctggccc gcaatgagaa 5820
cgatgagttt gagctcacgg gcaaggtgga ggctgagctg catttactga cagcagagga 5880
ggcagagaag aacccagtgg gcctggcccg caatgaacct gaccccctag agaaacccaa 5940
ccggcccgac acgagcttca tctggttcct gaaccctctc aagtcggctc gctacttctt 6000
gtggcacacg tatcgctggc tgctcctcaa actgttgctg ctcctgctgc tgctcctcct 6060
cctcgccctg ttcctctact ctgtgcctgg ctacctggtc aagaaaatcc tcggggcctg 6120
agcccagtgg cctcctggcc ggcccgacac ggccttcgtc tggttcctca accctctcaa 6180
gtccatcaag tacctcatct gcacccggta caagtggctc atcatcaaga tcgtgctggc 6240
gctgttgggg ctgctcatgt tggggctctt cctctacagc ctccctggct acatggtcaa 6300
aaagctcctt ggggcatgaa ggccgccagc tcccgccagc cgctccccag ccctgccgca 6360
tttcctttca gtggcttgga ctctttccca tctcccctgg ggagcctgag gagcccagcg 6420
tccactcttc atgccttggg ccgagcctgc ctcctgcttg cgggggccgc ctgtcctcac 6480
tgccccaggc tgcggcttgc ccagtcccgc ccctctgacc cctgcctgtg ggctggggag 6540
ccttggatgg ggtggggacc tggaatgggt ctctcttgcc ccacctggct gaggcgccac 6600
ccttcttcag gcccaggctc cagaggaaga ctcctgaaac cctccccagg tcttccaagt 6660
acaggattga agctttagtg aaattaacca aggaccatgg gtcagtgccc agggctttaa 6720
aaagaatgaa cgagcaaaag gtatccccgc cgtgacccct gcagatagca ccggtctttg 6780
atccgcagca ggggccagac cctgcccaca agtcccagcg cggctgcttc tgccactgct 6840
gggctccact tggctcctct cacttcccag ggggtcgcct gtcctgcctg tgggtttcca 6900
tggcttccca gagctccctc tgccccagcc agcgcctcca ggcccagctg aggagctgtg 6960
agaagcagca gaggggactc cccatcccgg gcacaccctg tcctcccacc cctgccccct 7020
tgcccttcca gccctttcag ctgcagctgg gagctggccc gtcaagtgct gcccctgcct 7080
gtgtctgggt ttctgttggc tgtttttctt ttcttgagtg gtgatttttc tctaaataaa 7140
agaagtcaag cactgaaaaa aaaaaaaaaa a 7171
<210> 3
<211> 2676
<212> DNA
<213> homo sapiens
<400> 3
atggccttgc tcatccacct caagacagtc tcggagctgc ggggcagggg cgaccggatc 60
gccaaagtga ctttccgagg gcaatccttc tactctcggg tcctggagaa ctgtgaggat 120
gtggctgact ttgatgagac atttcggtgg ccggtggcca gcagcatcga cagaaatgag 180
atgctggaga ttcaggtttt caactacagc aaagtcttca gcaacaagct catcgggacc 240
ttccgcatgg tgctgcagaa ggtggtagag gagagccatg tggaggtgac tgacacgctg 300
attgatgaca acaatgctat catcaagacc agcctgtgcg tggaggtccg gtatcaggcc 360
actgacggca cagtgggctc ctgggacgat ggggacttcc tgggagatga gtctcttcaa 420
gaggaagaga aggacagcca agagacggat ggactgctcc caggctcccg gcccagctcc 480
cggcccccag gagagaagag cttccggaga gccgggagga gcgtgttctc cgccatgaag 540
ctcggcaaaa accggtctca caaggaggag ccccaaagac cagatgaacc ggcggtgctg 600
gagatggaag accttgacca tctggccatt cggctaggag atggactgga tcccgactcg 660
gtgtctctag cctcagtcac agctctcacc actaatgtct ccaacaagcg atctaagcca 720
gacattaaga tggagccaag tgctgggcgg cccatggatt accaggtcag catcacggtg 780
atcgaggccc ggcagctggt gggcttgaac atggaccctg tggtgtgcgt ggaggtgggt 840
gacgacaaga agtacacatc catgaaggag tccactaact gcccctatta caacgagtac 900
ttcgtcttcg acttccatgt ctctccggat gtcatgtttg acaagatcat caagatttcg 960
gtgattcact ccaagaacct gctgcgcagt ggcaccctgg tgggctcctt caaaatggac 1020
gtgggaaccg tgtactcgca gccagagcac cagttccatc acaagtgggc catcctgtct 1080
gaccccgatg acatctcctc ggggctgaag ggctacgtga agtgtgacgt tgccgtggtg 1140
ggcaaagggg acaacatcaa gacgccccac aaggccaatg agaccgacga agatgacatt 1200
gaggggaact tgctgctccc cgagggggtg ccccccgaac gccagtgggc ccggttctat 1260
gtgaaaattt accgagcaga ggggctgccc cgtatgaaca caagcctcat ggccaatgta 1320
aagaaggctt tcatcggtga aaacaaggac ctcgtggacc cctacgtgca agtcttcttt 1380
gctggccaga agggcaagac ttcagtgcag aagagcagct atgagcccct gtggaatgag 1440
caggtcgtct ttacagacct cttcccccca ctctgcaaac gcatgaaggt gcagatccga 1500
gactcggaca aggtcaacga cgtggccatc ggcacccact tcattgacct gcgcaagatt 1560
tctaatgacg gagacaaagg cttcctgccc acactgggcc cagcctgggt gaacatgtac 1620
ggctccacac gtaactacac gctgctggat gagcatcagg acctgaacga gggcctgggg 1680
gagggtgtgt ccttccgggc ccggctcctg ctgggcctgg ctgtggagat cgtagacacc 1740
tccaaccctg agctcaccag ctccacagag gtgcaggtgg agcaggccac gcccatctcg 1800
gagagctgtg caggtaaaat ggaagaattc tttctctttg gagccttcct ggaggcctca 1860
atgatcgacc ggagaaacgg agacaagccc atcacctttg aggtcaccat aggcaactat 1920
gggaacgaag ttgatggcct gtcccggccc cagcggcctc ggccccggaa ggagccgggg 1980
gatgaggaag aagtagacct gattcagaac gcaagtgatg acgaggccgg tgatgccggg 2040
gacctggcct cagtctcctc cactccacca atgcggcccc aggtcaccga caggaactac 2100
ttccatctgc cctacctgga gcgaaagccc tgcatctaca tcaagagctg gtggccggac 2160
cagcgccgcc gcctctacaa tgccaacatc atggaccaca ttgccgacaa gctggaagaa 2220
ggcctgaacg acatacagga gatgatcaaa acggagaagt cctaccctga gcgtcgcctg 2280
cggggcgtcc tggaggagct gagctgtggc tgctgccgct tcctctccct cgctgacaag 2340
gaccagggcc actcatcccg caccaggctt gaccgggagc gcctcaagtc ctgcatgagg 2400
gagctggaaa acatggggca gcaggccagg atgctgcggg cccaggtgaa gcggcacacg 2460
gtgcgggaca agctgaggct gtgccagaac ttcctgcaga agctgcgctt cctggcggac 2520
gagccccagc acagcattcc cgacatcttc atctggatga tgagcaacaa caagcgtgtc 2580
gcctatgccc gtgtgccctc caaggacctg ctcttctcca tcgtggagga ggagactggc 2640
aaggactgcg ccaaggtcaa gacgctcttc cttaag 2676
<210> 4
<211> 3318
<212> DNA
<213> homo sapiens
<400> 4
ctgccaggga agcggggctt cggctcggca ggctggacag tgcaggccaa ggtggagctg 60
tacctgtggc tgggcctcag caaacagcgc aaggagttcc tgtgcggcct gccctgtggc 120
ttccaggagg tcaaggcagc ccagggcctg ggcctgcatg ccttcccacc cgtcagcctg 180
gtctacacca agaagcaggc gttccagctc cgagcgcaca tgtaccaggc ccgcagcctc 240
tttgccgccg acagcagcgg actctcagac ccctttgccc gcgtcttctt catcaatcag 300
agtcagtgca cagaggtgct gaatgagacc ctgtgtccca cctgggacca gatgctggtg 360
ttcgacaacc tggagctcta tggtgaagct catgagctga gggacgatcc gcccatcatt 420
gtcattgaaa tctatgacca ggattccatg ggcaaagctg acttcatggg ccggaccttc 480
gccaaacccc tggtgaagat ggcagacgag gcgtactgcc caccccgctt cccacctcag 540
ctcgagtact accagatcta ccgtggcaac gccacagctg gagacctgct ggcggccttc 600
gagctgctgc agattggacc agcagggaag gctgacctgc cccccatcaa tggcccggtg 660
gacgtggacc gaggtcccat catgcccgtg cccatgggca tccggcccgt gctcagcaag 720
taccgagtgg aggtgctgtt ctggggccta cgggacctaa agcgggtgaa cctggcccag 780
gtggaccggc cacgggtgga catcgagtgt gcagggaagg gggtgcagtc gtccctgatc 840
cacaattata agaagaaccc caacttcaac accctcgtca agtggtttga agtggacctc 900
ccagagaacg agctgctgca cccgcccttg aacatccgtg tggtggactg ccgggccttc 960
ggtcgctaca cactggtggg ctcccatgcc gtcagctccc tgcgacgctt catctaccgg 1020
cccccagacc gctcggcccc cagctggaac accacggtca ggcttctccg gcgctgccgt 1080
gtgctgtgca atgggggctc ctcctctcac tccacagggg aggttgtggt gactatggag 1140
ccagaggtac ccatcaagaa actggagacc atggtgaagc tggacgcgac ttctgaagct 1200
gttgtcaagg tggatgtggc tgaggaggag aaggagaaga agaagaagaa gaagggcact 1260
gcggaggagc cagaggagga ggagccagac gagagcatgc tggactggtg gtccaagtac 1320
tttgcctcca ttgacaccat gaaggagcaa cttcgacaac aagagccctc tggaattgac 1380
ttggaggaga aggaggaagt ggacaatacc gagggcctga aggggtcaat gaagggcaag 1440
gagaaggcaa gggctgccaa agaggagaag aagaagaaaa ctcagagctc tggctctggc 1500
caggggtccg aggcccccga gaagaagaaa cccaagattg atgagcttaa ggtatacccc 1560
aaagagctgg agtccgagtt tgataacttt gaggactggc tgcacacttt caacttgctt 1620
cggggcaaga ccggggatga tgaggatggc tccaccgagg aggagcgcat tgtgggacgc 1680
ttcaagggct ccctctgcgt gtacaaagtg ccactcccag aggacgtgtc ccgggaagcc 1740
ggctacgact ccacctacgg catgttccag ggcatcccga gcaatgaccc catcaatgtg 1800
ctggtccgag tctatgtggt ccgggccacg gacctgcacc ctgctgacat caacggcaaa 1860
gctgacccct acatcgccat ccggctaggc aagactgaca tccgcgacaa ggagaactac 1920
atctccaagc agctcaaccc tgtctttggg aagtcctttg acatcgaggc ctccttcccc 1980
atggaatcca tgctgacggt ggctgtgtat gactgggacc tggtgggcac tgatgacctc 2040
attggggaaa ccaagatcga cctggagaac cgcttctaca gcaagcaccg cgccacctgc 2100
ggcatcgccc agacctactc cacacatggc tacaatatct ggcgggaccc catgaagccc 2160
agccagatcc tgacccgcct ctgcaaagac ggcaaagtgg acggccccca ctttgggccc 2220
cctgggagag tgaaggtggc caaccgcgtc ttcactgggc cctctgagat tgaggacgag 2280
aacggtcaga ggaagcccac agacgagcat gtggcgctgt tggccctgag gcactgggag 2340
gacatccccc gcgcaggctg ccgcctggtg ccagagcatg tggagacgag gccgctgctc 2400
aaccccgaca agccgggcat cgagcagggc cgcctggagc tgtgggtgga catgttcccc 2460
atggacatgc cagcccctgg gacgcctctg gacatctcac ctcggaagcc caagaagtac 2520
gagctgcggg tcatcatctg gaacacagat gaggtggtct tggaggacga cgacttcttc 2580
acaggggaga agtccagtga catcttcgtg agggggtggc tgaagggcca gcaggaggac 2640
aagcaggaca cagacgtcca ctaccactcc ctcactggcg agggcaactt caactggcgc 2700
tacctgttcc ccttcgacta cctggcggcg gaggagaaga tcgtcatctc caagaaggag 2760
tccatgttct cctgggacga gaccgagtac aagatccccg cgcggctcac cctgcagatc 2820
tgggatgcgg accacttctc cgctgacgac ttcctggggg ccatcgagct ggacctgaac 2880
cggttcccgc ggggcgcaaa gacagccaag cagtgcacca tggagatggc caccggggag 2940
gtggacgtgc ccctcgtgtc catcttcaag caaaagcgcg tcaaaggctg gtggcccctc 3000
ctggcccgca atgagaacga tgagtttgag ctcacgggca aggtggaggc tgagctgcat 3060
ttactgacag cagaggaggc agagaagaac ccagtgggcc tggcccgcaa tgaacctgac 3120
cccctagaga aacccaaccg gcccgacacg agcttcatct ggttcctgaa ccctctcaag 3180
tcggctcgct acttcttgtg gcacacgtat cgctggctgc tcctcaaact gttgctgctc 3240
ctgctgctgc tcctcctcct cgccctgttc ctctactctg tgcctggcta cctggtcaag 3300
aaaatcctcg gggcctga 3318
<210> 5
<211> 1997
<212> PRT
<213> homo sapiens
<400> 5
Met Ala Leu Leu Ile His Leu Lys Thr Val Ser Glu Leu Arg Gly Arg
1 5 10 15
Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser
20 25 30
Arg Val Leu Glu Asn Cys Glu Asp Val Ala Asp Phe Asp Glu Thr Phe
35 40 45
Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Met Leu Glu Ile
50 55 60
Gln Val Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr
65 70 75 80
Phe Arg Met Val Leu Gln Lys Val Val Glu Glu Ser His Val Glu Val
85 90 95
Thr Asp Thr Leu Ile Asp Asp Asn Asn Ala Ile Ile Lys Thr Ser Leu
100 105 110
Cys Val Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Ser Trp
115 120 125
Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Glu Lys
130 135 140
Asp Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Ser
145 150 155 160
Arg Pro Pro Gly Glu Lys Ser Phe Arg Arg Ala Gly Arg Ser Val Phe
165 170 175
Ser Ala Met Lys Leu Gly Lys Asn Arg Ser His Lys Glu Glu Pro Gln
180 185 190
Arg Pro Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu
195 200 205
Ala Ile Arg Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala
210 215 220
Ser Val Thr Ala Leu Thr Thr Asn Val Ser Asn Lys Arg Ser Lys Pro
225 230 235 240
Asp Ile Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val
245 250 255
Ser Ile Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp
260 265 270
Pro Val Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met
275 280 285
Lys Glu Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp
290 295 300
Phe His Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser
305 310 315 320
Val Ile His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser
325 330 335
Phe Lys Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe
340 345 350
His His Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ser Gly
355 360 365
Leu Lys Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp
370 375 380
Asn Ile Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile
385 390 395 400
Glu Gly Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp
405 410 415
Ala Arg Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met
420 425 430
Asn Thr Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn
435 440 445
Lys Asp Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys
450 455 460
Gly Lys Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu
465 470 475 480
Gln Val Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys
485 490 495
Val Gln Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr
500 505 510
His Phe Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe
515 520 525
Leu Pro Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg
530 535 540
Asn Tyr Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly
545 550 555 560
Glu Gly Val Ser Phe Arg Ala Arg Leu Leu Leu Gly Leu Ala Val Glu
565 570 575
Ile Val Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln
580 585 590
Val Glu Gln Ala Thr Pro Ile Ser Glu Ser Cys Ala Gly Lys Met Glu
595 600 605
Glu Phe Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg
610 615 620
Arg Asn Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr
625 630 635 640
Gly Asn Glu Val Asp Gly Leu Ser Arg Pro Gln Arg Pro Arg Pro Arg
645 650 655
Lys Glu Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ala Ser
660 665 670
Asp Asp Glu Ala Gly Asp Ala Gly Asp Leu Ala Ser Val Ser Ser Thr
675 680 685
Pro Pro Met Arg Pro Gln Val Thr Asp Arg Asn Tyr Phe His Leu Pro
690 695 700
Tyr Leu Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp
705 710 715 720
Gln Arg Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp
725 730 735
Lys Leu Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu
740 745 750
Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser
755 760 765
Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His
770 775 780
Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg
785 790 795 800
Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val
805 810 815
Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu
820 825 830
Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp
835 840 845
Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg
850 855 860
Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly
865 870 875 880
Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys
885 890 895
Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu
900 905 910
Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly
915 920 925
Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu
930 935 940
His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe
945 950 955 960
Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp
965 970 975
Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln
980 985 990
Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp
995 1000 1005
Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His
1010 1015 1020
Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp
1025 1030 1035
Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala
1040 1045 1050
Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg
1055 1060 1065
Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala
1070 1075 1080
Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly
1085 1090 1095
Pro Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp
1100 1105 1110
Val Asp Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro
1115 1120 1125
Val Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg
1130 1135 1140
Asp Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val
1145 1150 1155
Asp Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His
1160 1165 1170
Asn Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe
1175 1180 1185
Glu Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn
1190 1195 1200
Ile Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val
1205 1210 1215
Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro
1220 1225 1230
Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu
1235 1240 1245
Arg Arg Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser
1250 1255 1260
Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys
1265 1270 1275
Lys Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val
1280 1285 1290
Val Lys Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys
1295 1300 1305
Lys Lys Gly Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu
1310 1315 1320
Ser Met Leu Asp Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr
1325 1330 1335
Met Lys Glu Gln Leu Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu
1340 1345 1350
Glu Glu Lys Glu Glu Val Asp Asn Thr Glu Gly Leu Lys Gly Ser
1355 1360 1365
Met Lys Gly Lys Glu Lys Ala Arg Ala Ala Lys Glu Glu Lys Lys
1370 1375 1380
Lys Lys Thr Gln Ser Ser Gly Ser Gly Gln Gly Ser Glu Ala Pro
1385 1390 1395
Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys
1400 1405 1410
Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu Asp Trp Leu His Thr
1415 1420 1425
Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser
1430 1435 1440
Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys
1445 1450 1455
Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly
1460 1465 1470
Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp
1475 1480 1485
Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp
1490 1495 1500
Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala
1505 1510 1515
Ile Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile
1520 1525 1530
Ser Lys Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu
1535 1540 1545
Ala Ser Phe Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp
1550 1555 1560
Trp Asp Leu Val Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile
1565 1570 1575
Asp Leu Glu Asn Arg Phe Tyr Ser Lys His Arg Ala Thr Cys Gly
1580 1585 1590
Ile Ala Gln Thr Tyr Ser Thr His Gly Tyr Asn Ile Trp Arg Asp
1595 1600 1605
Pro Met Lys Pro Ser Gln Ile Leu Thr Arg Leu Cys Lys Asp Gly
1610 1615 1620
Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly Arg Val Lys Val
1625 1630 1635
Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn
1640 1645 1650
Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Leu Ala Leu
1655 1660 1665
Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val Pro
1670 1675 1680
Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly
1685 1690 1695
Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met
1700 1705 1710
Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys
1715 1720 1725
Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu
1730 1735 1740
Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser
1745 1750 1755
Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys
1760 1765 1770
Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn
1775 1780 1785
Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu
1790 1795 1800
Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp
1805 1810 1815
Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp
1820 1825 1830
Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu
1835 1840 1845
Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln
1850 1855 1860
Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val
1865 1870 1875
Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu
1880 1885 1890
Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu
1895 1900 1905
Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro
1910 1915 1920
Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn
1925 1930 1935
Arg Pro Asp Thr Ala Phe Val Trp Phe Leu Asn Pro Leu Lys Ser
1940 1945 1950
Ile Lys Tyr Leu Ile Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys
1955 1960 1965
Ile Val Leu Ala Leu Leu Gly Leu Leu Met Leu Gly Leu Phe Leu
1970 1975 1980
Tyr Ser Leu Pro Gly Tyr Met Val Lys Lys Leu Leu Gly Ala
1985 1990 1995
<210> 6
<211> 1230
<212> PRT
<213> homo sapiens
<400> 6
Met Ile Lys Thr Glu Lys Ser Tyr Pro Glu Arg Arg Leu Arg Gly Val
1 5 10 15
Leu Glu Glu Leu Ser Cys Gly Cys Cys Arg Phe Leu Ser Leu Ala Asp
20 25 30
Lys Asp Gln Gly His Ser Ser Arg Thr Arg Leu Asp Arg Glu Arg Leu
35 40 45
Lys Ser Cys Met Arg Glu Leu Glu Asn Met Gly Gln Gln Ala Arg Met
50 55 60
Leu Arg Ala Gln Val Lys Arg His Thr Val Arg Asp Lys Leu Arg Leu
65 70 75 80
Cys Gln Asn Phe Leu Gln Lys Leu Arg Phe Leu Ala Asp Glu Pro Gln
85 90 95
His Ser Ile Pro Asp Ile Phe Ile Trp Met Met Ser Asn Asn Lys Arg
100 105 110
Val Ala Tyr Ala Arg Val Pro Ser Lys Asp Leu Leu Phe Ser Ile Val
115 120 125
Glu Glu Glu Thr Gly Lys Asp Cys Ala Lys Val Lys Thr Leu Phe Leu
130 135 140
Lys Leu Pro Gly Lys Arg Gly Phe Gly Ser Ala Gly Trp Thr Val Gln
145 150 155 160
Ala Lys Val Glu Leu Tyr Leu Trp Leu Gly Leu Ser Lys Gln Arg Lys
165 170 175
Glu Phe Leu Cys Gly Leu Pro Cys Gly Phe Gln Glu Val Lys Ala Ala
180 185 190
Gln Gly Leu Gly Leu His Ala Phe Pro Pro Val Ser Leu Val Tyr Thr
195 200 205
Lys Lys Gln Ala Phe Gln Leu Arg Ala His Met Tyr Gln Ala Arg Ser
210 215 220
Leu Phe Ala Ala Asp Ser Ser Gly Leu Ser Asp Pro Phe Ala Arg Val
225 230 235 240
Phe Phe Ile Asn Gln Ser Gln Cys Thr Glu Val Leu Asn Glu Thr Leu
245 250 255
Cys Pro Thr Trp Asp Gln Met Leu Val Phe Asp Asn Leu Glu Leu Tyr
260 265 270
Gly Glu Ala His Glu Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu
275 280 285
Ile Tyr Asp Gln Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr
290 295 300
Phe Ala Lys Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro
305 310 315 320
Arg Phe Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala
325 330 335
Thr Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro
340 345 350
Ala Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Val Asp
355 360 365
Arg Gly Pro Ile Met Pro Val Pro Met Gly Ile Arg Pro Val Leu Ser
370 375 380
Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp Leu Lys Arg
385 390 395 400
Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp Ile Glu Cys Ala
405 410 415
Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn Tyr Lys Lys Asn Pro
420 425 430
Asn Phe Asn Thr Leu Val Lys Trp Phe Glu Val Asp Leu Pro Glu Asn
435 440 445
Glu Leu Leu His Pro Pro Leu Asn Ile Arg Val Val Asp Cys Arg Ala
450 455 460
Phe Gly Arg Tyr Thr Leu Val Gly Ser His Ala Val Ser Ser Leu Arg
465 470 475 480
Arg Phe Ile Tyr Arg Pro Pro Asp Arg Ser Ala Pro Ser Trp Asn Thr
485 490 495
Thr Gly Glu Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys Lys
500 505 510
Leu Glu Thr Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val Val Lys
515 520 525
Val Asp Val Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys Lys Lys Gly
530 535 540
Thr Ala Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp
545 550 555 560
Trp Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu
565 570 575
Arg Gln Gln Glu Pro Ser Gly Ile Asp Leu Glu Glu Lys Glu Glu Val
580 585 590
Asp Asn Thr Glu Gly Leu Lys Gly Ser Met Lys Gly Lys Glu Lys Ala
595 600 605
Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Thr Gln Ser Ser Gly Ser
610 615 620
Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Pro Lys Ile Asp Glu
625 630 635 640
Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu
645 650 655
Asp Trp Leu His Thr Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp
660 665 670
Glu Asp Gly Ser Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly
675 680 685
Ser Leu Cys Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu
690 695 700
Ala Gly Tyr Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn
705 710 715 720
Asp Pro Ile Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp
725 730 735
Leu His Pro Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile
740 745 750
Arg Leu Gly Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys
755 760 765
Gln Leu Asn Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe
770 775 780
Pro Met Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val
785 790 795 800
Gly Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg
805 810 815
Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr Ser
820 825 830
Thr His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser Gln Ile
835 840 845
Leu Thr Arg Leu Cys Lys Asp Gly Lys Val Asp Gly Pro His Phe Gly
850 855 860
Pro Pro Gly Arg Val Lys Val Ala Asn Arg Val Phe Thr Gly Pro Ser
865 870 875 880
Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro Thr Asp Glu His Val
885 890 895
Ala Leu Leu Ala Leu Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys
900 905 910
Arg Leu Val Pro Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp
915 920 925
Lys Pro Gly Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe
930 935 940
Pro Met Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg
945 950 955 960
Lys Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu
965 970 975
Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp
980 985 990
Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp
995 1000 1005
Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn
1010 1015 1020
Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys
1025 1030 1035
Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr
1040 1045 1050
Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala
1055 1060 1065
Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp
1070 1075 1080
Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr
1085 1090 1095
Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile
1100 1105 1110
Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg
1115 1120 1125
Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu
1130 1135 1140
Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly
1145 1150 1155
Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro
1160 1165 1170
Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro Leu Lys Ser Ala Arg
1175 1180 1185
Tyr Phe Leu Trp His Thr Tyr Arg Trp Leu Leu Leu Lys Leu Leu
1190 1195 1200
Leu Leu Leu Leu Leu Leu Leu Leu Leu Ala Leu Phe Leu Tyr Ser
1205 1210 1215
Val Pro Gly Tyr Leu Val Lys Lys Ile Leu Gly Ala
1220 1225 1230
<210> 7
<211> 1992
<212> PRT
<213> musc musculus
<400> 7
Met Ala Leu Ile Val His Leu Lys Thr Val Ser Glu Leu Arg Gly Lys
1 5 10 15
Gly Asp Arg Ile Ala Lys Val Thr Phe Arg Gly Gln Ser Phe Tyr Ser
20 25 30
Arg Val Leu Glu Asn Cys Glu Gly Val Ala Asp Phe Asp Glu Thr Phe
35 40 45
Arg Trp Pro Val Ala Ser Ser Ile Asp Arg Asn Glu Val Leu Glu Ile
50 55 60
Gln Ile Phe Asn Tyr Ser Lys Val Phe Ser Asn Lys Leu Ile Gly Thr
65 70 75 80
Phe Cys Met Val Leu Gln Lys Val Val Glu Glu Asn Arg Val Glu Val
85 90 95
Thr Asp Thr Leu Met Asp Asp Ser Asn Ala Ile Ile Lys Thr Ser Leu
100 105 110
Ser Met Glu Val Arg Tyr Gln Ala Thr Asp Gly Thr Val Gly Pro Trp
115 120 125
Asp Asp Gly Asp Phe Leu Gly Asp Glu Ser Leu Gln Glu Glu Lys Asp
130 135 140
Ser Gln Glu Thr Asp Gly Leu Leu Pro Gly Ser Arg Pro Ser Thr Arg
145 150 155 160
Ile Ser Gly Glu Lys Ser Phe Arg Ser Lys Gly Arg Glu Lys Thr Lys
165 170 175
Gly Gly Arg Asp Gly Glu His Lys Ala Gly Arg Ser Val Phe Ser Ala
180 185 190
Met Lys Leu Gly Lys Thr Arg Ser His Lys Glu Glu Pro Gln Arg Gln
195 200 205
Asp Glu Pro Ala Val Leu Glu Met Glu Asp Leu Asp His Leu Ala Ile
210 215 220
Gln Leu Gly Asp Gly Leu Asp Pro Asp Ser Val Ser Leu Ala Ser Val
225 230 235 240
Thr Ala Leu Thr Ser Asn Val Ser Asn Lys Arg Ser Lys Pro Asp Ile
245 250 255
Lys Met Glu Pro Ser Ala Gly Arg Pro Met Asp Tyr Gln Val Ser Ile
260 265 270
Thr Val Ile Glu Ala Arg Gln Leu Val Gly Leu Asn Met Asp Pro Val
275 280 285
Val Cys Val Glu Val Gly Asp Asp Lys Lys Tyr Thr Ser Met Lys Glu
290 295 300
Ser Thr Asn Cys Pro Tyr Tyr Asn Glu Tyr Phe Val Phe Asp Phe His
305 310 315 320
Val Ser Pro Asp Val Met Phe Asp Lys Ile Ile Lys Ile Ser Val Ile
325 330 335
His Ser Lys Asn Leu Leu Arg Ser Gly Thr Leu Val Gly Ser Phe Lys
340 345 350
Met Asp Val Gly Thr Val Tyr Ser Gln Pro Glu His Gln Phe His His
355 360 365
Lys Trp Ala Ile Leu Ser Asp Pro Asp Asp Ile Ser Ala Gly Leu Lys
370 375 380
Gly Tyr Val Lys Cys Asp Val Ala Val Val Gly Lys Gly Asp Asn Ile
385 390 395 400
Lys Thr Pro His Lys Ala Asn Glu Thr Asp Glu Asp Asp Ile Glu Gly
405 410 415
Asn Leu Leu Leu Pro Glu Gly Val Pro Pro Glu Arg Gln Trp Ala Arg
420 425 430
Phe Tyr Val Lys Ile Tyr Arg Ala Glu Gly Leu Pro Arg Met Asn Thr
435 440 445
Ser Leu Met Ala Asn Val Lys Lys Ala Phe Ile Gly Glu Asn Lys Asp
450 455 460
Leu Val Asp Pro Tyr Val Gln Val Phe Phe Ala Gly Gln Lys Gly Lys
465 470 475 480
Thr Ser Val Gln Lys Ser Ser Tyr Glu Pro Leu Trp Asn Glu Gln Val
485 490 495
Val Phe Thr Asp Leu Phe Pro Pro Leu Cys Lys Arg Met Lys Val Gln
500 505 510
Ile Arg Asp Ser Asp Lys Val Asn Asp Val Ala Ile Gly Thr His Phe
515 520 525
Ile Asp Leu Arg Lys Ile Ser Asn Asp Gly Asp Lys Gly Phe Leu Pro
530 535 540
Thr Leu Gly Pro Ala Trp Val Asn Met Tyr Gly Ser Thr Arg Asn Tyr
545 550 555 560
Thr Leu Leu Asp Glu His Gln Asp Leu Asn Glu Gly Leu Gly Glu Gly
565 570 575
Val Ser Phe Arg Ala Arg Leu Met Leu Gly Leu Ala Val Glu Ile Leu
580 585 590
Asp Thr Ser Asn Pro Glu Leu Thr Ser Ser Thr Glu Val Gln Val Glu
595 600 605
Gln Ala Thr Pro Val Ser Glu Ser Cys Thr Gly Arg Met Glu Glu Phe
610 615 620
Phe Leu Phe Gly Ala Phe Leu Glu Ala Ser Met Ile Asp Arg Lys Asn
625 630 635 640
Gly Asp Lys Pro Ile Thr Phe Glu Val Thr Ile Gly Asn Tyr Gly Asn
645 650 655
Glu Val Asp Gly Met Ser Arg Pro Leu Arg Pro Arg Pro Arg Lys Glu
660 665 670
Pro Gly Asp Glu Glu Glu Val Asp Leu Ile Gln Asn Ser Ser Asp Asp
675 680 685
Glu Gly Asp Glu Ala Gly Asp Leu Ala Ser Val Ser Ser Thr Pro Pro
690 695 700
Met Arg Pro Gln Ile Thr Asp Arg Asn Tyr Phe His Leu Pro Tyr Leu
705 710 715 720
Glu Arg Lys Pro Cys Ile Tyr Ile Lys Ser Trp Trp Pro Asp Gln Arg
725 730 735
Arg Arg Leu Tyr Asn Ala Asn Ile Met Asp His Ile Ala Asp Lys Leu
740 745 750
Glu Glu Gly Leu Asn Asp Val Gln Glu Met Ile Lys Thr Glu Lys Ser
755 760 765
Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys Gly
770 775 780
Cys His Arg Phe Leu Ser Leu Ser Asp Lys Asp Gln Gly Arg Ser Ser
785 790 795 800
Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu Leu
805 810 815
Glu Ser Met Gly Gln Gln Ala Lys Ser Leu Arg Ala Gln Val Lys Arg
820 825 830
His Thr Val Arg Asp Lys Leu Arg Ser Cys Gln Asn Phe Leu Gln Lys
835 840 845
Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Val Phe
850 855 860
Ile Trp Met Met Ser Asn Asn Lys Arg Ile Ala Tyr Ala Arg Val Pro
865 870 875 880
Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Leu Gly Lys Asp
885 890 895
Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg Gly
900 905 910
Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Leu Glu Leu Tyr Leu
915 920 925
Trp Leu Gly Leu Ser Lys Gln Arg Lys Asp Phe Leu Cys Gly Leu Pro
930 935 940
Cys Gly Phe Glu Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His Ser
945 950 955 960
Phe Pro Pro Ile Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln Leu
965 970 975
Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser Ser
980 985 990
Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser Gln
995 1000 1005
Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln
1010 1015 1020
Met Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu
1025 1030 1035
Leu Arg Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln
1040 1045 1050
Asp Ser Met Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys
1055 1060 1065
Pro Leu Val Lys Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe
1070 1075 1080
Pro Pro Gln Leu Glu Tyr Tyr Gln Ile Tyr Arg Gly Ser Ala Thr
1085 1090 1095
Ala Gly Asp Leu Leu Ala Ala Phe Glu Leu Leu Gln Ile Gly Pro
1100 1105 1110
Ser Gly Lys Ala Asp Leu Pro Pro Ile Asn Gly Pro Val Asp Met
1115 1120 1125
Asp Arg Gly Pro Ile Met Pro Val Pro Val Gly Ile Arg Pro Val
1130 1135 1140
Leu Ser Lys Tyr Arg Val Glu Val Leu Phe Trp Gly Leu Arg Asp
1145 1150 1155
Leu Lys Arg Val Asn Leu Ala Gln Val Asp Arg Pro Arg Val Asp
1160 1165 1170
Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser Leu Ile His Asn
1175 1180 1185
Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys Trp Phe Glu
1190 1195 1200
Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu Asn Ile
1205 1210 1215
Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val Gly
1220 1225 1230
Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro
1235 1240 1245
Asp Arg Ser Ala Pro Asn Trp Asn Thr Thr Gly Glu Val Val Val
1250 1255 1260
Ser Met Glu Pro Glu Glu Pro Val Lys Lys Leu Glu Thr Met Val
1265 1270 1275
Lys Leu Asp Ala Thr Ser Asp Ala Val Val Lys Val Asp Val Ala
1280 1285 1290
Glu Asp Glu Lys Glu Arg Lys Lys Lys Lys Lys Lys Gly Pro Ser
1295 1300 1305
Glu Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp
1310 1315 1320
Trp Ser Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu
1325 1330 1335
Arg Gln His Glu Thr Ser Gly Thr Asp Leu Glu Glu Lys Glu Glu
1340 1345 1350
Met Glu Ser Ala Glu Gly Leu Lys Gly Pro Met Lys Ser Lys Glu
1355 1360 1365
Lys Ser Arg Ala Ala Lys Glu Glu Lys Lys Lys Lys Asn Gln Ser
1370 1375 1380
Pro Gly Pro Gly Gln Gly Ser Glu Ala Pro Glu Lys Lys Lys Ala
1385 1390 1395
Lys Ile Asp Glu Leu Lys Val Tyr Pro Lys Glu Leu Glu Ser Glu
1400 1405 1410
Phe Asp Ser Phe Glu Asp Trp Leu His Thr Phe Asn Leu Leu Arg
1415 1420 1425
Gly Lys Thr Gly Asp Asp Glu Asp Gly Ser Thr Glu Glu Glu Arg
1430 1435 1440
Ile Val Gly Arg Phe Lys Gly Ser Leu Cys Val Tyr Lys Val Pro
1445 1450 1455
Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr Asp Pro Thr Tyr
1460 1465 1470
Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile Asn Val Leu
1475 1480 1485
Val Arg Ile Tyr Val Val Arg Ala Thr Asp Leu His Pro Ala Asp
1490 1495 1500
Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Lys Leu Gly Lys
1505 1510 1515
Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn
1520 1525 1530
Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met
1535 1540 1545
Glu Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly
1550 1555 1560
Thr Asp Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg
1565 1570 1575
Phe Tyr Ser Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr
1580 1585 1590
Ser Ile His Gly Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser
1595 1600 1605
Gln Ile Leu Thr Arg Leu Cys Lys Glu Gly Lys Val Asp Gly Pro
1610 1615 1620
His Phe Gly Pro His Gly Arg Val Arg Val Ala Asn Arg Val Phe
1625 1630 1635
Thr Gly Pro Ser Glu Ile Glu Asp Glu Asn Gly Gln Arg Lys Pro
1640 1645 1650
Thr Asp Glu His Val Ala Leu Ser Ala Leu Arg His Trp Glu Asp
1655 1660 1665
Ile Pro Arg Val Gly Cys Arg Leu Val Pro Glu His Val Glu Thr
1670 1675 1680
Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly Ile Glu Gln Gly Arg
1685 1690 1695
Leu Glu Leu Trp Val Asp Met Phe Pro Met Asp Met Pro Ala Pro
1700 1705 1710
Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys Pro Lys Lys Tyr Glu
1715 1720 1725
Leu Arg Val Ile Val Trp Asn Thr Asp Glu Val Val Leu Glu Asp
1730 1735 1740
Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser Asp Ile Phe Val Arg
1745 1750 1755
Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys Gln Asp Thr Asp Val
1760 1765 1770
His Tyr His Ser Leu Thr Gly Glu Gly Asn Phe Asn Trp Arg Tyr
1775 1780 1785
Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu Glu Lys Ile Val Met
1790 1795 1800
Ser Lys Lys Glu Ser Met Phe Ser Trp Asp Glu Thr Glu Tyr Lys
1805 1810 1815
Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp Asp Ala Asp His Phe
1820 1825 1830
Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu Leu Asp Leu Asn Arg
1835 1840 1845
Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln Cys Thr Met Glu Met
1850 1855 1860
Ala Thr Gly Glu Val Asp Val Pro Leu Val Ser Ile Phe Lys Gln
1865 1870 1875
Lys Arg Val Lys Gly Trp Trp Pro Leu Leu Ala Arg Asn Glu Asn
1880 1885 1890
Asp Glu Phe Glu Leu Thr Gly Lys Val Glu Ala Glu Leu His Leu
1895 1900 1905
Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro Val Gly Leu Ala Arg
1910 1915 1920
Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn Arg Pro Asp Thr Ala
1925 1930 1935
Phe Val Trp Phe Leu Asn Pro Leu Lys Ser Ile Lys Tyr Leu Ile
1940 1945 1950
Cys Thr Arg Tyr Lys Trp Leu Ile Ile Lys Ile Val Leu Ala Leu
1955 1960 1965
Leu Gly Leu Leu Met Leu Ala Leu Phe Leu Tyr Ser Leu Pro Gly
1970 1975 1980
Tyr Met Val Lys Lys Leu Leu Gly Ala
1985 1990
<210> 8
<211> 650
<212> DNA
<213> artificial
<220>
<223> Promoter CMV-beta actin = SmCBA
<400> 8
ggtaccctag ttattaatag taatcaatta cggggtcatt agttcatagc ccatatatgg 60
agttccgcgt tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc 120
gcccattgac gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt 180
gacgtcaatg ggtggactat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc 240
atatgccaag tacgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg 300
cccagtacat gaccttatgg gactttccta cttggcagta catctacgta ttagtcatcg 360
ctattaccat ggtcgaggtg agccccacgt tctgcttcac tctccccatc tcccccccct 420
ccccaccccc aattttgtat ttatttattt tttaattatt ttgtgcagcg atgggggcgg 480
gggggggggg ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga 540
ggcggagagg tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg 600
cgaggcggcg gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg 650
<210> 9
<211> 287
<212> DNA
<213> artificial
<220>
<223> recombinogenic bridging sequence
<400> 9
ccccgggtgc gcggcgtcgg tggtgccggc ggggggcgcc aggtcgcagg cggtgtaggg 60
ctccaggcag gcggcgaagg ccatgacgtg cgctatgaag gtctgctcct gcacgccgtg 120
aaccaggtgc gcctgcgggc cgcgcgcgaa caccgccacg tcctcgcctg cgtgggtctc 180
ttcgtccagg ggcactgctg actgctgccg atactcgggg ctcccgctct cgctctcggt 240
aacatccggc cgggcgccgt ccttgagcac atagcctgga ccgtttc 287
<210> 10
<211> 143
<212> DNA
<213> artificial
<220>
<223> ITR from AAV2, 5' end
<400> 10
ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc 60
cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag agagggagtg 120
gccaactcca tcactagggg ttc 143
<210> 11
<211> 143
<212> DNA
<213> artificial
<220>
<223> ITR from AAV2, 3'end
<400> 11
acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca ctgaggccgc 60
ccgggcaaag cccgggcgtc gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc 120
gcgcagagag ggagtggcca acc 143
<210> 12
<211> 84
<212> DNA
<213> artificial
<220>
<223> Splice donor site of the Alkaline Phosphatase
<400> 12
gtaagtatca aggttacaag acaggtttaa ggagaccaat agaaactggg cttgtcgaga 60
cagagaagac tcttgcgttt ctga 84
<210> 13
<211> 49
<212> DNA
<213> artificial
<220>
<223> Splice acceptor site of the alkaline phosphatase
<400> 13
taggcaccta ttggtcttac tgacatccac tttgcctttc tctccacag 49
<210> 14
<211> 20
<212> DNA
<213> artificial
<220>
<223> forward primer to amplify a 2676 bp intermediate fragment
(nucleotides 27 to 2702) of the otoferlin cDNA
<400> 14
tgtctcagag ctccgaggca 20
<210> 15
<211> 22
<212> DNA
<213> artificial
<220>
<223> reverse primer to amplify a 2676 bp intermediate fragment
(nucleotides 27 to 2702) of the otoferlin cDNA
<400> 15
atcgtggagg aggaactggg ca 22
<210> 16
<211> 6907
<212> DNA
<213> musc musculus
<400> 16
ttggttgcct tggtctctgt gggcagcagc aggaggaggc ggcagcagcc agagaagagg 60
gaggcgtgtg agccacactc caccagcgag cttcttcccg ctgctctgga actgcccagg 120
ctctccccac cagcatggcc ctgattgttc acctcaagac tgtctcagag ctccgaggca 180
aaggtgaccg gattgccaaa gtcactttcc gagggcagtc tttctactcc cgggtcctgg 240
agaactgcga gggtgtggct gactttgatg agacgttccg gtggccagtg gccagcagca 300
tcgaccggaa tgaagtgttg gagattcaga ttttcaacta cagcaaagtc ttcagcaaca 360
agctgatagg gaccttctgc atggtgctgc agaaagtggt ggaggagaat cgggtagagg 420
tgaccgacac gctgatggat gacagcaatg ctatcatcaa gaccagcctg agcatggagg 480
tccggtatca ggccacagat ggcactgtgg gcccctggga tgatggagac ttcctgggag 540
atgaatccct ccaggaggag aaggacagcc aggagacaga tgggctgcta cctggttccc 600
gacccagcac ccggatatct ggcgagaaga gctttcgcag caaaggcaga gagaagacca 660
agggaggcag agatggcgag cacaaagcgg gaaggagtgt gttctcggcc atgaaactcg 720
gcaaaactcg gtcccacaaa gaggagcccc aaagacaaga tgagccagca gtgctggaga 780
tggaggacct ggaccaccta gccattcagc tgggggatgg gctggatcct gactccgtgt 840
ctctagcctc ggtcaccgct ctcaccagca atgtctccaa caaacggtct aagccagata 900
ttaagatgga gcccagtgct ggaaggccca tggattacca ggtcagcatc acagtgattg 960
aggctcggca gctggtgggc ttgaacatgg accctgtggt gtgtgtggag gtgggtgatg 1020
acaagaaata cacgtcaatg aaggagtcca caaactgccc ttactacaac gagtactttg 1080
tcttcgactt ccatgtctct cctgatgtca tgtttgacaa gatcatcaag atctcggtta 1140
tccattctaa gaacctgctt cggagcggca ccctggtggg ttccttcaaa atggatgtgg 1200
ggactgtgta ttcccagcct gaacaccagt tccatcacaa atgggccatc ctgtcagacc 1260
ccgatgacat ctctgctggg ttgaagggtt atgtaaagtg tgatgtcgct gtggtgggca 1320
agggagacaa catcaagaca ccccacaagg ccaacgagac ggatgaggac gacattgaag 1380
ggaacttgct gctccccgag ggcgtgcccc ccgaacggca gtgggcacgg ttctatgtga 1440
aaatttaccg agcagaggga ctgccccgga tgaacacaag cctcatggcc aacgtgaaga 1500
aggcgttcat cggtgagaac aaggacctcg tcgaccccta tgtgcaagtc ttctttgctg 1560
gacaaaaggg caaaacatca gtgcagaaga gcagctatga gccgctatgg aatgagcagg 1620
tcgtcttcac agacttgttc cccccactct gcaaacgcat gaaggtgcag atccgggact 1680
ctgacaaggt caatgatgtg gccatcggca cccacttcat cgacctgcgc aagatttcca 1740
acgatggaga caaaggcttc ctgcctaccc tcggtccagc ctgggtgaac atgtacggct 1800
ccacgcgcaa ctacacactg ctggacgagc accaggactt gaatgaaggc ctgggggagg 1860
gtgtgtcctt ccgggcccgc ctcatgttgg gactagctgt ggagatcctg gacacctcca 1920
acccagagct caccagctcc acggaggtgc aggtggagca ggccacgcct gtctcggaga 1980
gctgcacagg gagaatggaa gaattttttc tatttggagc cttcttggaa gcctcaatga 2040
ttgaccggaa aaatggggac aagccaatta cctttgaggt gaccatagga aactacggca 2100
atgaagtcga tggtatgtcc cggcccctga ggcctcggcc ccggaaagag cctggggatg 2160
aagaagaggt agacctgatt cagaactcca gtgacgatga aggtgacgaa gccggggacc 2220
tggcctcggt gtcctccacc ccacctatgc ggccccagat cacggacagg aactatttcc 2280
acctgcccta cctggagcgc aagccctgca tctatatcaa gagctggtgg cctgaccaga 2340
ggcggcgcct ctacaatgcc aacatcatgg atcacattgc tgacaagctg gaagaaggcc 2400
tgaatgatgt acaggagatg atcaaaacgg agaagtccta cccggagcgc cgcctgcggg 2460
gtgtgctaga ggaactcagc tgtggctgcc accgcttcct ctccctctcg gacaaggacc 2520
agggccgctc gtcccgcacc aggctggatc gagagcgtct taagtcctgt atgagggagt 2580
tggagagcat gggacagcag gccaagagcc tgagggctca ggtgaagcgg cacactgttc 2640
gggacaagct gaggtcatgc cagaactttc tgcagaagct acgcttcctg gcggatgagc 2700
cccagcacag cattcctgat gtgttcattt ggatgatgag caacaacaaa cgtatcgcct 2760
atgcccgcgt gccttccaaa gacctgctct tctccatcgt ggaggaggaa ctgggcaagg 2820
actgcgccaa agtcaagacc ctcttcctga agctgccagg gaagaggggc ttcggctcgg 2880
caggctggac agtacaggcc aagctggagc tctacctgtg gctgggcctc agcaagcagc 2940
gaaaggactt cctgtgtggt ctgccctgtg gcttcgagga ggtcaaggca gcccaaggcc 3000
tgggcctgca ttcctttccg cccatcagcc tagtctacac caagaagcaa gccttccagc 3060
tccgagcaca catgtatcag gcccgaagcc tctttgctgc tgacagcagt gggctctctg 3120
atccctttgc ccgtgtcttc ttcatcaacc agagccaatg cactgaggtt ctaaacgaga 3180
cactgtgtcc cacctgggac cagatgctgg tatttgacaa cctggagctg tacggtgaag 3240
ctcacgagtt acgagatgat ccccccatca ttgtcattga aatctacgac caggacagca 3300
tgggcaaagc cgacttcatg ggccggacct tcgccaagcc cctggtgaag atggcagatg 3360
aagcatactg cccacctcgc ttcccgccgc agcttgagta ctaccagatc taccgaggca 3420
gtgccactgc cggagaccta ctggctgcct tcgagctgct gcagattggg ccatcaggga 3480
aggctgacct gccacccatc aatggcccag tggacatgga cagagggccc atcatgcctg 3540
tgcccgtggg aatccggcca gtgctcagca agtaccgagt ggaggtgctg ttctggggcc 3600
tgagggacct aaagagggtg aacctggccc aggtggaccg accacgggtg gacatcgagt 3660
gtgcaggaaa gggggtacaa tcctccctga ttcacaatta taagaagaac cccaacttca 3720
acacgctggt caagtggttt gaagtggacc tcccggagaa tgagctcctg cacccaccct 3780
tgaacatccg agtggtagat tgccgggcct ttggacgata caccctggtg ggttcccacg 3840
cagtcagctc actgaggcgc ttcatctacc gacctccaga ccgctcagcc cccaactgga 3900
acaccacagg ggaggttgta gtaagcatgg agcctgagga gccagttaag aagctggaga 3960
ccatggtgaa actggatgcg acttctgatg ctgtggtcaa ggtggatgtg gctgaagatg 4020
agaaggaaag gaagaagaag aaaaagaaag gcccgtcaga ggagccagag gaggaagagc 4080
ccgatgagag catgctggat tggtggtcca agtacttcgc ctccatcgac acaatgaagg 4140
agcaacttcg acaacatgag acctctggaa ctgacttgga agagaaggaa gagatggaaa 4200
gcgctgaggg cctgaaggga ccaatgaaga gcaaggagaa gtccagagct gcaaaggagg 4260
agaaaaagaa gaaaaaccag agccctggcc ctggccaggg atcggaggct cctgagaaga 4320
agaaagccaa gatcgatgag cttaaggtgt accccaagga gctggaatcg gagtttgaca 4380
gctttgagga ctggctgcac accttcaacc tgttgagggg caagacggga gatgatgagg 4440
atggctccac agaggaggag cgcatagtag gccgattcaa gggctccctc tgtgtgtaca 4500
aagtgccact cccagaagat gtatctcgag aagctggcta tgatcccacc tatggaatgt 4560
tccagggcat cccaagcaat gaccccatca atgtgctggt ccgaatctat gtggtccggg 4620
ccacagacct gcacccggcc gacatcaatg gcaaagctga cccctatatt gccatcaagt 4680
taggcaagac cgacatccga gacaaggaga actacatctc caagcagctc aaccctgtgt 4740
ttgggaagtc ctttgacatt gaggcctcct tccccatgga gtccatgttg acagtggccg 4800
tgtacgactg ggatctggtg ggcactgatg acctcatcgg agaaaccaag attgacctgg 4860
aaaaccgctt ctacagcaag catcgcgcca cctgcggcat cgcacagacc tattccatac 4920
atggctacaa tatctggagg gaccccatga agcccagcca gatcctgaca cgcctctgta 4980
aagagggcaa agtggacggc ccccactttg gtccccatgg gagagtgagg gttgccaacc 5040
gtgtcttcac ggggccttca gaaatagagg atgagaatgg tcagaggaag cccacagatg 5100
agcacgtggc actgtctgct ctgagacact gggaggacat cccccgggtg ggctgccgcc 5160
ttgtgccgga acacgtggag accaggccgc tgctcaaccc tgacaagcca ggcattgagc 5220
agggccgcct ggagctgtgg gtggacatgt tccccatgga catgccagcc cctgggacac 5280
ctctggatat atcccccagg aaacccaaga agtacgagct gcgggtcatc gtgtggaaca 5340
cagacgaggt ggtcctggaa gacgatgatt tcttcacggg agagaagtcc agtgacattt 5400
ttgtgagggg gtggctgaag ggccagcagg aggacaaaca ggacacagat gtccactatc 5460
actccctcac gggggagggc aacttcaact ggagatacct cttccccttc gactacctag 5520
cggccgaaga gaagatcgtt atgtccaaaa aggagtctat gttctcctgg gatgagacgg 5580
agtacaagat ccctgcgcgg ctcaccctgc agatctggga cgctgaccac ttctcggctg 5640
acgacttcct gggggctatc gagctggacc tgaaccggtt cccgaggggc gctaagacag 5700
ccaagcagtg caccatggag atggccaccg gggaggtgga cgtacccctg gtttccatct 5760
ttaaacagaa acgtgtcaaa ggctggtggc ccctcctggc ccgcaatgag aatgatgagt 5820
ttgagctcac aggcaaagtg gaggcggagc tacacctact cacggcagag gaggcagaga 5880
agaaccctgt gggcctggct cgcaatgaac ctgatcccct agaaaaaccc aaccggcctg 5940
acacggcatt cgtctggttc ctgaacccac tcaaatctat caagtacctc atctgcaccc 6000
ggtacaagtg gctgatcatc aagatcgtgc tggcgctgct ggggctgctc atgctggccc 6060
tcttccttta cagcctccca ggctacatgg tcaagaagct cctaggggcc tgaagtgtgc 6120
cccaccccag cccgctccag catccctcca ggggctgctg cgtattttgc cttccctcac 6180
ctggactctc tcccaactcc ctgaggagcc ctcccacgcc tgccagcctt gagcaagaca 6240
cctgcttgct ggacttcatc cccaccccac acccaaactg ttgcttgcct gatcttgtcc 6300
caggcctgcc tggggtttgg ggcacagttg gcctccaaaa ccagataccc tcttgtctaa 6360
agtaccaggt tcctctgccc aaccccaaga gtggtagtgg cccaaccctc cctgtgcttt 6420
ccaaatcttg tcttaaggca ccagtgaaat taaccaagaa acgcggagca atgcccaagg 6480
ctctgatgag taggaacacg tggaaagcac caggaatgcc agcagaggcg aggcggcaca 6540
cctctctgca gagcatccag gccgagcggc gggcagcggc cagctgcttc tgcgcatgct 6600
ctcctcttgg ctctgcttct ttctcacagt cacagtcact tcacagctta gccttgggct 6660
tcccatcact tccaggggtg cctctgcctt ggccagtgtg tgtcagctag tacacaagct 6720
ccaagtgtga atcaggtgta ctggccgtcc tgaagactga ctgccctgtc cttcctgccg 6780
acagccacac ccgagtgtac acttaaagcg gtgcccttct gcctctgtgg gcctgctggc 6840
tgctgttcct ttcttgagtg tgattttttt tttctctccc tcaataaaat aaatcaaact 6900
ctgagac 6907
<210> 17
<211> 7009
<212> DNA
<213> artificial
<220>
<223> pTR22-ITR-SmCBA-5'cDNA-otof-SD-RH-ITR
<400> 17
aggggggggg gggggggggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 60
cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 120
agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctcagatc tggcgcgccc 180
aattcggtac cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata 240
tatggagttc cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga 300
cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt 360
ccattgacgt caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt 420
gtatcatatg ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca 480
ttatgcccag tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt 540
catcgctatt accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc 600
cccctcccca cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg 660
ggcggggggg gggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg 720
ggcgaggcgg agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt 780
tatggcgagg cggcggcggc ggcggcccta taaaaagcga agcgcgcggc gggcgggagt 840
cgctgcgacg ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc 900
ggctctgact gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg 960
gctgtaatta gcgcttggtt taatgacggc ttgtttcttt tctgtggctg cgtgaaagcc 1020
ttgaggggct ccgggagcta gagcctctgc taaccatgtt catgccttct tctttttcct 1080
acagctcctg ggcaacgtgc tggttattgt gctgtctcat cattttggca aagaattcta 1140
gcggccgcca ccatggccct gattgttcac ctcaagactg tctcagagct ccgaggcaaa 1200
ggtgaccgga ttgccaaagt cactttccga gggcagtctt tctactcccg ggtcctggag 1260
aactgcgagg gtgtggctga ctttgatgag acgttccggt ggccagtggc cagcagcatc 1320
gaccggaatg aagtgttgga gattcagatt ttcaactaca gcaaagtctt cagcaacaag 1380
ctgataggga ccttctgcat ggtgctgcag aaagtggtgg aggagaatcg ggtagaggtg 1440
accgacacgc tgatggatga cagcaatgct atcatcaaga ccagcctgag catggaggtc 1500
cggtatcagg ccacagatgg cactgtgggc ccctgggatg atggagactt cctgggagat 1560
gaatccctcc aggaggagaa ggacagccag gagacagatg ggctgctacc tggttcccga 1620
cccagcaccc ggatatctgg cgagaagagc tttcgcagca aaggcagaga gaagaccaag 1680
ggaggcagag atggcgagca caaagcggga aggagtgtgt tctcggccat gaaactcggc 1740
aaaactcggt cccacaaaga ggagccccaa agacaagatg agccagcagt gctggagatg 1800
gaggacctgg accacctagc cattcagctg ggggatgggc tggatcctga ctccgtgtct 1860
ctagcctcgg tcaccgctct caccagcaat gtctccaaca aacggtctaa gccagatatt 1920
aagatggagc ccagtgctgg aaggcccatg gattaccagg tcagcatcac agtgattgag 1980
gctcggcagc tggtgggctt gaacatggac cctgtggtgt gtgtggaggt gggtgatgac 2040
aagaaataca cgtcaatgaa ggagtccaca aactgccctt actacaacga gtactttgtc 2100
ttcgacttcc atgtctctcc tgatgtcatg tttgacaaga tcatcaagat ctcggttatc 2160
cattctaaga acctgcttcg gagcggcacc ctggtgggtt ccttcaaaat ggatgtgggg 2220
actgtgtatt cccagcctga acaccagttc catcacaaat gggccatcct gtcagacccc 2280
gatgacatct ctgctgggtt gaagggttat gtaaagtgtg atgtcgctgt ggtgggcaag 2340
ggagacaaca tcaagacacc ccacaaggcc aacgagacgg atgaggacga cattgaaggg 2400
aacttgctgc tccccgaggg cgtgcccccc gaacggcagt gggcacggtt ctatgtgaaa 2460
atttaccgag cagagggact gccccggatg aacacaagcc tcatggccaa cgtgaagaag 2520
gcgttcatcg gtgagaacaa ggacctcgtc gacccctatg tgcaagtctt ctttgctgga 2580
caaaagggca aaacatcagt gcagaagagc agctatgagc cgctatggaa tgagcaggtc 2640
gtcttcacag acttgttccc cccactctgc aaacgcatga aggtgcagat ccgggactct 2700
gacaaggtca atgatgtggc catcggcacc cacttcatcg acctgcgcaa gatttccaac 2760
gatggagaca aaggcttcct gcctaccctc ggtccagcct gggtgaacat gtacggctcc 2820
acgcgcaact acacactgct ggacgagcac caggacttga atgaaggcct gggggagggt 2880
gtgtccttcc gggcccgcct catgttggga ctagctgtgg agatcctgga cacctccaac 2940
ccagagctca ccagctccac ggaggtgcag gtggagcagg ccacgcctgt ctcggagagc 3000
tgcacaggga gaatggaaga attttttcta tttggagcct tcttggaagc ctcaatgatt 3060
gaccggaaaa atggggacaa gccaattacc tttgaggtga ccataggaaa ctacggcaat 3120
gaagtcgatg gtatgtcccg gcccctgagg cctcggcccc ggaaagagcc tggggatgaa 3180
gaagaggtag acctgattca gaactccagt gacgatgaag gtgacgaagc cggggacctg 3240
gcctcggtgt cctccacccc acctatgcgg ccccagatca cggacaggaa ctatttccac 3300
ctgccctacc tggagcgcaa gccctgcatc tatatcaaga gctggtggcc tgaccagagg 3360
cggcgcctct acaatgccaa catcatggat cacattgctg acaagctgga agaaggcctg 3420
aatgatgtac aggagatgat caaaacggag aagtcctacc cggagcgccg cctgcggggt 3480
gtgctagagg aactcagctg tggctgccac cgcttcctct ccctctcgga caaggaccag 3540
ggccgctcgt cccgcaccag gctggatcga gagcgtctta agtcctgtat gagggagttg 3600
gtaagtatca aggttacaag acaggtttaa ggagaccaat agaaactggg cttgtcgaga 3660
cagagaagac tcttgcgttt ctgagctagc ccccgggtgc gcggcgtcgg tggtgccggc 3720
ggggggcgcc aggtcgcagg cggtgtaggg ctccaggcag gcggcgaagg ccatgacgtg 3780
cgctatgaag gtctgctcct gcacgccgtg aaccaggtgc gcctgcgggc cgcgcgcgaa 3840
caccgccacg tcctcgcctg cgtgggtctc ttcgtccagg ggcactgctg actgctgccg 3900
atactcgggg ctcccgctct cgctctcggt aacatccggc cgggcgccgt ccttgagcac 3960
atagcctgga ccgtttcgtc gactgttaat taagcatgct ggggagagat ctaggaaccc 4020
ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga ggccgcccgg 4080
gcaaagcccg ggcgtcgggc gacctttggt cgcccggcct cagtgagcga gcgagcgcgc 4140
agagagggag tggccaaccc cccccccccc ccccctgcag ccctgcatta atgaatcggc 4200
caacgcgcgg ggagaggcgg tttgcgtatt gggcgctctt ccgcttcctc gctcactgac 4260
tcgctgcgct cggtcgttcg gctgcggcga gcggtatcag ctcactcaaa ggcggtaata 4320
cggttatcca cagaatcagg ggataacgca ggaaagaaca tgtgagcaaa aggccagcaa 4380
aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct 4440
gacgagcatc acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa 4500
agataccagg cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg 4560
cttaccggat acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcaatgctca 4620
cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa 4680
ccccccgttc agcccgaccg ctgcgcctta tccggtaact atcgtcttga gtccaacccg 4740
gtaagacacg acttatcgcc actggcagca gccactggta acaggattag cagagcgagg 4800
tatgtaggcg gtgctacaga gttcttgaag tggtggccta actacggcta cactagaagg 4860
acagtatttg gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc 4920
tcttgatccg gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag 4980
attacgcgca gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac 5040
gctcagtgga acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc 5100
ttcacctaga tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag 5160
taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc agcgatctgt 5220
ctatttcgtt catccatagt tgcctgactc cccgtcgtgt agataactac gatacgggag 5280
ggcttaccat ctggccccag tgctgcaatg ataccgcgag acccacgctc accggctcca 5340
gatttatcag caataaacca gccagccgga agggccgagc gcagaagtgg tcctgcaact 5400
ttatccgcct ccatccagtc tattaattgt tgccgggaag ctagagtaag tagttcgcca 5460
gttaatagtt tgcgcaacgt tgttgccatt gctacaggca tcgtggtgtc acgctcgtcg 5520
tttggtatgg cttcattcag ctccggttcc caacgatcaa ggcgagttac atgatccccc 5580
atgttgtgca aaaaagcggt tagctccttc ggtcctccga tcgttgtcag aagtaagttg 5640
gccgcagtgt tatcactcat ggttatggca gcactgcata attctcttac tgtcatgcca 5700
tccgtaagat gcttttctgt gactggtgag tactcaacca agtcattctg agaatagtgt 5760
atgcggcgac cgagttgctc ttgcccggcg tcaatacggg ataataccgc gccacatagc 5820
agaactttaa aagtgctcat cattggaaaa cgttcttcgg ggcgaaaact ctcaaggatc 5880
ttaccgctgt tgagatccag ttcgatgtaa cccactcgtg cacccaactg atcttcagca 5940
tcttttactt tcaccagcgt ttctgggtga gcaaaaacag gaaggcaaaa tgccgcaaaa 6000
aagggaataa gggcgacacg gaaatgttga atactcatac tcttcctttt tcaatattat 6060
tgaagcattt atcagggtta ttgtctcatg agcggataca tatttgaatg tatttagaaa 6120
aataaacaaa taggggttcc gcgcacattt ccccgaaaag tgccacctga cgtctaagaa 6180
accattatta tcatgacatt aacctataaa aataggcgta tcacgaggcc ctttcgtctc 6240
gcgcgtttcg gtgatgacgg tgaaaacctc tgacacatgc agctcccgga gacggtcaca 6300
gcttgtctgt aagcggatgc cgggagcaga caagcccgtc agggcgcgtc agcgggtgtt 6360
ggcgggtgtc ggggctggct taactatgcg gcatcagagc agattgtact gagagtgcac 6420
catatgcggt gtgaaatacc gcacagatgc gtaaggagaa aataccgcat caggaaattg 6480
taaacgttaa tattttgtta aaattcgcgt taaatttttg ttaaatcagc tcatttttta 6540
accaataggc cgaaatcggc aaaatccctt ataaatcaaa agaatagacc gagatagggt 6600
tgagtgttgt tccagtttgg aacaagagtc cactattaaa gaacgtggac tccaacgtca 6660
aagggcgaaa aaccgtctat cagggcgatg gcccactacg tgaaccatca ccctaatcaa 6720
gttttttggg gtcgaggtgc cgtaaagcac taaatcggaa ccctaaaggg agcccccgat 6780
ttagagcttg acggggaaag ccggcgaacg tggcgagaaa ggaagggaag aaagcgaaag 6840
gagcgggcgc tagggcgctg gcaagtgtag cggtcacgct gcgcgtaacc accacacccg 6900
ccgcgcttaa tgcgccgcta cagggcgcgt cgcgccattc gccattcagg ctacgcaact 6960
gttgggaagg gcgatcggtg cgggcctctt cgctattacg ccaggctgc 7009
<210> 18
<211> 7413
<212> DNA
<213> artificial
<220>
<223> pTR22-ITR-RH-SA- 3'cDNAerlin-polyA-ITR
<400> 18
aggggggggg gggggggggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 60
cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 120
agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctcagatc tggcgcgccc 180
aattggcttc gaattctagc ggccgccccc gggtgcgcgg cgtcggtggt gccggcgggg 240
ggcgccaggt cgcaggcggt gtagggctcc aggcaggcgg cgaaggccat gacgtgcgct 300
atgaaggtct gctcctgcac gccgtgaacc aggtgcgcct gcgggccgcg cgcgaacacc 360
gccacgtcct cgcctgcgtg ggtctcttcg tccaggggca ctgctgactg ctgccgatac 420
tcggggctcc cgctctcgct ctcggtaaca tccggccggg cgccgtcctt gagcacatag 480
cctggaccgt ttccttaagc gacgcatgct cgcgataggc acctattggt cttactgaca 540
tccactttgc ctttctctcc acaggagagc atgggacagc aggccaagag cctgagggct 600
caggtgaagc ggcacactgt tcgggacaag ctgaggtcat gccagaactt tctgcagaag 660
ctacgcttcc tggcggatga gccccagcac agcattcctg atgtgttcat ttggatgatg 720
agcaacaaca aacgtatcgc ctatgcccgc gtgccttcca aagacctgct cttctccatc 780
gtggaggagg aactgggcaa ggactgcgcc aaagtcaaga ccctcttcct gaagctgcca 840
gggaagaggg gcttcggctc ggcaggctgg acagtacagg ccaagctgga gctctacctg 900
tggctgggcc tcagcaagca gcgaaaggac ttcctgtgtg gtctgccctg tggcttcgag 960
gaggtcaagg cagcccaagg cctgggcctg cattcctttc cgcccatcag cctagtctac 1020
accaagaagc aagccttcca gctccgagca cacatgtatc aggcccgaag cctctttgct 1080
gctgacagca gtgggctctc tgatcccttt gcccgtgtct tcttcatcaa ccagagccaa 1140
tgcactgagg ttctaaacga gacactgtgt cccacctggg accagatgct ggtatttgac 1200
aacctggagc tgtacggtga agctcacgag ttacgagatg atccccccat cattgtcatt 1260
gaaatctacg accaggacag catgggcaaa gccgacttca tgggccggac cttcgccaag 1320
cccctggtga agatggcaga tgaagcatac tgcccacctc gcttcccgcc gcagcttgag 1380
tactaccaga tctaccgagg cagtgccact gccggagacc tactggctgc cttcgagctg 1440
ctgcagattg ggccatcagg gaaggctgac ctgccaccca tcaatggccc agtggacatg 1500
gacagagggc ccatcatgcc tgtgcccgtg ggaatccggc cagtgctcag caagtaccga 1560
gtggaggtgc tgttctgggg cctgagggac ctaaagaggg tgaacctggc ccaggtggac 1620
cgaccacggg tggacatcga gtgtgcagga aagggggtac aatcctccct gattcacaat 1680
tataagaaga accccaactt caacacgctg gtcaagtggt ttgaagtgga cctcccggag 1740
aatgagctcc tgcacccacc cttgaacatc cgagtggtag attgccgggc ctttggacga 1800
tacaccctgg tgggttccca cgcagtcagc tcactgaggc gcttcatcta ccgacctcca 1860
gaccgctcag cccccaactg gaacaccaca ggggaggttg tagtaagcat ggagcctgag 1920
gagccagtta agaagctgga gaccatggtg aaactggatg cgacttctga tgctgtggtc 1980
aaggtggatg tggctgaaga tgagaaggaa aggaagaaga agaaaaagaa aggcccgtca 2040
gaggagccag aggaggaaga gcccgatgag agcatgctgg attggtggtc caagtacttc 2100
gcctccatcg acacaatgaa ggagcaactt cgacaacatg agacctctgg aactgacttg 2160
gaagagaagg aagagatgga aagcgctgag ggcctgaagg gaccaatgaa gagcaaggag 2220
aagtccagag ctgcaaagga ggagaaaaag aagaaaaacc agagccctgg ccctggccag 2280
ggatcggagg ctcctgagaa gaagaaagcc aagatcgatg agcttaaggt gtaccccaag 2340
gagctggaat cggagtttga cagctttgag gactggctgc acaccttcaa cctgttgagg 2400
ggcaagacgg gagatgatga ggatggctcc acagaggagg agcgcatagt aggccgattc 2460
aagggctccc tctgtgtgta caaagtgcca ctcccagaag atgtatctcg agaagctggc 2520
tatgatccca cctatggaat gttccagggc atcccaagca atgaccccat caatgtgctg 2580
gtccgaatct atgtggtccg ggccacagac ctgcacccgg ccgacatcaa tggcaaagct 2640
gacccctata ttgccatcaa gttaggcaag accgacatcc gagacaagga gaactacatc 2700
tccaagcagc tcaaccctgt gtttgggaag tcctttgaca ttgaggcctc cttccccatg 2760
gagtccatgt tgacagtggc cgtgtacgac tgggatctgg tgggcactga tgacctcatc 2820
ggagaaacca agattgacct ggaaaaccgc ttctacagca agcatcgcgc cacctgcggc 2880
atcgcacaga cctattccat acatggctac aatatctgga gggaccccat gaagcccagc 2940
cagatcctga cacgcctctg taaagagggc aaagtggacg gcccccactt tggtccccat 3000
gggagagtga gggttgccaa ccgtgtcttc acggggcctt cagaaataga ggatgagaat 3060
ggtcagagga agcccacaga tgagcacgtg gcactgtctg ctctgagaca ctgggaggac 3120
atcccccggg tgggctgccg ccttgtgccg gaacacgtgg agaccaggcc gctgctcaac 3180
cctgacaagc caggcattga gcagggccgc ctggagctgt gggtggacat gttccccatg 3240
gacatgccag cccctgggac acctctggat atatccccca ggaaacccaa gaagtacgag 3300
ctgcgggtca tcgtgtggaa cacagacgag gtggtcctgg aagacgatga tttcttcacg 3360
ggagagaagt ccagtgacat ttttgtgagg gggtggctga agggccagca ggaggacaaa 3420
caggacacag atgtccacta tcactccctc acgggggagg gcaacttcaa ctggagatac 3480
ctcttcccct tcgactacct agcggccgaa gagaagatcg ttatgtccaa aaaggagtct 3540
atgttctcct gggatgagac ggagtacaag atccctgcgc ggctcaccct gcagatctgg 3600
gacgctgacc acttctcggc tgacgacttc ctgggggcta tcgagctgga cctgaaccgg 3660
ttcccgaggg gcgctaagac agccaagcag tgcaccatgg agatggccac cggggaggtg 3720
gacgtacccc tggtttccat ctttaaacag aaacgtgtca aaggctggtg gcccctcctg 3780
gcccgcaatg agaatgatga gtttgagctc acaggcaaag tggaggcgga gctacaccta 3840
ctcacggcag aggaggcaga gaagaaccct gtgggcctgg ctcgcaatga acctgatccc 3900
ctagaaaaac ccaaccggcc tgacacggca ttcgtctggt tcctgaaccc actcaaatct 3960
atcaagtacc tcatctgcac ccggtacaag tggctgatca tcaagatcgt gctggcgctg 4020
ctggggctgc tcatgctggc cctcttcctt tacagcctcc caggctacat ggtcaagaag 4080
ctcctagggg cctgagcggc cgcggtacca agggcgaatt ctgcagtcga ctagagctcg 4140
ctgatcagcc tcgactgtgc cttctagttg ccagccatct gttgtttgcc cctcccccgt 4200
gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataaa atgaggaaat 4260
tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg ggcaggacag 4320
caagggggag gattgggaag acaatagcag gcatgctggg gagagatctg aggactagtc 4380
cgtcgactgt taattaagca tgctggggag agatctagga acccctagtg atggagttgg 4440
ccactccctc tctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 4500
gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 4560
accccccccc ccccccccct gcagccctgc attaatgaat cggccaacgc gcggggagag 4620
gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg cgctcggtcg 4680
ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta tccacagaat 4740
caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta 4800
aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag catcacaaaa 4860
atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac caggcgtttc 4920
cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc ggatacctgt 4980
ccgcctttct cccttcggga agcgtggcgc tttctcaatg ctcacgctgt aggtatctca 5040
gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc gttcagcccg 5100
accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga cacgacttat 5160
cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta ggcggtgcta 5220
cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta tttggtatct 5280
gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga tccggcaaac 5340
aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg cgcagaaaaa 5400
aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa 5460
actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt 5520
taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca 5580
gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca 5640
tagttgcctg actccccgtc gtgtagataa ctacgatacg ggagggctta ccatctggcc 5700
ccagtgctgc aatgataccg cgagacccac gctcaccggc tccagattta tcagcaataa 5760
accagccagc cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc 5820
agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat agtttgcgca 5880
acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat 5940
tcagctccgg ttcccaacga tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag 6000
cggttagctc cttcggtcct ccgatcgttg tcagaagtaa gttggccgca gtgttatcac 6060
tcatggttat ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt 6120
ctgtgactgg tgagtactca accaagtcat tctgagaata gtgtatgcgg cgaccgagtt 6180
gctcttgccc ggcgtcaata cgggataata ccgcgccaca tagcagaact ttaaaagtgc 6240
tcatcattgg aaaacgttct tcggggcgaa aactctcaag gatcttaccg ctgttgagat 6300
ccagttcgat gtaacccact cgtgcaccca actgatcttc agcatctttt actttcacca 6360
gcgtttctgg gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga 6420
cacggaaatg ttgaatactc atactcttcc tttttcaata ttattgaagc atttatcagg 6480
gttattgtct catgagcgga tacatatttg aatgtattta gaaaaataaa caaatagggg 6540
ttccgcgcac atttccccga aaagtgccac ctgacgtcta agaaaccatt attatcatga 6600
cattaaccta taaaaatagg cgtatcacga ggccctttcg tctcgcgcgt ttcggtgatg 6660
acggtgaaaa cctctgacac atgcagctcc cggagacggt cacagcttgt ctgtaagcgg 6720
atgccgggag cagacaagcc cgtcagggcg cgtcagcggg tgttggcggg tgtcggggct 6780
ggcttaacta tgcggcatca gagcagattg tactgagagt gcaccatatg cggtgtgaaa 6840
taccgcacag atgcgtaagg agaaaatacc gcatcaggaa attgtaaacg ttaatatttt 6900
gttaaaattc gcgttaaatt tttgttaaat cagctcattt tttaaccaat aggccgaaat 6960
cggcaaaatc ccttataaat caaaagaata gaccgagata gggttgagtg ttgttccagt 7020
ttggaacaag agtccactat taaagaacgt ggactccaac gtcaaagggc gaaaaaccgt 7080
ctatcagggc gatggcccac tacgtgaacc atcaccctaa tcaagttttt tggggtcgag 7140
gtgccgtaaa gcactaaatc ggaaccctaa agggagcccc cgatttagag cttgacgggg 7200
aaagccggcg aacgtggcga gaaaggaagg gaagaaagcg aaaggagcgg gcgctagggc 7260
gctggcaagt gtagcggtca cgctgcgcgt aaccaccaca cccgccgcgc ttaatgcgcc 7320
gctacagggc gcgtcgcgcc attcgccatt caggctacgc aactgttggg aagggcgatc 7380
ggtgcgggcc tcttcgctat tacgccaggc tgc 7413
<210> 19
<211> 6967
<212> DNA
<213> artificial
<220>
<223> pTR22-SmCBA-OtoferlinNT-SD-RH-ITR
<400> 19
aggggggggg gggggggggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 60
cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 120
agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctcagatc tggcgcgccc 180
aattcggtac cctagttatt aatagtaatc aattacgggg tcattagttc atagcccata 240
tatggagttc cgcgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga 300
cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt 360
ccattgacgt caatgggtgg actatttacg gtaaactgcc cacttggcag tacatcaagt 420
gtatcatatg ccaagtacgc cccctattga cgtcaatgac ggtaaatggc ccgcctggca 480
ttatgcccag tacatgacct tatgggactt tcctacttgg cagtacatct acgtattagt 540
catcgctatt accatggtcg aggtgagccc cacgttctgc ttcactctcc ccatctcccc 600
cccctcccca cccccaattt tgtatttatt tattttttaa ttattttgtg cagcgatggg 660
ggcggggggg gggggggggc gcgcgccagg cggggcgggg cggggcgagg ggcggggcgg 720
ggcgaggcgg agaggtgcgg cggcagccaa tcagagcggc gcgctccgaa agtttccttt 780
tatggcgagg cggcggcggc ggcggcccta taaaaagcga agcgcgcggc gggcgggagt 840
cgctgcgacg ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc 900
ggctctgact gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg 960
gctgtaatta gcgcttggtt taatgacggc ttgtttcttt tctgtggctg cgtgaaagcc 1020
ttgaggggct ccgggagcta gagcctctgc taaccatgtt catgccttct tctttttcct 1080
acagctcctg ggcaacgtgc tggttattgt gctgtctcat cattttggca aagaattcta 1140
gcggccgcca ccatggcctt gctcatccac ctcaagacag tctcggagct gcggggcagg 1200
ggcgaccgga tcgccaaagt gactttccga gggcaatcct tctactctcg ggtcctggag 1260
aactgtgagg atgtggctga ctttgatgag acatttcggt ggccggtggc cagcagcatc 1320
gacagaaatg agatgctgga gattcaggtt ttcaactaca gcaaagtctt cagcaacaag 1380
ctcatcggga ccttccgcat ggtgctgcag aaggtggtag aggagagcca tgtggaggtg 1440
actgacacgc tgattgatga caacaatgct atcatcaaga ccagcctgtg cgtggaggtc 1500
cggtatcagg ccactgacgg cacagtgggc tcctgggacg atggggactt cctgggagat 1560
gagtctcttc aagaggaaga gaaggacagc caagagacgg atggactgct cccaggctcc 1620
cggcccagct cccggccccc aggagagaag agcttccgga gagccgggag gagcgtgttc 1680
tccgccatga agctcggcaa aaaccggtct cacaaggagg agccccaaag accagatgaa 1740
ccggcggtgc tggagatgga agaccttgac catctggcca ttcggctagg agatggactg 1800
gatcccgact cggtgtctct agcctcagtc acagctctca ccactaatgt ctccaacaag 1860
cgatctaagc cagacattaa gatggagcca agtgctgggc ggcccatgga ttaccaggtc 1920
agcatcacgg tgatcgaggc ccggcagctg gtgggcttga acatggaccc tgtggtgtgc 1980
gtggaggtgg gtgacgacaa gaagtacaca tccatgaagg agtccactaa ctgcccctat 2040
tacaacgagt acttcgtctt cgacttccat gtctctccgg atgtcatgtt tgacaagatc 2100
atcaagattt cggtgattca ctccaagaac ctgctgcgca gtggcaccct ggtgggctcc 2160
ttcaaaatgg acgtgggaac cgtgtactcg cagccagagc accagttcca tcacaagtgg 2220
gccatcctgt ctgaccccga tgacatctcc tcggggctga agggctacgt gaagtgtgac 2280
gttgccgtgg tgggcaaagg ggacaacatc aagacgcccc acaaggccaa tgagaccgac 2340
gaagatgaca ttgaggggaa cttgctgctc cccgaggggg tgccccccga acgccagtgg 2400
gcccggttct atgtgaaaat ttaccgagca gaggggctgc cccgtatgaa cacaagcctc 2460
atggccaatg taaagaaggc tttcatcggt gaaaacaagg acctcgtgga cccctacgtg 2520
caagtcttct ttgctggcca gaagggcaag acttcagtgc agaagagcag ctatgagccc 2580
ctgtggaatg agcaggtcgt ctttacagac ctcttccccc cactctgcaa acgcatgaag 2640
gtgcagatcc gagactcgga caaggtcaac gacgtggcca tcggcaccca cttcattgac 2700
ctgcgcaaga tttctaatga cggagacaaa ggcttcctgc ccacactggg cccagcctgg 2760
gtgaacatgt acggctccac acgtaactac acgctgctgg atgagcatca ggacctgaac 2820
gagggcctgg gggagggtgt gtccttccgg gcccggctcc tgctgggcct ggctgtggag 2880
atcgtagaca cctccaaccc tgagctcacc agctccacag aggtgcaggt ggagcaggcc 2940
acgcccatct cggagagctg tgcaggtaaa atggaagaat tctttctctt tggagccttc 3000
ctggaggcct caatgatcga ccggagaaac ggagacaagc ccatcacctt tgaggtcacc 3060
ataggcaact atgggaacga agttgatggc ctgtcccggc cccagcggcc tcggccccgg 3120
aaggagccgg gggatgagga agaagtagac ctgattcaga acgcaagtga tgacgaggcc 3180
ggtgatgccg gggacctggc ctcagtctcc tccactccac caatgcggcc ccaggtcacc 3240
gacaggaact acttccatct gccctacctg gagcgaaagc cctgcatcta catcaagagc 3300
tggtggccgg accagcgccg ccgcctctac aatgccaaca tcatggacca cattgccgac 3360
aagctggaag aaggcctgaa cgacatacag gagatgatca aaacggagaa gtcctaccct 3420
gagcgtcgcc tgcggggcgt cctggaggag ctgagctgtg gctgctgccg cttcctctcc 3480
ctcgctgaca aggaccaggg ccactcatcc cgcaccaggc ttgaccggga gcgcctcaag 3540
tcctgcatga gggagctggt aagtatcaag gttacaagac aggtttaagg agaccaatag 3600
aaactgggct tgtcgagaca gagaagactc ttgcgtttct gagctagccc ccgggtgcgc 3660
ggcgtcggtg gtgccggcgg ggggcgccag gtcgcaggcg gtgtagggct ccaggcaggc 3720
ggcgaaggcc atgacgtgcg ctatgaaggt ctgctcctgc acgccgtgaa ccaggtgcgc 3780
ctgcgggccg cgcgcgaaca ccgccacgtc ctcgcctgcg tgggtctctt cgtccagggg 3840
cactgctgac tgctgccgat actcggggct cccgctctcg ctctcggtaa catccggccg 3900
ggcgccgtcc ttgagcacat agcctggacc gtttcgtcga ctgttaatta agcatgctgg 3960
ggagagatct aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg 4020
ctcactgagg ccgcccgggc aaagcccggg cgtcgggcga cctttggtcg cccggcctca 4080
gtgagcgagc gagcgcgcag agagggagtg gccaaccccc cccccccccc ccctgcagcc 4140
ctgcattaat gaatcggcca acgcgcgggg agaggcggtt tgcgtattgg gcgctcttcc 4200
gcttcctcgc tcactgactc gctgcgctcg gtcgttcggc tgcggcgagc ggtatcagct 4260
cactcaaagg cggtaatacg gttatccaca gaatcagggg ataacgcagg aaagaacatg 4320
tgagcaaaag gccagcaaaa ggccaggaac cgtaaaaagg ccgcgttgct ggcgtttttc 4380
cataggctcc gcccccctga cgagcatcac aaaaatcgac gctcaagtca gaggtggcga 4440
aacccgacag gactataaag ataccaggcg tttccccctg gaagctccct cgtgcgctct 4500
cctgttccga ccctgccgct taccggatac ctgtccgcct ttctcccttc gggaagcgtg 4560
gcgctttctc aatgctcacg ctgtaggtat ctcagttcgg tgtaggtcgt tcgctccaag 4620
ctgggctgtg tgcacgaacc ccccgttcag cccgaccgct gcgccttatc cggtaactat 4680
cgtcttgagt ccaacccggt aagacacgac ttatcgccac tggcagcagc cactggtaac 4740
aggattagca gagcgaggta tgtaggcggt gctacagagt tcttgaagtg gtggcctaac 4800
tacggctaca ctagaaggac agtatttggt atctgcgctc tgctgaagcc agttaccttc 4860
ggaaaaagag ttggtagctc ttgatccggc aaacaaacca ccgctggtag cggtggtttt 4920
tttgtttgca agcagcagat tacgcgcaga aaaaaaggat ctcaagaaga tcctttgatc 4980
ttttctacgg ggtctgacgc tcagtggaac gaaaactcac gttaagggat tttggtcatg 5040
agattatcaa aaaggatctt cacctagatc cttttaaatt aaaaatgaag ttttaaatca 5100
atctaaagta tatatgagta aacttggtct gacagttacc aatgcttaat cagtgaggca 5160
cctatctcag cgatctgtct atttcgttca tccatagttg cctgactccc cgtcgtgtag 5220
ataactacga tacgggaggg cttaccatct ggccccagtg ctgcaatgat accgcgagac 5280
ccacgctcac cggctccaga tttatcagca ataaaccagc cagccggaag ggccgagcgc 5340
agaagtggtc ctgcaacttt atccgcctcc atccagtcta ttaattgttg ccgggaagct 5400
agagtaagta gttcgccagt taatagtttg cgcaacgttg ttgccattgc tacaggcatc 5460
gtggtgtcac gctcgtcgtt tggtatggct tcattcagct ccggttccca acgatcaagg 5520
cgagttacat gatcccccat gttgtgcaaa aaagcggtta gctccttcgg tcctccgatc 5580
gttgtcagaa gtaagttggc cgcagtgtta tcactcatgg ttatggcagc actgcataat 5640
tctcttactg tcatgccatc cgtaagatgc ttttctgtga ctggtgagta ctcaaccaag 5700
tcattctgag aatagtgtat gcggcgaccg agttgctctt gcccggcgtc aatacgggat 5760
aataccgcgc cacatagcag aactttaaaa gtgctcatca ttggaaaacg ttcttcgggg 5820
cgaaaactct caaggatctt accgctgttg agatccagtt cgatgtaacc cactcgtgca 5880
cccaactgat cttcagcatc ttttactttc accagcgttt ctgggtgagc aaaaacagga 5940
aggcaaaatg ccgcaaaaaa gggaataagg gcgacacgga aatgttgaat actcatactc 6000
ttcctttttc aatattattg aagcatttat cagggttatt gtctcatgag cggatacata 6060
tttgaatgta tttagaaaaa taaacaaata ggggttccgc gcacatttcc ccgaaaagtg 6120
ccacctgacg tctaagaaac cattattatc atgacattaa cctataaaaa taggcgtatc 6180
acgaggccct ttcgtctcgc gcgtttcggt gatgacggtg aaaacctctg acacatgcag 6240
ctcccggaga cggtcacagc ttgtctgtaa gcggatgccg ggagcagaca agcccgtcag 6300
ggcgcgtcag cgggtgttgg cgggtgtcgg ggctggctta actatgcggc atcagagcag 6360
attgtactga gagtgcacca tatgcggtgt gaaataccgc acagatgcgt aaggagaaaa 6420
taccgcatca ggaaattgta aacgttaata ttttgttaaa attcgcgtta aatttttgtt 6480
aaatcagctc attttttaac caataggccg aaatcggcaa aatcccttat aaatcaaaag 6540
aatagaccga gatagggttg agtgttgttc cagtttggaa caagagtcca ctattaaaga 6600
acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggc ccactacgtg 6660
aaccatcacc ctaatcaagt tttttggggt cgaggtgccg taaagcacta aatcggaacc 6720
ctaaagggag cccccgattt agagcttgac ggggaaagcc ggcgaacgtg gcgagaaagg 6780
aagggaagaa agcgaaagga gcgggcgcta gggcgctggc aagtgtagcg gtcacgctgc 6840
gcgtaaccac cacacccgcc gcgcttaatg cgccgctaca gggcgcgtcg cgccattcgc 6900
cattcaggct acgcaactgt tgggaagggc gatcggtgcg ggcctcttcg ctattacgcc 6960
aggctgc 6967
<210> 20
<211> 7470
<212> DNA
<213> artificial
<220>
<223> pTR22-ITR-RH-SA-OtoferlinCT-polyA-ITR
<400> 20
aggggggggg gggggggggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 60
cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 120
agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctcagatc tggcgcgccc 180
aattggcttc gaattctagc ggccgccccc gggtgcgcgg cgtcggtggt gccggcgggg 240
ggcgccaggt cgcaggcggt gtagggctcc aggcaggcgg cgaaggccat gacgtgcgct 300
atgaaggtct gctcctgcac gccgtgaacc aggtgcgcct gcgggccgcg cgcgaacacc 360
gccacgtcct cgcctgcgtg ggtctcttcg tccaggggca ctgctgactg ctgccgatac 420
tcggggctcc cgctctcgct ctcggtaaca tccggccggg cgccgtcctt gagcacatag 480
cctggaccgt ttccttaagc gacgcatgct cgcgataggc acctattggt cttactgaca 540
tccactttgc ctttctctcc acaggaaaac atggggcagc aggccaggat gctgcgggcc 600
caggtgaagc ggcacacggt gcgggacaag ctgaggctgt gccagaactt cctgcagaag 660
ctgcgcttcc tggcggacga gccccagcac agcattcccg acatcttcat ctggatgatg 720
agcaacaaca agcgtgtcgc ctatgcccgt gtgccctcca aggacctgct cttctccatc 780
gtggaggagg agactggcaa ggactgcgcc aaggtcaaga cgctcttcct taagctgcca 840
gggaagcggg gcttcggctc ggcaggctgg acagtgcagg ccaaggtgga gctgtacctg 900
tggctgggcc tcagcaaaca gcgcaaggag ttcctgtgcg gcctgccctg tggcttccag 960
gaggtcaagg cagcccaggg cctgggcctg catgccttcc cacccgtcag cctggtctac 1020
accaagaagc aggcgttcca gctccgagcg cacatgtacc aggcccgcag cctctttgcc 1080
gccgacagca gcggactctc agaccccttt gcccgcgtct tcttcatcaa tcagagtcag 1140
tgcacagagg tgctgaatga gaccctgtgt cccacctggg accagatgct ggtgttcgac 1200
aacctggagc tctatggtga agctcatgag ctgagggacg atccgcccat cattgtcatt 1260
gaaatctatg accaggattc catgggcaaa gctgacttca tgggccggac cttcgccaaa 1320
cccctggtga agatggcaga cgaggcgtac tgcccacccc gcttcccacc tcagctcgag 1380
tactaccaga tctaccgtgg caacgccaca gctggagacc tgctggcggc cttcgagctg 1440
ctgcagattg gaccagcagg gaaggctgac ctgcccccca tcaatggccc ggtggacgtg 1500
gaccgaggtc ccatcatgcc cgtgcccatg ggcatccggc ccgtgctcag caagtaccga 1560
gtggaggtgc tgttctgggg cctacgggac ctaaagcggg tgaacctggc ccaggtggac 1620
cggccacggg tggacatcga gtgtgcaggg aagggggtgc agtcgtccct gatccacaat 1680
tataagaaga accccaactt caacaccctc gtcaagtggt ttgaagtgga cctcccagag 1740
aacgagctgc tgcacccgcc cttgaacatc cgtgtggtgg actgccgggc cttcggtcgc 1800
tacacactgg tgggctccca tgccgtcagc tccctgcgac gcttcatcta ccggccccca 1860
gaccgctcgg cccccagctg gaacaccacg gtcaggcttc tccggcgctg ccgtgtgctg 1920
tgcaatgggg gctcctcctc tcactccaca ggggaggttg tggtgactat ggagccagag 1980
gtacccatca agaaactgga gaccatggtg aagctggacg cgacttctga agctgttgtc 2040
aaggtggatg tggctgagga ggagaaggag aagaagaaga agaagaaggg cactgcggag 2100
gagccagagg aggaggagcc agacgagagc atgctggact ggtggtccaa gtactttgcc 2160
tccattgaca ccatgaagga gcaacttcga caacaagagc cctctggaat tgacttggag 2220
gagaaggagg aagtggacaa taccgagggc ctgaaggggt caatgaaggg caaggagaag 2280
gcaagggctg ccaaagagga gaagaagaag aaaactcaga gctctggctc tggccagggg 2340
tccgaggccc ccgagaagaa gaaacccaag attgatgagc ttaaggtata ccccaaagag 2400
ctggagtccg agtttgataa ctttgaggac tggctgcaca ctttcaactt gcttcggggc 2460
aagaccgggg atgatgagga tggctccacc gaggaggagc gcattgtggg acgcttcaag 2520
ggctccctct gcgtgtacaa agtgccactc ccagaggacg tgtcccggga agccggctac 2580
gactccacct acggcatgtt ccagggcatc ccgagcaatg accccatcaa tgtgctggtc 2640
cgagtctatg tggtccgggc cacggacctg caccctgctg acatcaacgg caaagctgac 2700
ccctacatcg ccatccggct aggcaagact gacatccgcg acaaggagaa ctacatctcc 2760
aagcagctca accctgtctt tgggaagtcc tttgacatcg aggcctcctt ccccatggaa 2820
tccatgctga cggtggctgt gtatgactgg gacctggtgg gcactgatga cctcattggg 2880
gaaaccaaga tcgacctgga gaaccgcttc tacagcaagc accgcgccac ctgcggcatc 2940
gcccagacct actccacaca tggctacaat atctggcggg accccatgaa gcccagccag 3000
atcctgaccc gcctctgcaa agacggcaaa gtggacggcc cccactttgg gccccctggg 3060
agagtgaagg tggccaaccg cgtcttcact gggccctctg agattgagga cgagaacggt 3120
cagaggaagc ccacagacga gcatgtggcg ctgttggccc tgaggcactg ggaggacatc 3180
ccccgcgcag gctgccgcct ggtgccagag catgtggaga cgaggccgct gctcaacccc 3240
gacaagccgg gcatcgagca gggccgcctg gagctgtggg tggacatgtt ccccatggac 3300
atgccagccc ctgggacgcc tctggacatc tcacctcgga agcccaagaa gtacgagctg 3360
cgggtcatca tctggaacac agatgaggtg gtcttggagg acgacgactt cttcacaggg 3420
gagaagtcca gtgacatctt cgtgaggggg tggctgaagg gccagcagga ggacaagcag 3480
gacacagacg tccactacca ctccctcact ggcgagggca acttcaactg gcgctacctg 3540
ttccccttcg actacctggc ggcggaggag aagatcgtca tctccaagaa ggagtccatg 3600
ttctcctggg acgagaccga gtacaagatc cccgcgcggc tcaccctgca gatctgggat 3660
gcggaccact tctccgctga cgacttcctg ggggccatcg agctggacct gaaccggttc 3720
ccgcggggcg caaagacagc caagcagtgc accatggaga tggccaccgg ggaggtggac 3780
gtgcccctcg tgtccatctt caagcaaaag cgcgtcaaag gctggtggcc cctcctggcc 3840
cgcaatgaga acgatgagtt tgagctcacg ggcaaggtgg aggctgagct gcatttactg 3900
acagcagagg aggcagagaa gaacccagtg ggcctggccc gcaatgaacc tgacccccta 3960
gagaaaccca accggcccga cacgagcttc atctggttcc tgaaccctct caagtcggct 4020
cgctacttct tgtggcacac gtatcgctgg ctgctcctca aactgttgct gctcctgctg 4080
ctgctcctcc tcctcgccct gttcctctac tctgtgcctg gctacctggt caagaaaatc 4140
ctcggggcct gagcggccgc ggtaccaagg gcgaattctg cagtcgacta gagctcgctg 4200
atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct cccccgtgcc 4260
ttccttgacc ctggaaggtg ccactcccac tgtcctttcc taataaaatg aggaaattgc 4320
atcgcattgt ctgagtaggt gtcattctat tctggggggt ggggtggggc aggacagcaa 4380
gggggaggat tgggaagaca atagcaggca tgctggggag agatctgagg actagtccgt 4440
cgactgttaa ttaagcatgc tggggagaga tctaggaacc cctagtgatg gagttggcca 4500
ctccctctct gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg 4560
cgacctttgg tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaacc 4620
cccccccccc cccccctgca gccctgcatt aatgaatcgg ccaacgcgcg gggagaggcg 4680
gtttgcgtat tgggcgctct tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc 4740
ggctgcggcg agcggtatca gctcactcaa aggcggtaat acggttatcc acagaatcag 4800
gggataacgc aggaaagaac atgtgagcaa aaggccagca aaaggccagg aaccgtaaaa 4860
aggccgcgtt gctggcgttt ttccataggc tccgcccccc tgacgagcat cacaaaaatc 4920
gacgctcaag tcagaggtgg cgaaacccga caggactata aagataccag gcgtttcccc 4980
ctggaagctc cctcgtgcgc tctcctgttc cgaccctgcc gcttaccgga tacctgtccg 5040
cctttctccc ttcgggaagc gtggcgcttt ctcaatgctc acgctgtagg tatctcagtt 5100
cggtgtaggt cgttcgctcc aagctgggct gtgtgcacga accccccgtt cagcccgacc 5160
gctgcgcctt atccggtaac tatcgtcttg agtccaaccc ggtaagacac gacttatcgc 5220
cactggcagc agccactggt aacaggatta gcagagcgag gtatgtaggc ggtgctacag 5280
agttcttgaa gtggtggcct aactacggct acactagaag gacagtattt ggtatctgcg 5340
ctctgctgaa gccagttacc ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa 5400
ccaccgctgg tagcggtggt ttttttgttt gcaagcagca gattacgcgc agaaaaaaag 5460
gatctcaaga agatcctttg atcttttcta cggggtctga cgctcagtgg aacgaaaact 5520
cacgttaagg gattttggtc atgagattat caaaaaggat cttcacctag atccttttaa 5580
attaaaaatg aagttttaaa tcaatctaaa gtatatatga gtaaacttgg tctgacagtt 5640
accaatgctt aatcagtgag gcacctatct cagcgatctg tctatttcgt tcatccatag 5700
ttgcctgact ccccgtcgtg tagataacta cgatacggga gggcttacca tctggcccca 5760
gtgctgcaat gataccgcga gacccacgct caccggctcc agatttatca gcaataaacc 5820
agccagccgg aagggccgag cgcagaagtg gtcctgcaac tttatccgcc tccatccagt 5880
ctattaattg ttgccgggaa gctagagtaa gtagttcgcc agttaatagt ttgcgcaacg 5940
ttgttgccat tgctacaggc atcgtggtgt cacgctcgtc gtttggtatg gcttcattca 6000
gctccggttc ccaacgatca aggcgagtta catgatcccc catgttgtgc aaaaaagcgg 6060
ttagctcctt cggtcctccg atcgttgtca gaagtaagtt ggccgcagtg ttatcactca 6120
tggttatggc agcactgcat aattctctta ctgtcatgcc atccgtaaga tgcttttctg 6180
tgactggtga gtactcaacc aagtcattct gagaatagtg tatgcggcga ccgagttgct 6240
cttgcccggc gtcaatacgg gataataccg cgccacatag cagaacttta aaagtgctca 6300
tcattggaaa acgttcttcg gggcgaaaac tctcaaggat cttaccgctg ttgagatcca 6360
gttcgatgta acccactcgt gcacccaact gatcttcagc atcttttact ttcaccagcg 6420
tttctgggtg agcaaaaaca ggaaggcaaa atgccgcaaa aaagggaata agggcgacac 6480
ggaaatgttg aatactcata ctcttccttt ttcaatatta ttgaagcatt tatcagggtt 6540
attgtctcat gagcggatac atatttgaat gtatttagaa aaataaacaa ataggggttc 6600
cgcgcacatt tccccgaaaa gtgccacctg acgtctaaga aaccattatt atcatgacat 6660
taacctataa aaataggcgt atcacgaggc cctttcgtct cgcgcgtttc ggtgatgacg 6720
gtgaaaacct ctgacacatg cagctcccgg agacggtcac agcttgtctg taagcggatg 6780
ccgggagcag acaagcccgt cagggcgcgt cagcgggtgt tggcgggtgt cggggctggc 6840
ttaactatgc ggcatcagag cagattgtac tgagagtgca ccatatgcgg tgtgaaatac 6900
cgcacagatg cgtaaggaga aaataccgca tcaggaaatt gtaaacgtta atattttgtt 6960
aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg ccgaaatcgg 7020
caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtgttg ttccagtttg 7080
gaacaagagt ccactattaa agaacgtgga ctccaacgtc aaagggcgaa aaaccgtcta 7140
tcagggcgat ggcccactac gtgaaccatc accctaatca agttttttgg ggtcgaggtg 7200
ccgtaaagca ctaaatcgga accctaaagg gagcccccga tttagagctt gacggggaaa 7260
gccggcgaac gtggcgagaa aggaagggaa gaaagcgaaa ggagcgggcg ctagggcgct 7320
ggcaagtgta gcggtcacgc tgcgcgtaac caccacaccc gccgcgctta atgcgccgct 7380
acagggcgcg tcgcgccatt cgccattcag gctacgcaac tgttgggaag ggcgatcggt 7440
gcgggcctct tcgctattac gccaggctgc 7470
<210> 21
<211> 7470
<212> DNA
<213> artificial
<220>
<223> pTR22-ITR-RH-SA-OtoferlinCT-polyA-ITR
<400> 21
aggggggggg gggggggggt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc 60
cgggcgacca aaggtcgccc gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg 120
agcgcgcaga gagggagtgg ccaactccat cactaggggt tcctcagatc tggcgcgccc 180
aattggcttc gaattctagc ggccgccccc gggtgcgcgg cgtcggtggt gccggcgggg 240
ggcgccaggt cgcaggcggt gtagggctcc aggcaggcgg cgaaggccat gacgtgcgct 300
atgaaggtct gctcctgcac gccgtgaacc aggtgcgcct gcgggccgcg cgcgaacacc 360
gccacgtcct cgcctgcgtg ggtctcttcg tccaggggca ctgctgactg ctgccgatac 420
tcggggctcc cgctctcgct ctcggtaaca tccggccggg cgccgtcctt gagcacatag 480
cctggaccgt ttccttaagc gacgcatgct cgcgataggc acctattggt cttactgaca 540
tccactttgc ctttctctcc acaggaaaac atggggcagc aggccaggat gctgcgggcc 600
caggtgaagc ggcacacggt gcgggacaag ctgaggctgt gccagaactt cctgcagaag 660
ctgcgcttcc tggcggacga gccccagcac agcattcccg acatcttcat ctggatgatg 720
agcaacaaca agcgtgtcgc ctatgcccgt gtgccctcca aggacctgct cttctccatc 780
gtggaggagg agactggcaa ggactgcgcc aaggtcaaga cgctcttcct taagctgcca 840
gggaagcggg gcttcggctc ggcaggctgg acagtgcagg ccaaggtgga gctgtacctg 900
tggctgggcc tcagcaaaca gcgcaaggag ttcctgtgcg gcctgccctg tggcttccag 960
gaggtcaagg cagcccaggg cctgggcctg catgccttcc cacccgtcag cctggtctac 1020
accaagaagc aggcgttcca gctccgagcg cacatgtacc aggcccgcag cctctttgcc 1080
gccgacagca gcggactctc agaccccttt gcccgcgtct tcttcatcaa tcagagtcag 1140
tgcacagagg tgctgaatga gaccctgtgt cccacctggg accagatgct ggtgttcgac 1200
aacctggagc tctatggtga agctcatgag ctgagggacg atccgcccat cattgtcatt 1260
gaaatctatg accaggattc catgggcaaa gctgacttca tgggccggac cttcgccaaa 1320
cccctggtga agatggcaga cgaggcgtac tgcccacccc gcttcccacc tcagctcgag 1380
tactaccaga tctaccgtgg caacgccaca gctggagacc tgctggcggc cttcgagctg 1440
ctgcagattg gaccagcagg gaaggctgac ctgcccccca tcaatggccc ggtggacgtg 1500
gaccgaggtc ccatcatgcc cgtgcccatg ggcatccggc ccgtgctcag caagtaccga 1560
gtggaggtgc tgttctgggg cctacgggac ctaaagcggg tgaacctggc ccaggtggac 1620
cggccacggg tggacatcga gtgtgcaggg aagggggtgc agtcgtccct gatccacaat 1680
tataagaaga accccaactt caacaccctc gtcaagtggt ttgaagtgga cctcccagag 1740
aacgagctgc tgcacccgcc cttgaacatc cgtgtggtgg actgccgggc cttcggtcgc 1800
tacacactgg tgggctccca tgccgtcagc tccctgcgac gcttcatcta ccggccccca 1860
gaccgctcgg cccccagctg gaacaccacg gtcaggcttc tccggcgctg ccgtgtgctg 1920
tgcaatgggg gctcctcctc tcactccaca ggggaggttg tggtgactat ggagccagag 1980
gtacccatca agaaactgga gaccatggtg aagctggacg cgacttctga agctgttgtc 2040
aaggtggatg tggctgagga ggagaaggag aagaagaaga agaagaaggg cactgcggag 2100
gagccagagg aggaggagcc agacgagagc atgctggact ggtggtccaa gtactttgcc 2160
tccattgaca ccatgaagga gcaacttcga caacaagagc cctctggaat tgacttggag 2220
gagaaggagg aagtggacaa taccgagggc ctgaaggggt caatgaaggg caaggagaag 2280
gcaagggctg ccaaagagga gaagaagaag aaaactcaga gctctggctc tggccagggg 2340
tccgaggccc ccgagaagaa gaaacccaag attgatgagc ttaaggtata ccccaaagag 2400
ctggagtccg agtttgataa ctttgaggac tggctgcaca ctttcaactt gcttcggggc 2460
aagaccgggg atgatgagga tggctccacc gaggaggagc gcattgtggg acgcttcaag 2520
ggctccctct gcgtgtacaa agtgccactc ccagaggacg tgtcccggga agccggctac 2580
gactccacct acggcatgtt ccagggcatc ccgagcaatg accccatcaa tgtgctggtc 2640
cgagtctatg tggtccgggc cacggacctg caccctgctg acatcaacgg caaagctgac 2700
ccctacatcg ccatccggct aggcaagact gacatccgcg acaaggagaa ctacatctcc 2760
aagcagctca accctgtctt tgggaagtcc tttgacatcg aggcctcctt ccccatggaa 2820
tccatgctga cggtggctgt gtatgactgg gacctggtgg gcactgatga cctcattggg 2880
gaaaccaaga tcgacctgga gaaccgcttc tacagcaagc accgcgccac ctgcggcatc 2940
gcccagacct actccacaca tggctacaat atctggcggg accccatgaa gcccagccag 3000
atcctgaccc gcctctgcaa agacggcaaa gtggacggcc cccactttgg gccccctggg 3060
agagtgaagg tggccaaccg cgtcttcact gggccctctg agattgagga cgagaacggt 3120
cagaggaagc ccacagacga gcatgtggcg ctgttggccc tgaggcactg ggaggacatc 3180
ccccgcgcag gctgccgcct ggtgccagag catgtggaga cgaggccgct gctcaacccc 3240
gacaagccgg gcatcgagca gggccgcctg gagctgtggg tggacatgtt ccccatggac 3300
atgccagccc ctgggacgcc tctggacatc tcacctcgga agcccaagaa gtacgagctg 3360
cgggtcatca tctggaacac agatgaggtg gtcttggagg acgacgactt cttcacaggg 3420
gagaagtcca gtgacatctt cgtgaggggg tggctgaagg gccagcagga ggacaagcag 3480
gacacagacg tccactacca ctccctcact ggcgagggca acttcaactg gcgctacctg 3540
ttccccttcg actacctggc ggcggaggag aagatcgtca tctccaagaa ggagtccatg 3600
ttctcctggg acgagaccga gtacaagatc cccgcgcggc tcaccctgca gatctgggat 3660
gcggaccact tctccgctga cgacttcctg ggggccatcg agctggacct gaaccggttc 3720
ccgcggggcg caaagacagc caagcagtgc accatggaga tggccaccgg ggaggtggac 3780
gtgcccctcg tgtccatctt caagcaaaag cgcgtcaaag gctggtggcc cctcctggcc 3840
cgcaatgaga acgatgagtt tgagctcacg ggcaaggtgg aggctgagct gcatttactg 3900
acagcagagg aggcagagaa gaacccagtg ggcctggccc gcaatgaacc tgacccccta 3960
gagaaaccca accggcccga cacggccttc gtctggttcc tcaaccctct caagtccatc 4020
aagtacctca tctgcacccg gtacaagtgg ctcatcatca agatcgtgct ggcgctgttg 4080
gggctgctca tgttggggct cttcctctac agcctccctg gctacatggt caaaaagctc 4140
cttggggcat gagcggccgc ggtaccaagg gcgaattctg cagtcgacta gagctcgctg 4200
atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct cccccgtgcc 4260
ttccttgacc ctggaaggtg ccactcccac tgtcctttcc taataaaatg aggaaattgc 4320
atcgcattgt ctgagtaggt gtcattctat tctggggggt ggggtggggc aggacagcaa 4380
gggggaggat tgggaagaca atagcaggca tgctggggag agatctgagg actagtccgt 4440
cgactgttaa ttaagcatgc tggggagaga tctaggaacc cctagtgatg gagttggcca 4500
ctccctctct gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg 4560
cgacctttgg tcgcccggcc tcagtgagcg agcgagcgcg cagagaggga gtggccaacc 4620
cccccccccc cccccctgca gccctgcatt aatgaatcgg ccaacgcgcg gggagaggcg 4680
gtttgcgtat tgggcgctct tccgcttcct cgctcactga ctcgctgcgc tcggtcgttc 4740
ggctgcggcg agcggtatca gctcactcaa aggcggtaat acggttatcc acagaatcag 4800
gggataacgc aggaaagaac atgtgagcaa aaggccagca aaaggccagg aaccgtaaaa 4860
aggccgcgtt gctggcgttt ttccataggc tccgcccccc tgacgagcat cacaaaaatc 4920
gacgctcaag tcagaggtgg cgaaacccga caggactata aagataccag gcgtttcccc 4980
ctggaagctc cctcgtgcgc tctcctgttc cgaccctgcc gcttaccgga tacctgtccg 5040
cctttctccc ttcgggaagc gtggcgcttt ctcaatgctc acgctgtagg tatctcagtt 5100
cggtgtaggt cgttcgctcc aagctgggct gtgtgcacga accccccgtt cagcccgacc 5160
gctgcgcctt atccggtaac tatcgtcttg agtccaaccc ggtaagacac gacttatcgc 5220
cactggcagc agccactggt aacaggatta gcagagcgag gtatgtaggc ggtgctacag 5280
agttcttgaa gtggtggcct aactacggct acactagaag gacagtattt ggtatctgcg 5340
ctctgctgaa gccagttacc ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa 5400
ccaccgctgg tagcggtggt ttttttgttt gcaagcagca gattacgcgc agaaaaaaag 5460
gatctcaaga agatcctttg atcttttcta cggggtctga cgctcagtgg aacgaaaact 5520
cacgttaagg gattttggtc atgagattat caaaaaggat cttcacctag atccttttaa 5580
attaaaaatg aagttttaaa tcaatctaaa gtatatatga gtaaacttgg tctgacagtt 5640
accaatgctt aatcagtgag gcacctatct cagcgatctg tctatttcgt tcatccatag 5700
ttgcctgact ccccgtcgtg tagataacta cgatacggga gggcttacca tctggcccca 5760
gtgctgcaat gataccgcga gacccacgct caccggctcc agatttatca gcaataaacc 5820
agccagccgg aagggccgag cgcagaagtg gtcctgcaac tttatccgcc tccatccagt 5880
ctattaattg ttgccgggaa gctagagtaa gtagttcgcc agttaatagt ttgcgcaacg 5940
ttgttgccat tgctacaggc atcgtggtgt cacgctcgtc gtttggtatg gcttcattca 6000
gctccggttc ccaacgatca aggcgagtta catgatcccc catgttgtgc aaaaaagcgg 6060
ttagctcctt cggtcctccg atcgttgtca gaagtaagtt ggccgcagtg ttatcactca 6120
tggttatggc agcactgcat aattctctta ctgtcatgcc atccgtaaga tgcttttctg 6180
tgactggtga gtactcaacc aagtcattct gagaatagtg tatgcggcga ccgagttgct 6240
cttgcccggc gtcaatacgg gataataccg cgccacatag cagaacttta aaagtgctca 6300
tcattggaaa acgttcttcg gggcgaaaac tctcaaggat cttaccgctg ttgagatcca 6360
gttcgatgta acccactcgt gcacccaact gatcttcagc atcttttact ttcaccagcg 6420
tttctgggtg agcaaaaaca ggaaggcaaa atgccgcaaa aaagggaata agggcgacac 6480
ggaaatgttg aatactcata ctcttccttt ttcaatatta ttgaagcatt tatcagggtt 6540
attgtctcat gagcggatac atatttgaat gtatttagaa aaataaacaa ataggggttc 6600
cgcgcacatt tccccgaaaa gtgccacctg acgtctaaga aaccattatt atcatgacat 6660
taacctataa aaataggcgt atcacgaggc cctttcgtct cgcgcgtttc ggtgatgacg 6720
gtgaaaacct ctgacacatg cagctcccgg agacggtcac agcttgtctg taagcggatg 6780
ccgggagcag acaagcccgt cagggcgcgt cagcgggtgt tggcgggtgt cggggctggc 6840
ttaactatgc ggcatcagag cagattgtac tgagagtgca ccatatgcgg tgtgaaatac 6900
cgcacagatg cgtaaggaga aaataccgca tcaggaaatt gtaaacgtta atattttgtt 6960
aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg ccgaaatcgg 7020
caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtgttg ttccagtttg 7080
gaacaagagt ccactattaa agaacgtgga ctccaacgtc aaagggcgaa aaaccgtcta 7140
tcagggcgat ggcccactac gtgaaccatc accctaatca agttttttgg ggtcgaggtg 7200
ccgtaaagca ctaaatcgga accctaaagg gagcccccga tttagagctt gacggggaaa 7260
gccggcgaac gtggcgagaa aggaagggaa gaaagcgaaa ggagcgggcg ctagggcgct 7320
ggcaagtgta gcggtcacgc tgcgcgtaac caccacaccc gccgcgctta atgcgccgct 7380
acagggcgcg tcgcgccatt cgccattcag gctacgcaac tgttgggaag ggcgatcggt 7440
gcgggcctct tcgctattac gccaggctgc 7470
<210> 22
<211> 6973
<212> DNA
<213> homo sapiens
<400> 22
atcggagggg ggtcgggagg aggaggagga ggcagcggca gagaagagag aggcgtgtga 60
gccgtgctcc accggctagc tccttcccgc tgctcctgcc tggcagtgcc aggcagccca 120
caccagcatg gccttgctca tccacctcaa gacagtctcg gagctgcggg gcaggggcga 180
ccggatcgcc aaagtgactt tccgagggca atccttctac tctcgggtcc tggagaactg 240
tgaggatgtg gctgactttg atgagacatt tcggtggccg gtggccagca gcatcgacag 300
aaatgagatg ctggagattc aggttttcaa ctacagcaaa gtcttcagca acaagctcat 360
cgggaccttc cgcatggtgc tgcagaaggt ggtagaggag agccatgtgg aggtgactga 420
cacgctgatt gatgacaaca atgctatcat caagaccagc ctgtgcgtgg aggtccggta 480
tcaggccact gacggcacag tgggctcctg ggacgatggg gacttcctgg gagatgagtc 540
tcttcaagag gaagagaagg acagccaaga gacggatgga ctgctcccag gctcccggcc 600
cagctcccgg cccccaggag agaagagctt ccggagagcc gggaggagcg tgttctccgc 660
catgaagctc ggcaaaaacc ggtctcacaa ggaggagccc caaagaccag atgaaccggc 720
ggtgctggag atggaagacc ttgaccatct ggccattcgg ctaggagatg gactggatcc 780
cgactcggtg tctctagcct cagtcacagc tctcaccact aatgtctcca acaagcgatc 840
taagccagac attaagatgg agccaagtgc tgggcggccc atggattacc aggtcagcat 900
cacggtgatc gaggcccggc agctggtggg cttgaacatg gaccctgtgg tgtgcgtgga 960
ggtgggtgac gacaagaagt acacatccat gaaggagtcc actaactgcc cctattacaa 1020
cgagtacttc gtcttcgact tccatgtctc tccggatgtc atgtttgaca agatcatcaa 1080
gatttcggtg attcactcca agaacctgct gcgcagtggc accctggtgg gctccttcaa 1140
aatggacgtg ggaaccgtgt actcgcagcc agagcaccag ttccatcaca agtgggccat 1200
cctgtctgac cccgatgaca tctcctcggg gctgaagggc tacgtgaagt gtgacgttgc 1260
cgtggtgggc aaaggggaca acatcaagac gccccacaag gccaatgaga ccgacgaaga 1320
tgacattgag gggaacttgc tgctccccga gggggtgccc cccgaacgcc agtgggcccg 1380
gttctatgtg aaaatttacc gagcagaggg gctgccccgt atgaacacaa gcctcatggc 1440
caatgtaaag aaggctttca tcggtgaaaa caaggacctc gtggacccct acgtgcaagt 1500
cttctttgct ggccagaagg gcaagacttc agtgcagaag agcagctatg agcccctgtg 1560
gaatgagcag gtcgtcttta cagacctctt ccccccactc tgcaaacgca tgaaggtgca 1620
gatccgagac tcggacaagg tcaacgacgt ggccatcggc acccacttca ttgacctgcg 1680
caagatttct aatgacggag acaaaggctt cctgcccaca ctgggcccag cctgggtgaa 1740
catgtacggc tccacacgta actacacgct gctggatgag catcaggacc tgaacgaggg 1800
cctgggggag ggtgtgtcct tccgggcccg gctcctgctg ggcctggctg tggagatcgt 1860
agacacctcc aaccctgagc tcaccagctc cacagaggtg caggtggagc aggccacgcc 1920
catctcggag agctgtgcag gtaaaatgga agaattcttt ctctttggag ccttcctgga 1980
ggcctcaatg atcgaccgga gaaacggaga caagcccatc acctttgagg tcaccatagg 2040
caactatggg aacgaagttg atggcctgtc ccggccccag cggcctcggc cccggaagga 2100
gccgggggat gaggaagaag tagacctgat tcagaacgca agtgatgacg aggccggtga 2160
tgccggggac ctggcctcag tctcctccac tccaccaatg cggccccagg tcaccgacag 2220
gaactacttc catctgccct acctggagcg aaagccctgc atctacatca agagctggtg 2280
gccggaccag cgccgccgcc tctacaatgc caacatcatg gaccacattg ccgacaagct 2340
ggaagaaggc ctgaacgaca tacaggagat gatcaaaacg gagaagtcct accctgagcg 2400
tcgcctgcgg ggcgtcctgg aggagctgag ctgtggctgc tgccgcttcc tctccctcgc 2460
tgacaaggac cagggccact catcccgcac caggcttgac cgggagcgcc tcaagtcctg 2520
catgagggag ctggaaaaca tggggcagca ggccaggatg ctgcgggccc aggtgaagcg 2580
gcacacggtg cgggacaagc tgaggctgtg ccagaacttc ctgcagaagc tgcgcttcct 2640
ggcggacgag ccccagcaca gcattcccga catcttcatc tggatgatga gcaacaacaa 2700
gcgtgtcgcc tatgcccgtg tgccctccaa ggacctgctc ttctccatcg tggaggagga 2760
gactggcaag gactgcgcca aggtcaagac gctcttcctt aagctgccag ggaagcgggg 2820
cttcggctcg gcaggctgga cagtgcaggc caaggtggag ctgtacctgt ggctgggcct 2880
cagcaaacag cgcaaggagt tcctgtgcgg cctgccctgt ggcttccagg aggtcaaggc 2940
agcccagggc ctgggcctgc atgccttccc acccgtcagc ctggtctaca ccaagaagca 3000
ggcgttccag ctccgagcgc acatgtacca ggcccgcagc ctctttgccg ccgacagcag 3060
cggactctca gacccctttg cccgcgtctt cttcatcaat cagagtcagt gcacagaggt 3120
gctgaatgag accctgtgtc ccacctggga ccagatgctg gtgttcgaca acctggagct 3180
ctatggtgaa gctcatgagc tgagggacga tccgcccatc attgtcattg aaatctatga 3240
ccaggattcc atgggcaaag ctgacttcat gggccggacc ttcgccaaac ccctggtgaa 3300
gatggcagac gaggcgtact gcccaccccg cttcccacct cagctcgagt actaccagat 3360
ctaccgtggc aacgccacag ctggagacct gctggcggcc ttcgagctgc tgcagattgg 3420
accagcaggg aaggctgacc tgccccccat caatggcccg gtggacgtgg accgaggtcc 3480
catcatgccc gtgcccatgg gcatccggcc cgtgctcagc aagtaccgag tggaggtgct 3540
gttctggggc ctacgggacc taaagcgggt gaacctggcc caggtggacc ggccacgggt 3600
ggacatcgag tgtgcaggga agggggtgca gtcgtccctg atccacaatt ataagaagaa 3660
ccccaacttc aacaccctcg tcaagtggtt tgaagtggac ctcccagaga acgagctgct 3720
gcacccgccc ttgaacatcc gtgtggtgga ctgccgggcc ttcggtcgct acacactggt 3780
gggctcccat gccgtcagct ccctgcgacg cttcatctac cggcccccag accgctcggc 3840
ccccagctgg aacaccacgg tcaggcttct ccggcgctgc cgtgtgctgt gcaatggggg 3900
ctcctcctct cactccacag gggaggttgt ggtgactatg gagccagagg tacccatcaa 3960
gaaactggag accatggtga agctggacgc gacttctgaa gctgttgtca aggtggatgt 4020
ggctgaggag gagaaggaga agaagaagaa gaagaagggc actgcggagg agccagagga 4080
ggaggagcca gacgagagca tgctggactg gtggtccaag tactttgcct ccattgacac 4140
catgaaggag caacttcgac aacaagagcc ctctggaatt gacttggagg agaaggagga 4200
agtggacaat accgagggcc tgaaggggtc aatgaagggc aaggagaagg caagggctgc 4260
caaagaggag aagaagaaga aaactcagag ctctggctct ggccaggggt ccgaggcccc 4320
cgagaagaag aaacccaaga ttgatgagct taaggtatac cccaaagagc tggagtccga 4380
gtttgataac tttgaggact ggctgcacac tttcaacttg cttcggggca agaccgggga 4440
tgatgaggat ggctccaccg aggaggagcg cattgtggga cgcttcaagg gctccctctg 4500
cgtgtacaaa gtgccactcc cagaggacgt gtcccgggaa gccggctacg actccaccta 4560
cggcatgttc cagggcatcc cgagcaatga ccccatcaat gtgctggtcc gagtctatgt 4620
ggtccgggcc acggacctgc accctgctga catcaacggc aaagctgacc cctacatcgc 4680
catccggcta ggcaagactg acatccgcga caaggagaac tacatctcca agcagctcaa 4740
ccctgtcttt gggaagtcct ttgacatcga ggcctccttc cccatggaat ccatgctgac 4800
ggtggctgtg tatgactggg acctggtggg cactgatgac ctcattgggg aaaccaagat 4860
cgacctggag aaccgcttct acagcaagca ccgcgccacc tgcggcatcg cccagaccta 4920
ctccacacat ggctacaata tctggcggga ccccatgaag cccagccaga tcctgacccg 4980
cctctgcaaa gacggcaaag tggacggccc ccactttggg ccccctggga gagtgaaggt 5040
ggccaaccgc gtcttcactg ggccctctga gattgaggac gagaacggtc agaggaagcc 5100
cacagacgag catgtggcgc tgttggccct gaggcactgg gaggacatcc cccgcgcagg 5160
ctgccgcctg gtgccagagc atgtggagac gaggccgctg ctcaaccccg acaagccggg 5220
catcgagcag ggccgcctgg agctgtgggt ggacatgttc cccatggaca tgccagcccc 5280
tgggacgcct ctggacatct cacctcggaa gcccaagaag tacgagctgc gggtcatcat 5340
ctggaacaca gatgaggtgg tcttggagga cgacgacttc ttcacagggg agaagtccag 5400
tgacatcttc gtgagggggt ggctgaaggg ccagcaggag gacaagcagg acacagacgt 5460
ccactaccac tccctcactg gcgagggcaa cttcaactgg cgctacctgt tccccttcga 5520
ctacctggcg gcggaggaga agatcgtcat ctccaagaag gagtccatgt tctcctggga 5580
cgagaccgag tacaagatcc ccgcgcggct caccctgcag atctgggatg cggaccactt 5640
ctccgctgac gacttcctgg gggccatcga gctggacctg aaccggttcc cgcggggcgc 5700
aaagacagcc aagcagtgca ccatggagat ggccaccggg gaggtggacg tgcccctcgt 5760
gtccatcttc aagcaaaagc gcgtcaaagg ctggtggccc ctcctggccc gcaatgagaa 5820
cgatgagttt gagctcacgg gcaaggtgga ggctgagctg catttactga cagcagagga 5880
ggcagagaag aacccagtgg gcctggcccg caatgaacct gaccccctag agaaacccaa 5940
ccggcccgac acggccttcg tctggttcct caaccctctc aagtccatca agtacctcat 6000
ctgcacccgg tacaagtggc tcatcatcaa gatcgtgctg gcgctgttgg ggctgctcat 6060
gttggggctc ttcctctaca gcctccctgg ctacatggtc aaaaagctcc ttggggcatg 6120
aaggccgcca gctcccgcca gccgctcccc agccctgccg catttccttt cagtggcttg 6180
gactctttcc catctcccct ggggagcctg aggagcccag cgtccactct tcatgccttg 6240
ggccgagcct gcctcctgct tgcgggggcc gcctgtcctc actgccccag gctgcggctt 6300
gcccagtccc gcccctctga cccctgcctg tgggctgggg agccttggat ggggtgggga 6360
cctggaatgg gtctctcttg ccccacctgg ctgaggcgcc acccttcttc aggcccaggc 6420
tccagaggaa gactcctgaa accctcccca ggtcttccaa gtacaggatt gaagctttag 6480
tgaaattaac caaggaccat gggtcagtgc ccagggcttt aaaaagaatg aacgagcaaa 6540
aggtatcccc gccgtgaccc ctgcagatag caccggtctt tgatccgcag caggggccag 6600
accctgccca caagtcccag cgcggctgct tctgccactg ctgggctcca cttggctcct 6660
ctcacttccc agggggtcgc ctgtcctgcc tgtgggtttc catggcttcc cagagctccc 6720
tctgccccag ccagcgcctc caggcccagc tgaggagctg tgagaagcag cagaggggac 6780
tccccatccc gggcacaccc tgtcctccca cccctgcccc cttgcccttc cagccctttc 6840
agctgcagct gggagctggc ccgtcaagtg ctgcccctgc ctgtgtctgg gtttctgttg 6900
gctgtttttc ttttcttgag tggtgatttt tctctaaata aaagaagtca agcactgaaa 6960
aaaaaaaaaa aaa 6973
<210> 23
<211> 3318
<212> DNA
<213> homo sapiens
<400> 23
ctgccaggga agcggggctt cggctcggca ggctggacag tgcaggccaa ggtggagctg 60
tacctgtggc tgggcctcag caaacagcgc aaggagttcc tgtgcggcct gccctgtggc 120
ttccaggagg tcaaggcagc ccagggcctg ggcctgcatg ccttcccacc cgtcagcctg 180
gtctacacca agaagcaggc gttccagctc cgagcgcaca tgtaccaggc ccgcagcctc 240
tttgccgccg acagcagcgg actctcagac ccctttgccc gcgtcttctt catcaatcag 300
agtcagtgca cagaggtgct gaatgagacc ctgtgtccca cctgggacca gatgctggtg 360
ttcgacaacc tggagctcta tggtgaagct catgagctga gggacgatcc gcccatcatt 420
gtcattgaaa tctatgacca ggattccatg ggcaaagctg acttcatggg ccggaccttc 480
gccaaacccc tggtgaagat ggcagacgag gcgtactgcc caccccgctt cccacctcag 540
ctcgagtact accagatcta ccgtggcaac gccacagctg gagacctgct ggcggccttc 600
gagctgctgc agattggacc agcagggaag gctgacctgc cccccatcaa tggcccggtg 660
gacgtggacc gaggtcccat catgcccgtg cccatgggca tccggcccgt gctcagcaag 720
taccgagtgg aggtgctgtt ctggggccta cgggacctaa agcgggtgaa cctggcccag 780
gtggaccggc cacgggtgga catcgagtgt gcagggaagg gggtgcagtc gtccctgatc 840
cacaattata agaagaaccc caacttcaac accctcgtca agtggtttga agtggacctc 900
ccagagaacg agctgctgca cccgcccttg aacatccgtg tggtggactg ccgggccttc 960
ggtcgctaca cactggtggg ctcccatgcc gtcagctccc tgcgacgctt catctaccgg 1020
cccccagacc gctcggcccc cagctggaac accacggtca ggcttctccg gcgctgccgt 1080
gtgctgtgca atgggggctc ctcctctcac tccacagggg aggttgtggt gactatggag 1140
ccagaggtac ccatcaagaa actggagacc atggtgaagc tggacgcgac ttctgaagct 1200
gttgtcaagg tggatgtggc tgaggaggag aaggagaaga agaagaagaa gaagggcact 1260
gcggaggagc cagaggagga ggagccagac gagagcatgc tggactggtg gtccaagtac 1320
tttgcctcca ttgacaccat gaaggagcaa cttcgacaac aagagccctc tggaattgac 1380
ttggaggaga aggaggaagt ggacaatacc gagggcctga aggggtcaat gaagggcaag 1440
gagaaggcaa gggctgccaa agaggagaag aagaagaaaa ctcagagctc tggctctggc 1500
caggggtccg aggcccccga gaagaagaaa cccaagattg atgagcttaa ggtatacccc 1560
aaagagctgg agtccgagtt tgataacttt gaggactggc tgcacacttt caacttgctt 1620
cggggcaaga ccggggatga tgaggatggc tccaccgagg aggagcgcat tgtgggacgc 1680
ttcaagggct ccctctgcgt gtacaaagtg ccactcccag aggacgtgtc ccgggaagcc 1740
ggctacgact ccacctacgg catgttccag ggcatcccga gcaatgaccc catcaatgtg 1800
ctggtccgag tctatgtggt ccgggccacg gacctgcacc ctgctgacat caacggcaaa 1860
gctgacccct acatcgccat ccggctaggc aagactgaca tccgcgacaa ggagaactac 1920
atctccaagc agctcaaccc tgtctttggg aagtcctttg acatcgaggc ctccttcccc 1980
atggaatcca tgctgacggt ggctgtgtat gactgggacc tggtgggcac tgatgacctc 2040
attggggaaa ccaagatcga cctggagaac cgcttctaca gcaagcaccg cgccacctgc 2100
ggcatcgccc agacctactc cacacatggc tacaatatct ggcgggaccc catgaagccc 2160
agccagatcc tgacccgcct ctgcaaagac ggcaaagtgg acggccccca ctttgggccc 2220
cctgggagag tgaaggtggc caaccgcgtc ttcactgggc cctctgagat tgaggacgag 2280
aacggtcaga ggaagcccac agacgagcat gtggcgctgt tggccctgag gcactgggag 2340
gacatccccc gcgcaggctg ccgcctggtg ccagagcatg tggagacgag gccgctgctc 2400
aaccccgaca agccgggcat cgagcagggc cgcctggagc tgtgggtgga catgttcccc 2460
atggacatgc cagcccctgg gacgcctctg gacatctcac ctcggaagcc caagaagtac 2520
gagctgcggg tcatcatctg gaacacagat gaggtggtct tggaggacga cgacttcttc 2580
acaggggaga agtccagtga catcttcgtg agggggtggc tgaagggcca gcaggaggac 2640
aagcaggaca cagacgtcca ctaccactcc ctcactggcg agggcaactt caactggcgc 2700
tacctgttcc ccttcgacta cctggcggcg gaggagaaga tcgtcatctc caagaaggag 2760
tccatgttct cctgggacga gaccgagtac aagatccccg cgcggctcac cctgcagatc 2820
tgggatgcgg accacttctc cgctgacgac ttcctggggg ccatcgagct ggacctgaac 2880
cggttcccgc ggggcgcaaa gacagccaag cagtgcacca tggagatggc caccggggag 2940
gtggacgtgc ccctcgtgtc catcttcaag caaaagcgcg tcaaaggctg gtggcccctc 3000
ctggcccgca atgagaacga tgagtttgag ctcacgggca aggtggaggc tgagctgcat 3060
ttactgacag cagaggaggc agagaagaac ccagtgggcc tggcccgcaa tgaacctgac 3120
cccctagaga aacccaaccg gcccgacacg gccttcgtct ggttcctcaa ccctctcaag 3180
tccatcaagt acctcatctg cacccggtac aagtggctca tcatcaagat cgtgctggcg 3240
ctgttggggc tgctcatgtt ggggctcttc ctctacagcc tccctggcta catggtcaaa 3300
aagctccttg gggcatga 3318
<210> 24
<211> 1260
<212> PRT
<213> homo sapiens
<400> 24
Met Met Thr Asp Thr Gln Asp Gly Pro Ser Glu Ser Ser Gln Ile Met
1 5 10 15
Arg Ser Leu Thr Pro Leu Ile Asn Arg Glu Glu Ala Phe Gly Glu Ala
20 25 30
Gly Glu Ala Gly Leu Trp Pro Ser Ile Thr His Thr Pro Asp Ser Gln
35 40 45
Glu Glu Gly Leu Asn Asp Ile Gln Glu Met Ile Lys Thr Glu Lys Ser
50 55 60
Tyr Pro Glu Arg Arg Leu Arg Gly Val Leu Glu Glu Leu Ser Cys Gly
65 70 75 80
Cys Cys Arg Phe Leu Ser Leu Ala Asp Lys Asp Gln Gly His Ser Ser
85 90 95
Arg Thr Arg Leu Asp Arg Glu Arg Leu Lys Ser Cys Met Arg Glu Leu
100 105 110
Glu Asn Met Gly Gln Gln Ala Arg Met Leu Arg Ala Gln Val Lys Arg
115 120 125
His Thr Val Arg Asp Lys Leu Arg Leu Cys Gln Asn Phe Leu Gln Lys
130 135 140
Leu Arg Phe Leu Ala Asp Glu Pro Gln His Ser Ile Pro Asp Ile Phe
145 150 155 160
Ile Trp Met Met Ser Asn Asn Lys Arg Val Ala Tyr Ala Arg Val Pro
165 170 175
Ser Lys Asp Leu Leu Phe Ser Ile Val Glu Glu Glu Thr Gly Lys Asp
180 185 190
Cys Ala Lys Val Lys Thr Leu Phe Leu Lys Leu Pro Gly Lys Arg Gly
195 200 205
Phe Gly Ser Ala Gly Trp Thr Val Gln Ala Lys Val Glu Leu Tyr Leu
210 215 220
Trp Leu Gly Leu Ser Lys Gln Arg Lys Glu Phe Leu Cys Gly Leu Pro
225 230 235 240
Cys Gly Phe Gln Glu Val Lys Ala Ala Gln Gly Leu Gly Leu His Ala
245 250 255
Phe Pro Pro Val Ser Leu Val Tyr Thr Lys Lys Gln Ala Phe Gln Leu
260 265 270
Arg Ala His Met Tyr Gln Ala Arg Ser Leu Phe Ala Ala Asp Ser Ser
275 280 285
Gly Leu Ser Asp Pro Phe Ala Arg Val Phe Phe Ile Asn Gln Ser Gln
290 295 300
Cys Thr Glu Val Leu Asn Glu Thr Leu Cys Pro Thr Trp Asp Gln Met
305 310 315 320
Leu Val Phe Asp Asn Leu Glu Leu Tyr Gly Glu Ala His Glu Leu Arg
325 330 335
Asp Asp Pro Pro Ile Ile Val Ile Glu Ile Tyr Asp Gln Asp Ser Met
340 345 350
Gly Lys Ala Asp Phe Met Gly Arg Thr Phe Ala Lys Pro Leu Val Lys
355 360 365
Met Ala Asp Glu Ala Tyr Cys Pro Pro Arg Phe Pro Pro Gln Leu Glu
370 375 380
Tyr Tyr Gln Ile Tyr Arg Gly Asn Ala Thr Ala Gly Asp Leu Leu Ala
385 390 395 400
Ala Phe Glu Leu Leu Gln Ile Gly Pro Ala Gly Lys Ala Asp Leu Pro
405 410 415
Pro Ile Asn Gly Pro Val Asp Val Asp Arg Gly Pro Ile Met Pro Val
420 425 430
Pro Met Gly Ile Arg Pro Val Leu Ser Lys Tyr Arg Val Glu Val Leu
435 440 445
Phe Trp Gly Leu Arg Asp Leu Lys Arg Val Asn Leu Ala Gln Val Asp
450 455 460
Arg Pro Arg Val Asp Ile Glu Cys Ala Gly Lys Gly Val Gln Ser Ser
465 470 475 480
Leu Ile His Asn Tyr Lys Lys Asn Pro Asn Phe Asn Thr Leu Val Lys
485 490 495
Trp Phe Glu Val Asp Leu Pro Glu Asn Glu Leu Leu His Pro Pro Leu
500 505 510
Asn Ile Arg Val Val Asp Cys Arg Ala Phe Gly Arg Tyr Thr Leu Val
515 520 525
Gly Ser His Ala Val Ser Ser Leu Arg Arg Phe Ile Tyr Arg Pro Pro
530 535 540
Asp Arg Ser Ala Pro Ser Trp Asn Thr Thr Val Arg Leu Leu Arg Arg
545 550 555 560
Cys Arg Val Leu Cys Asn Gly Gly Ser Ser Ser His Ser Thr Gly Glu
565 570 575
Val Val Val Thr Met Glu Pro Glu Val Pro Ile Lys Lys Leu Glu Thr
580 585 590
Met Val Lys Leu Asp Ala Thr Ser Glu Ala Val Val Lys Val Asp Val
595 600 605
Ala Glu Glu Glu Lys Glu Lys Lys Lys Lys Lys Lys Gly Thr Ala Glu
610 615 620
Glu Pro Glu Glu Glu Glu Pro Asp Glu Ser Met Leu Asp Trp Trp Ser
625 630 635 640
Lys Tyr Phe Ala Ser Ile Asp Thr Met Lys Glu Gln Leu Arg Gln Gln
645 650 655
Glu Pro Ser Gly Ile Asp Leu Glu Glu Lys Glu Glu Val Asp Asn Thr
660 665 670
Glu Gly Leu Lys Gly Ser Met Lys Gly Lys Glu Lys Ala Arg Ala Ala
675 680 685
Lys Glu Glu Lys Lys Lys Lys Thr Gln Ser Ser Gly Ser Gly Gln Gly
690 695 700
Ser Glu Ala Pro Glu Lys Lys Lys Pro Lys Ile Asp Glu Leu Lys Val
705 710 715 720
Tyr Pro Lys Glu Leu Glu Ser Glu Phe Asp Asn Phe Glu Asp Trp Leu
725 730 735
His Thr Phe Asn Leu Leu Arg Gly Lys Thr Gly Asp Asp Glu Asp Gly
740 745 750
Ser Thr Glu Glu Glu Arg Ile Val Gly Arg Phe Lys Gly Ser Leu Cys
755 760 765
Val Tyr Lys Val Pro Leu Pro Glu Asp Val Ser Arg Glu Ala Gly Tyr
770 775 780
Asp Ser Thr Tyr Gly Met Phe Gln Gly Ile Pro Ser Asn Asp Pro Ile
785 790 795 800
Asn Val Leu Val Arg Val Tyr Val Val Arg Ala Thr Asp Leu His Pro
805 810 815
Ala Asp Ile Asn Gly Lys Ala Asp Pro Tyr Ile Ala Ile Arg Leu Gly
820 825 830
Lys Thr Asp Ile Arg Asp Lys Glu Asn Tyr Ile Ser Lys Gln Leu Asn
835 840 845
Pro Val Phe Gly Lys Ser Phe Asp Ile Glu Ala Ser Phe Pro Met Glu
850 855 860
Ser Met Leu Thr Val Ala Val Tyr Asp Trp Asp Leu Val Gly Thr Asp
865 870 875 880
Asp Leu Ile Gly Glu Thr Lys Ile Asp Leu Glu Asn Arg Phe Tyr Ser
885 890 895
Lys His Arg Ala Thr Cys Gly Ile Ala Gln Thr Tyr Ser Thr His Gly
900 905 910
Tyr Asn Ile Trp Arg Asp Pro Met Lys Pro Ser Gln Ile Leu Thr Arg
915 920 925
Leu Cys Lys Asp Gly Lys Val Asp Gly Pro His Phe Gly Pro Pro Gly
930 935 940
Arg Val Lys Val Ala Asn Arg Val Phe Thr Gly Pro Ser Glu Ile Glu
945 950 955 960
Asp Glu Asn Gly Gln Arg Lys Pro Thr Asp Glu His Val Ala Leu Leu
965 970 975
Ala Leu Arg His Trp Glu Asp Ile Pro Arg Ala Gly Cys Arg Leu Val
980 985 990
Pro Glu His Val Glu Thr Arg Pro Leu Leu Asn Pro Asp Lys Pro Gly
995 1000 1005
Ile Glu Gln Gly Arg Leu Glu Leu Trp Val Asp Met Phe Pro Met
1010 1015 1020
Asp Met Pro Ala Pro Gly Thr Pro Leu Asp Ile Ser Pro Arg Lys
1025 1030 1035
Pro Lys Lys Tyr Glu Leu Arg Val Ile Ile Trp Asn Thr Asp Glu
1040 1045 1050
Val Val Leu Glu Asp Asp Asp Phe Phe Thr Gly Glu Lys Ser Ser
1055 1060 1065
Asp Ile Phe Val Arg Gly Trp Leu Lys Gly Gln Gln Glu Asp Lys
1070 1075 1080
Gln Asp Thr Asp Val His Tyr His Ser Leu Thr Gly Glu Gly Asn
1085 1090 1095
Phe Asn Trp Arg Tyr Leu Phe Pro Phe Asp Tyr Leu Ala Ala Glu
1100 1105 1110
Glu Lys Ile Val Ile Ser Lys Lys Glu Ser Met Phe Ser Trp Asp
1115 1120 1125
Glu Thr Glu Tyr Lys Ile Pro Ala Arg Leu Thr Leu Gln Ile Trp
1130 1135 1140
Asp Ala Asp His Phe Ser Ala Asp Asp Phe Leu Gly Ala Ile Glu
1145 1150 1155
Leu Asp Leu Asn Arg Phe Pro Arg Gly Ala Lys Thr Ala Lys Gln
1160 1165 1170
Cys Thr Met Glu Met Ala Thr Gly Glu Val Asp Val Pro Leu Val
1175 1180 1185
Ser Ile Phe Lys Gln Lys Arg Val Lys Gly Trp Trp Pro Leu Leu
1190 1195 1200
Ala Arg Asn Glu Asn Asp Glu Phe Glu Leu Thr Gly Lys Val Glu
1205 1210 1215
Ala Glu Leu His Leu Leu Thr Ala Glu Glu Ala Glu Lys Asn Pro
1220 1225 1230
Val Gly Leu Ala Arg Asn Glu Pro Asp Pro Leu Glu Lys Pro Asn
1235 1240 1245
Arg Pro Asp Thr Ser Phe Ile Trp Phe Leu Asn Pro
1250 1255 1260
Claims (12)
- DFNB9 청각장애(deafness)를 앓는 환자를 치료하거나 DFNB9 돌연변이를 갖는 환자에서 DFNB9 청각장애를 예방하는데 사용하기 위한, 내부 모 세포(inner hair cell)내에서 전체 길이의 오토페를린 폴리펩타이드, 또는 이의 기능성 단편의 발현을 허용하는 벡터 시스템으로서, 상기 환자가 발달한 및 성숙한 청각 시스템을 가진 사람, 예를 들면, 출생아, 영아, 유아, 십대(teenagers) 또는 성인인, 벡터 시스템.
- 제1항에 있어서, 상기 오토페를린 폴리펩타이드가 서열 번호: 1의 서열을 갖는, 벡터 시스템.
- 제1항에 있어서, 오토페를린 폴리펩타이드 또는 이의 기능성 단편의 전체 길이를 암호화하는 폴리뉴클레오타이드를 포함하는 적어도 하나의 AAV 입자를 포함하는, 벡터 시스템.
- 제1항에 있어서, 적어도 2개의 AAV 입자를 포함하고, 이들 각각이 i) 하나에 대해, 오토페를린 폴리펩타이드 또는 이의 기능성 단편의 N-말단 부분, 및 ii) 다른 것에 대해, 오토페를린 폴리펩타이드 또는 이의 기능성 단편의 C-말단 부분을 암호화하는 부분 암호화 서열을 포함하는 폴리뉴클레오타이드를 포함하는, 벡터 시스템.
- 제1항에 있어서, 적어도 2개의 AAV 입자를 포함하고, 상기 AAV 입자 각각이:
a) 제1 폴리뉴클레오타이드로, 상기 폴리뉴클레오타이드 각각의 말단에서 역위된 말단 반복체, 및, 5'로부터 3'까지, 상기 역위된 말단 반복체 사이에: 적합한 프로모터에 이어 오토페를린 유전자의 N-말단 부분을 함유하는 부분 암호화 서열, 및 스플라이스 공여체 부위를 포함하는 제1 폴리뉴클레오타이드, 또는
b) 제2 폴리뉴클레오타이드로, 상기 폴리뉴클레오타이드 각각의 말단에서 역위된 말단 반복체, 및, 5'로부터 3'까지, 상기 역위된 말단 반복체 사이에: 스플라이스 수용체 부위, 오토페를린 유전자의 C-말단 부분을 함유하는 부분 암호화 서열, 이어서 임의로 폴리아데닐화 서열을 포함하는 제2 폴리뉴클레오타이드,
를 포함하고,
상기 제1 및 제2 폴리뉴클레오타이드가 또한 상기 제1 폴리뉴클레오타이드내 스플라이스 공여체 부위 이후에 및 상기 제2 폴리뉴클레오타이드내 스플라이스 수용체 부위 앞에 위치하는 재조합유전성 서열(recombinogenic sequence)을 포함하는, 벡터 시스템. - 제5항에 있어서, 오토페를린 유전자가 서열 번호: 2의 서열을 갖는, 벡터 시스템.
- 제5항에 있어서, 오토페를린 유전자의 상기 N-말단 부분이 서열 번호: 3의 서열이고 오토페를린 유전자의 상기 C-말단 부분이 서열 번호: 4의 서열인, 벡터 시스템.
- 제3항에 있어서, 상기 AAV 입자가 AAV2 혈청형의 것인, 벡터 시스템.
- 제1항에 있어서, 캡시드가 타이로신 아미노산 잔기를 페닐알라닌 아미노산 잔기로 치환시킴에 의해 변형된 AAV2 입자를 포함하는, 벡터 시스템.
- 제1항에 있어서, 상기 사람 환자가 언어 습득 후 DFNB9 청각장애로 진단된, 벡터 시스템.
- 제1항에 있어서, 상기 환자가 바람직하게는 P.Q994VfsX6, P.I515T, p.G541S, PR1607W, p.E1804del로부터 선택된, 열민감성 돌연변이에 의해 유도된 DFNB9 청각장애를 앓고 있는 십대 또는 성인 사람인, 벡터 시스템.
- 제1항 내지 제9항 중 어느 한 항에 따른 벡터 시스템을 포함하고 약제학적으로 허용되는 비히클(vehicle)을 포함하는, DFNB9 청각장애를 앓고 있는 환자를 치료하거나 DFNB9 돌연변이를 갖는 환자에서 DFNB9 청각장애를 예방하는데 사용하기 위한 약제학적 조성물로서, 상기 환자가 발달한 및 성숙한 청각 시스템을 갖는 사람, 예를 들면, 신생아, 영아, 유아, 십대 또는 성인인, 약제학적 조성물.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP19305071.3 | 2019-01-18 | ||
| EP19305071 | 2019-01-18 | ||
| PCT/EP2020/051283 WO2020148458A1 (en) | 2019-01-18 | 2020-01-20 | Aav-mediated gene therapy restoring the otoferlin gene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20210118112A true KR20210118112A (ko) | 2021-09-29 |
Family
ID=65351986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020217026056A KR20210118112A (ko) | 2019-01-18 | 2020-01-20 | 오토페를린 유전자을 회복시키는 aav-매개된 유전자 치료요법 |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US20220125875A1 (ko) |
| EP (2) | EP4295913A3 (ko) |
| JP (1) | JP2022522996A (ko) |
| KR (1) | KR20210118112A (ko) |
| CN (1) | CN113924109A (ko) |
| AU (1) | AU2020208933A1 (ko) |
| BR (1) | BR112021013996A2 (ko) |
| CA (1) | CA3126884A1 (ko) |
| DK (1) | DK3911354T5 (ko) |
| ES (1) | ES2960880T3 (ko) |
| FI (1) | FI3911354T3 (ko) |
| HR (1) | HRP20231296T1 (ko) |
| HU (1) | HUE063458T2 (ko) |
| IL (1) | IL284742B2 (ko) |
| LT (1) | LT3911354T (ko) |
| MX (1) | MX2021008622A (ko) |
| PL (1) | PL3911354T3 (ko) |
| PT (1) | PT3911354T (ko) |
| RS (1) | RS64794B1 (ko) |
| SI (1) | SI3911354T1 (ko) |
| WO (1) | WO2020148458A1 (ko) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11660353B2 (en) | 2018-04-27 | 2023-05-30 | Decibel Therapeutics, Inc. | Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems |
| MX2022010050A (es) | 2020-02-21 | 2022-09-05 | Akouos Inc | Composiciones y metodos para tratar deficiencia auditiva no asociada con la edad en un sujeto humano. |
| KR20240004253A (ko) * | 2021-02-19 | 2024-01-11 | 데시벨 테라퓨틱스, 인크. | 오토펄린 듀얼 벡터 시스템을 사용한 감각신경성 난청을 치료하기 위한 방법 |
| WO2023036966A1 (en) * | 2021-09-10 | 2023-03-16 | Institut Pasteur | Dual recombinant aav8 vector system encoding isoform 5 of otoferlin and uses thereof |
| CN117106824A (zh) * | 2022-05-17 | 2023-11-24 | 复旦大学附属眼耳鼻喉科医院 | 一种治疗听力损伤的双载体系统及其应用 |
| CN116925239B (zh) * | 2023-07-17 | 2024-10-18 | 苏州星奥拓维生物技术有限公司 | 双载体系统表达Otof基因的组合物和方法 |
| CN117305367A (zh) * | 2023-08-21 | 2023-12-29 | 复旦大学附属眼耳鼻喉科医院 | 一种表达全长耳畸蛋白的双aav载体系统及其应用 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1453547T (pt) | 2001-12-17 | 2016-12-28 | Univ Pennsylvania | Sequências do vírus adeno-associado (aav) do serotipo 8, vetores contendo as mesmas, e utilizações destas |
| WO2003059396A1 (en) | 2002-01-11 | 2003-07-24 | Sergei Zolotukhin | Adiponectin gene therapy |
| WO2006036465A2 (en) | 2004-09-03 | 2006-04-06 | University Of Florida | Compositions and methods for treating cystic fibrosis |
| US8298818B2 (en) | 2006-04-28 | 2012-10-30 | University Of Florida Research Foundation, Inc. | Self-complementary adeno-associated virus having a truncated CMV-chicken β-actin promoter |
| WO2011075838A1 (en) | 2009-12-21 | 2011-06-30 | Audigen Inc. | Method of treating or preventing hearing loss |
| WO2013075008A1 (en) | 2011-11-16 | 2013-05-23 | University Of Florida Research Foundation Inc. | Aav dual vector systems for gene therapy |
| EP3492597A3 (en) | 2013-05-21 | 2019-08-28 | University of Florida Research Foundation, Inc. | Capsid-modified, raav3 vector compositions and methods of use in gene therapy of human liver cancer |
| CN116236591A (zh) * | 2015-12-11 | 2023-06-09 | 马萨诸塞眼科耳科诊所 | 用于将核酸递送至耳蜗和前庭细胞的材料和方法 |
| AU2017315679B2 (en) * | 2016-08-23 | 2023-12-14 | Akouos, Inc. | Compositions and methods for treating non-age-associated hearing impairment in a human subject |
| KR20230167138A (ko) * | 2017-05-05 | 2023-12-07 | 유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드 | 오토펄린을 발현시키기 위한 조성물 및 방법 |
| MX2020008763A (es) | 2018-02-22 | 2021-02-15 | Akouos Inc | Composiciones y metodos para tratar el deterioro auditivo no asociado con la edad en un sujeto humano. |
| US11660353B2 (en) * | 2018-04-27 | 2023-05-30 | Decibel Therapeutics, Inc. | Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems |
| CA3159549A1 (en) | 2019-10-30 | 2021-05-06 | Decibel Therapeutics, Inc. | Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems |
-
2020
- 2020-01-20 KR KR1020217026056A patent/KR20210118112A/ko active Search and Examination
- 2020-01-20 IL IL284742A patent/IL284742B2/en unknown
- 2020-01-20 JP JP2021541524A patent/JP2022522996A/ja active Pending
- 2020-01-20 LT LTEPPCT/EP2020/051283T patent/LT3911354T/lt unknown
- 2020-01-20 FI FIEP20701951.4T patent/FI3911354T3/fi active
- 2020-01-20 AU AU2020208933A patent/AU2020208933A1/en active Pending
- 2020-01-20 CN CN202080022300.3A patent/CN113924109A/zh active Pending
- 2020-01-20 MX MX2021008622A patent/MX2021008622A/es unknown
- 2020-01-20 DK DK20701951.4T patent/DK3911354T5/da active
- 2020-01-20 WO PCT/EP2020/051283 patent/WO2020148458A1/en active Application Filing
- 2020-01-20 SI SI202030290T patent/SI3911354T1/sl unknown
- 2020-01-20 BR BR112021013996-6A patent/BR112021013996A2/pt unknown
- 2020-01-20 EP EP23184106.5A patent/EP4295913A3/en active Pending
- 2020-01-20 HU HUE20701951A patent/HUE063458T2/hu unknown
- 2020-01-20 EP EP20701951.4A patent/EP3911354B8/en active Active
- 2020-01-20 ES ES20701951T patent/ES2960880T3/es active Active
- 2020-01-20 HR HRP20231296TT patent/HRP20231296T1/hr unknown
- 2020-01-20 PT PT207019514T patent/PT3911354T/pt unknown
- 2020-01-20 PL PL20701951.4T patent/PL3911354T3/pl unknown
- 2020-01-20 RS RS20230958A patent/RS64794B1/sr unknown
- 2020-01-20 CA CA3126884A patent/CA3126884A1/en active Pending
-
2021
- 2021-01-20 US US17/422,737 patent/US20220125875A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| BR112021013996A2 (pt) | 2021-10-26 |
| PL3911354T3 (pl) | 2024-03-11 |
| EP3911354B1 (en) | 2023-07-19 |
| PT3911354T (pt) | 2023-10-24 |
| EP3911354B8 (en) | 2024-04-03 |
| EP3911354A1 (en) | 2021-11-24 |
| CN113924109A (zh) | 2022-01-11 |
| WO2020148458A1 (en) | 2020-07-23 |
| ES2960880T3 (es) | 2024-03-07 |
| IL284742B2 (en) | 2024-06-01 |
| RS64794B1 (sr) | 2023-11-30 |
| EP4295913A3 (en) | 2024-03-06 |
| IL284742B1 (en) | 2024-02-01 |
| US20220125875A1 (en) | 2022-04-28 |
| AU2020208933A1 (en) | 2021-07-29 |
| CA3126884A1 (en) | 2020-07-23 |
| DK3911354T3 (da) | 2023-10-16 |
| EP4295913A2 (en) | 2023-12-27 |
| FI3911354T3 (fi) | 2023-10-17 |
| AU2020208933A8 (en) | 2021-08-26 |
| MX2021008622A (es) | 2021-12-15 |
| DK3911354T5 (da) | 2024-08-05 |
| HRP20231296T1 (hr) | 2024-02-16 |
| IL284742A (en) | 2021-08-31 |
| HUE063458T2 (hu) | 2024-01-28 |
| SI3911354T1 (sl) | 2023-12-29 |
| JP2022522996A (ja) | 2022-04-21 |
| LT3911354T (lt) | 2023-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102606810B1 (ko) | 오토펄린을 발현시키기 위한 조성물 및 방법 | |
| KR20210118112A (ko) | 오토페를린 유전자을 회복시키는 aav-매개된 유전자 치료요법 | |
| KR102446169B1 (ko) | 리소좀 저장 장애의 치료를 위한 아데노연관 바이러스 벡터 | |
| CN112553210B (zh) | 用于溶酶体障碍的基因疗法 | |
| CN109863243B (zh) | 用于治疗粘多糖症的腺相关病毒载体 | |
| ES2819976T3 (es) | Composiciones y usos médicos para la reprogramación de TCR con proteínas de fusión | |
| JP4843663B2 (ja) | 神経系の細胞へのｄｎａのａａｖ仲介送達 | |
| CA2776272C (en) | Development of a preventive vaccine for filovirus infection in primates | |
| KR20180048743A (ko) | 2a 펩타이드를 포함하는 재조합 벡터 | |
| PT2048955E (pt) | Administração de gene alvo para vacinação de células dendríticas | |
| AU2016378480A1 (en) | Endothelium-specific nucleic acid regulatory elements and methods and use thereof | |
| KR20210150486A (ko) | 리소좀 장애에 대한 유전자 요법 | |
| CN116437968A (zh) | 用于神经退行性病症的基因疗法 | |
| KR20110126586A (ko) | 단일 재조합 계 및 그의 사용 방법 | |
| KR20230054840A (ko) | rAAV 비리온의 유도 생산을 위한 안정화된 세포주 | |
| KR20220016485A (ko) | 미엘린 단백질 제로 프로모터를 갖는 aav 벡터, 및 샤르코-마리-투스 질환과 같은 슈반 세포-관련 질환을 치료하기 위한 이의 용도 | |
| JP2000514422A (ja) | 肥満のための遺伝子治療 | |
| KR20240021906A (ko) | 발현 벡터, 박테리아 서열-무함유 벡터, 및 이를 제조하고 사용하는 방법 | |
| JPH09510357A (ja) | 酸性繊維芽細胞成長因子（ａＦＧＦ）をコードする組み換えアデノウィルス | |
| KR102346159B1 (ko) | 고효율 발현 벡터 및 이의 용도 | |
| US20020031493A1 (en) | Recombinant adenoviruses coding for glial-derived cell neurotrophic factor (gdnf) | |
| CN114364792B (zh) | 溶瘤牛痘病毒 | |
| RU2808459C2 (ru) | Геннотерапевтические векторы для лечения болезни данона | |
| KR20240023100A (ko) | 유전자 발현을 조절하기 위한 조성물 및 방법 | |
| KR20210150487A (ko) | 리소좀 장애를 위한 유전자 요법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination |