CN107109381A - 治疗组织钙化的方法 - Google Patents
治疗组织钙化的方法 Download PDFInfo
- Publication number
- CN107109381A CN107109381A CN201580069537.6A CN201580069537A CN107109381A CN 107109381 A CN107109381 A CN 107109381A CN 201580069537 A CN201580069537 A CN 201580069537A CN 107109381 A CN107109381 A CN 107109381A
- Authority
- CN
- China
- Prior art keywords
- leu
- ser
- pro
- lys
- glu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 106
- 230000002308 calcification Effects 0.000 title claims abstract description 51
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 161
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 54
- 230000001965 increasing effect Effects 0.000 claims abstract description 45
- 201000010099 disease Diseases 0.000 claims abstract description 41
- 230000007547 defect Effects 0.000 claims abstract description 32
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 24
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 23
- 210000002966 serum Anatomy 0.000 claims abstract description 21
- 102100028187 ATP-binding cassette sub-family C member 6 Human genes 0.000 claims abstract description 18
- 201000004613 Pseudoxanthoma elasticum Diseases 0.000 claims abstract description 17
- 208000023558 pseudoxanthoma elasticum (inherited or acquired) Diseases 0.000 claims abstract description 17
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 208000010444 Acidosis Diseases 0.000 claims abstract description 11
- 208000007442 rickets Diseases 0.000 claims abstract description 11
- 108090001061 Insulin Proteins 0.000 claims abstract description 8
- 102000004877 Insulin Human genes 0.000 claims abstract description 8
- 208000009469 Ossification of Posterior Longitudinal Ligament Diseases 0.000 claims abstract description 8
- 229940125396 insulin Drugs 0.000 claims abstract description 8
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 6
- 206010003422 Articular calcification Diseases 0.000 claims abstract description 5
- 208000005598 Angioid Streaks Diseases 0.000 claims abstract description 4
- 208000033825 Chorioretinal atrophy Diseases 0.000 claims abstract description 4
- 108020001507 fusion proteins Proteins 0.000 claims description 120
- 102000037865 fusion proteins Human genes 0.000 claims description 120
- 210000002381 plasma Anatomy 0.000 claims description 92
- 239000012634 fragment Substances 0.000 claims description 60
- 238000011282 treatment Methods 0.000 claims description 55
- 241000282414 Homo sapiens Species 0.000 claims description 36
- 238000001990 intravenous administration Methods 0.000 claims description 24
- 238000000926 separation method Methods 0.000 claims description 17
- 210000001519 tissue Anatomy 0.000 claims description 15
- 108060003951 Immunoglobulin Proteins 0.000 claims description 13
- 102000018358 immunoglobulin Human genes 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000002773 nucleotide Substances 0.000 claims description 11
- 125000003729 nucleotide group Chemical group 0.000 claims description 11
- 238000007920 subcutaneous administration Methods 0.000 claims description 11
- 210000001367 artery Anatomy 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 108010009413 Pyrophosphatases Proteins 0.000 claims description 9
- 102000009609 Pyrophosphatases Human genes 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 201000000523 end stage renal failure Diseases 0.000 claims description 8
- 230000008685 targeting Effects 0.000 claims description 8
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 7
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000003442 weekly effect Effects 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 235000003704 aspartic acid Nutrition 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 229910052816 inorganic phosphate Inorganic materials 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 206010048214 Xanthoma Diseases 0.000 claims description 2
- 206010048215 Xanthomatosis Diseases 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 150000001510 aspartic acids Chemical class 0.000 claims 1
- 230000036765 blood level Effects 0.000 claims 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 claims 1
- 238000010606 normalization Methods 0.000 claims 1
- 239000002777 nucleoside Substances 0.000 claims 1
- 125000003835 nucleoside group Chemical group 0.000 claims 1
- 238000007781 pre-processing Methods 0.000 claims 1
- 208000004434 Calcinosis Diseases 0.000 abstract description 48
- 101150011046 NPP1 gene Proteins 0.000 abstract description 6
- 208000033173 Generalized arterial calcification of infancy Diseases 0.000 abstract description 3
- 208000004900 arterial calcification of infancy Diseases 0.000 abstract description 3
- 208000011111 hypophosphatemic rickets Diseases 0.000 abstract description 2
- 208000001040 ossification of the posterior longitudinal ligament of the spine Diseases 0.000 abstract description 2
- 101100080092 Phytophthora capsici NLP1 gene Proteins 0.000 abstract 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 46
- 108090000765 processed proteins & peptides Proteins 0.000 description 39
- 230000000975 bioactive effect Effects 0.000 description 38
- 125000003275 alpha amino acid group Chemical group 0.000 description 36
- 230000000694 effects Effects 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 30
- 101150017770 ENPP1 gene Proteins 0.000 description 29
- 229940024606 amino acid Drugs 0.000 description 29
- 150000001413 amino acids Chemical class 0.000 description 28
- 210000004369 blood Anatomy 0.000 description 28
- 239000008280 blood Substances 0.000 description 28
- 239000002609 medium Substances 0.000 description 27
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 26
- 108010034529 leucyl-lysine Proteins 0.000 description 25
- 238000012545 processing Methods 0.000 description 25
- 229920001184 polypeptide Polymers 0.000 description 23
- 102000004196 processed proteins & peptides Human genes 0.000 description 23
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 21
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 21
- 239000011575 calcium Substances 0.000 description 21
- 229910052791 calcium Inorganic materials 0.000 description 21
- 108010051242 phenylalanylserine Proteins 0.000 description 21
- 229940048084 pyrophosphate Drugs 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 108010060199 cysteinylproline Proteins 0.000 description 19
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 19
- 241000880493 Leptailurus serval Species 0.000 description 18
- 108010049041 glutamylalanine Proteins 0.000 description 18
- 210000003734 kidney Anatomy 0.000 description 18
- 108010051110 tyrosyl-lysine Proteins 0.000 description 18
- 230000037396 body weight Effects 0.000 description 17
- 108010050848 glycylleucine Proteins 0.000 description 17
- 108010036413 histidylglycine Proteins 0.000 description 17
- 108010092114 histidylphenylalanine Proteins 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 238000002560 therapeutic procedure Methods 0.000 description 17
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 16
- 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 16
- 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 16
- 108010077245 asparaginyl-proline Proteins 0.000 description 16
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 16
- 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 14
- 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 14
- 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 14
- 108010093581 aspartyl-proline Proteins 0.000 description 14
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 14
- 235000005911 diet Nutrition 0.000 description 14
- 230000037213 diet Effects 0.000 description 14
- 230000004927 fusion Effects 0.000 description 14
- 108010078144 glutaminyl-glycine Proteins 0.000 description 14
- 108010057821 leucylproline Proteins 0.000 description 14
- 108010003700 lysyl aspartic acid Proteins 0.000 description 14
- 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 13
- 108010087924 alanylproline Proteins 0.000 description 13
- 108010092854 aspartyllysine Proteins 0.000 description 13
- 230000008859 change Effects 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 108010090894 prolylleucine Proteins 0.000 description 13
- 108010061238 threonyl-glycine Proteins 0.000 description 13
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 description 12
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 12
- 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 12
- 241001465754 Metazoa Species 0.000 description 12
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 12
- 108010017391 lysylvaline Proteins 0.000 description 12
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 11
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 11
- 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 11
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 230000002255 enzymatic effect Effects 0.000 description 11
- 239000011574 phosphorus Substances 0.000 description 11
- 229910052698 phosphorus Inorganic materials 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 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 10
- FYTCLUIYTYFGPT-YUMQZZPRSA-N His-Gly-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FYTCLUIYTYFGPT-YUMQZZPRSA-N 0.000 description 10
- 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 10
- YRRCOJOXAJNSAX-IHRRRGAJSA-N Leu-Pro-Lys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N YRRCOJOXAJNSAX-IHRRRGAJSA-N 0.000 description 10
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 10
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 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 10
- 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 10
- 108010085059 glutamyl-arginyl-proline Proteins 0.000 description 10
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 10
- 108010028188 glycyl-histidyl-serine Proteins 0.000 description 10
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 10
- 108010076756 leucyl-alanyl-phenylalanine Proteins 0.000 description 10
- 108010030617 leucyl-phenylalanyl-valine Proteins 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 108010005652 splenotritin Proteins 0.000 description 10
- 108010058119 tryptophyl-glycyl-glycine Proteins 0.000 description 10
- QBQVKUNBCAFXSV-ULQDDVLXSA-N Arg-Lys-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QBQVKUNBCAFXSV-ULQDDVLXSA-N 0.000 description 9
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 9
- XMKXONRMGJXCJV-LAEOZQHASA-N Asp-Val-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XMKXONRMGJXCJV-LAEOZQHASA-N 0.000 description 9
- 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 9
- VZBIUJURDLFFOE-IHRRRGAJSA-N Leu-His-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VZBIUJURDLFFOE-IHRRRGAJSA-N 0.000 description 9
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 9
- CQRGINSEMFBACV-WPRPVWTQSA-N Met-Val-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O CQRGINSEMFBACV-WPRPVWTQSA-N 0.000 description 9
- 108010065395 Neuropep-1 Proteins 0.000 description 9
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 9
- KMWFXJCGRXBQAC-CIUDSAMLSA-N Ser-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N KMWFXJCGRXBQAC-CIUDSAMLSA-N 0.000 description 9
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 9
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 9
- 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 9
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 108010015792 glycyllysine Proteins 0.000 description 9
- 108010009298 lysylglutamic acid Proteins 0.000 description 9
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 8
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 8
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 8
- GGLIDLCEPDHEJO-BQBZGAKWSA-N Gly-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CN GGLIDLCEPDHEJO-BQBZGAKWSA-N 0.000 description 8
- 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 8
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 8
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 8
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 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
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 8
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 8
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 8
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 8
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 108010029020 prolylglycine Proteins 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 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 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 7
- 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 7
- QPBSRMDNJOTFAL-AICCOOGYSA-N Ala-Leu-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QPBSRMDNJOTFAL-AICCOOGYSA-N 0.000 description 7
- RUXQNKVQSKOOBS-JURCDPSOSA-N Ala-Phe-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RUXQNKVQSKOOBS-JURCDPSOSA-N 0.000 description 7
- 102000009027 Albumins Human genes 0.000 description 7
- 108010088751 Albumins Proteins 0.000 description 7
- 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 7
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 7
- SJPZTWAYTJPPBI-GUBZILKMSA-N Asn-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](CC(=O)N)N SJPZTWAYTJPPBI-GUBZILKMSA-N 0.000 description 7
- 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 7
- BZWRLDPIWKOVKB-ZPFDUUQYSA-N Asn-Leu-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BZWRLDPIWKOVKB-ZPFDUUQYSA-N 0.000 description 7
- ICDDSTLEMLGSTB-GUBZILKMSA-N Asn-Met-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ICDDSTLEMLGSTB-GUBZILKMSA-N 0.000 description 7
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 7
- JDHOJQJMWBKHDB-CIUDSAMLSA-N Asp-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)O)N JDHOJQJMWBKHDB-CIUDSAMLSA-N 0.000 description 7
- YNCHFVRXEQFPBY-BQBZGAKWSA-N Asp-Gly-Arg Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N YNCHFVRXEQFPBY-BQBZGAKWSA-N 0.000 description 7
- ILQCHXURSRRIRY-YUMQZZPRSA-N Asp-His-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)O)N ILQCHXURSRRIRY-YUMQZZPRSA-N 0.000 description 7
- SBMGKDLRJLYZCU-BIIVOSGPSA-N Cys-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N)C(=O)O SBMGKDLRJLYZCU-BIIVOSGPSA-N 0.000 description 7
- YZFCGHIBLBDZDA-ZLUOBGJFSA-N Cys-Asp-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O YZFCGHIBLBDZDA-ZLUOBGJFSA-N 0.000 description 7
- OXOQBEVULIBOSH-ZDLURKLDSA-N Cys-Gly-Thr Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O OXOQBEVULIBOSH-ZDLURKLDSA-N 0.000 description 7
- JXVFJOMFOLFPMP-KKUMJFAQSA-N Cys-Leu-Tyr Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JXVFJOMFOLFPMP-KKUMJFAQSA-N 0.000 description 7
- UOEYKPDDHSFMLI-DCAQKATOSA-N Cys-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CS)N UOEYKPDDHSFMLI-DCAQKATOSA-N 0.000 description 7
- KVYVOGYEMPEXBT-GUBZILKMSA-N Gln-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O KVYVOGYEMPEXBT-GUBZILKMSA-N 0.000 description 7
- 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 7
- PODFFOWWLUPNMN-DCAQKATOSA-N Gln-His-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PODFFOWWLUPNMN-DCAQKATOSA-N 0.000 description 7
- HYPVLWGNBIYTNA-GUBZILKMSA-N Gln-Leu-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HYPVLWGNBIYTNA-GUBZILKMSA-N 0.000 description 7
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 7
- ZOXBSICWUDAOHX-GUBZILKMSA-N Glu-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(O)=O ZOXBSICWUDAOHX-GUBZILKMSA-N 0.000 description 7
- HLYCMRDRWGSTPZ-CIUDSAMLSA-N Glu-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CS)C(=O)O HLYCMRDRWGSTPZ-CIUDSAMLSA-N 0.000 description 7
- SYAYROHMAIHWFB-KBIXCLLPSA-N Glu-Ser-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SYAYROHMAIHWFB-KBIXCLLPSA-N 0.000 description 7
- FGGKGJHCVMYGCD-UKJIMTQDSA-N Glu-Val-Ile 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)CC)C(O)=O FGGKGJHCVMYGCD-UKJIMTQDSA-N 0.000 description 7
- 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 7
- QCTLGOYODITHPQ-WHFBIAKZSA-N Gly-Cys-Ser Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O QCTLGOYODITHPQ-WHFBIAKZSA-N 0.000 description 7
- AAHSHTLISQUZJL-QSFUFRPTSA-N Gly-Ile-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AAHSHTLISQUZJL-QSFUFRPTSA-N 0.000 description 7
- 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 7
- IUKIDFVOUHZRAK-QWRGUYRKSA-N Gly-Lys-His Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IUKIDFVOUHZRAK-QWRGUYRKSA-N 0.000 description 7
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 7
- 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 7
- LYDKQVYYCMYNMC-SRVKXCTJSA-N His-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 LYDKQVYYCMYNMC-SRVKXCTJSA-N 0.000 description 7
- 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 7
- JATYGDHMDRAISQ-KKUMJFAQSA-N His-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O JATYGDHMDRAISQ-KKUMJFAQSA-N 0.000 description 7
- XLCZWMJPVGRWHJ-KQXIARHKSA-N Ile-Glu-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N XLCZWMJPVGRWHJ-KQXIARHKSA-N 0.000 description 7
- GAZGFPOZOLEYAJ-YTFOTSKYSA-N Ile-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N GAZGFPOZOLEYAJ-YTFOTSKYSA-N 0.000 description 7
- 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 7
- 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 7
- APQYGMBHIVXFML-OSUNSFLBSA-N Ile-Val-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N APQYGMBHIVXFML-OSUNSFLBSA-N 0.000 description 7
- 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 7
- 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 7
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 7
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- 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 7
- ULUQBUKAPDUKOC-GVXVVHGQSA-N Lys-Glu-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O ULUQBUKAPDUKOC-GVXVVHGQSA-N 0.000 description 7
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 7
- XATKLFSXFINPSB-JYJNAYRXSA-N Lys-Tyr-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O XATKLFSXFINPSB-JYJNAYRXSA-N 0.000 description 7
- IMDJSVBFQKDDEQ-MGHWNKPDSA-N Lys-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCCCN)N IMDJSVBFQKDDEQ-MGHWNKPDSA-N 0.000 description 7
- MIMXMVDLMDMOJD-BZSNNMDCSA-N Lys-Tyr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O MIMXMVDLMDMOJD-BZSNNMDCSA-N 0.000 description 7
- FPQMQEOVSKMVMA-ACRUOGEOSA-N Lys-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCCCN)N)O FPQMQEOVSKMVMA-ACRUOGEOSA-N 0.000 description 7
- YLDSJJOGQNEQJK-AVGNSLFASA-N Met-Pro-Leu Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O YLDSJJOGQNEQJK-AVGNSLFASA-N 0.000 description 7
- OOLVTRHJJBCJKB-IHRRRGAJSA-N Met-Tyr-Asp Chemical compound CSCC[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 OOLVTRHJJBCJKB-IHRRRGAJSA-N 0.000 description 7
- 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 7
- 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 7
- MFQXSDWKUXTOPZ-DZKIICNBSA-N Phe-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N MFQXSDWKUXTOPZ-DZKIICNBSA-N 0.000 description 7
- BNRFQGLWLQESBG-YESZJQIVSA-N Phe-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O BNRFQGLWLQESBG-YESZJQIVSA-N 0.000 description 7
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-N 0.000 description 7
- RVEVENLSADZUMS-IHRRRGAJSA-N Phe-Pro-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RVEVENLSADZUMS-IHRRRGAJSA-N 0.000 description 7
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 7
- APXXVISUHOLGEE-ILWGZMRPSA-N Phe-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CC=CC=C4)N)C(=O)O APXXVISUHOLGEE-ILWGZMRPSA-N 0.000 description 7
- QUUCAHIYARMNBL-FHWLQOOXSA-N Phe-Tyr-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N QUUCAHIYARMNBL-FHWLQOOXSA-N 0.000 description 7
- XALFIVXGQUEGKV-JSGCOSHPSA-N Phe-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 XALFIVXGQUEGKV-JSGCOSHPSA-N 0.000 description 7
- WWAQEUOYCYMGHB-FXQIFTODSA-N Pro-Asn-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 WWAQEUOYCYMGHB-FXQIFTODSA-N 0.000 description 7
- 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 7
- 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 7
- YSUZKYSRAFNLRB-ULQDDVLXSA-N Pro-Gln-Trp Chemical compound N([C@@H](CCC(=O)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C(=O)[C@@H]1CCCN1 YSUZKYSRAFNLRB-ULQDDVLXSA-N 0.000 description 7
- ZTMLZUNPFDGPKY-VKOGCVSHSA-N Pro-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]3CCCN3 ZTMLZUNPFDGPKY-VKOGCVSHSA-N 0.000 description 7
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 7
- JDJMFMVVJHLWDP-UNQGMJICSA-N Pro-Thr-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JDJMFMVVJHLWDP-UNQGMJICSA-N 0.000 description 7
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 7
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 7
- RIAKPZVSNBBNRE-BJDJZHNGSA-N Ser-Ile-Leu Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O RIAKPZVSNBBNRE-BJDJZHNGSA-N 0.000 description 7
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 7
- 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 7
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-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](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 7
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 7
- ANOQEBQWIAYIMV-AEJSXWLSSA-N Ser-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N ANOQEBQWIAYIMV-AEJSXWLSSA-N 0.000 description 7
- CTONFVDJYCAMQM-IUKAMOBKSA-N Thr-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H]([C@@H](C)O)N CTONFVDJYCAMQM-IUKAMOBKSA-N 0.000 description 7
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 7
- AYCQVUUPIJHJTA-IXOXFDKPSA-N Thr-His-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O AYCQVUUPIJHJTA-IXOXFDKPSA-N 0.000 description 7
- DDDLIMCZFKOERC-SVSWQMSJSA-N Thr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N DDDLIMCZFKOERC-SVSWQMSJSA-N 0.000 description 7
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 7
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 7
- NBIIPOKZPUGATB-BWBBJGPYSA-N Thr-Ser-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O NBIIPOKZPUGATB-BWBBJGPYSA-N 0.000 description 7
- JVTHMUDOKPQBOT-NSHDSACASA-N Trp-Gly-Gly Chemical compound C1=CC=C2C(C[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O)=CNC2=C1 JVTHMUDOKPQBOT-NSHDSACASA-N 0.000 description 7
- YVXIAOOYAKBAAI-SZMVWBNQSA-N Trp-Leu-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 YVXIAOOYAKBAAI-SZMVWBNQSA-N 0.000 description 7
- VMXLNDRJXVAJFT-JYBASQMISA-N Trp-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O VMXLNDRJXVAJFT-JYBASQMISA-N 0.000 description 7
- LNGFWVPNKLWATF-ZVZYQTTQSA-N Trp-Val-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LNGFWVPNKLWATF-ZVZYQTTQSA-N 0.000 description 7
- GFHYISDTIWZUSU-QWRGUYRKSA-N Tyr-Asn-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GFHYISDTIWZUSU-QWRGUYRKSA-N 0.000 description 7
- FQNUWOHNGJWNLM-QWRGUYRKSA-N Tyr-Cys-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FQNUWOHNGJWNLM-QWRGUYRKSA-N 0.000 description 7
- HZZKQZDUIKVFDZ-AVGNSLFASA-N Tyr-Gln-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)O HZZKQZDUIKVFDZ-AVGNSLFASA-N 0.000 description 7
- HVHJYXDXRIWELT-RYUDHWBXSA-N Tyr-Glu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O HVHJYXDXRIWELT-RYUDHWBXSA-N 0.000 description 7
- NOOMDULIORCDNF-IRXDYDNUSA-N Tyr-Gly-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NOOMDULIORCDNF-IRXDYDNUSA-N 0.000 description 7
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 7
- BSCBBPKDVOZICB-KKUMJFAQSA-N Tyr-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O BSCBBPKDVOZICB-KKUMJFAQSA-N 0.000 description 7
- GZOCMHSZGGJBCX-ULQDDVLXSA-N Tyr-Lys-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O GZOCMHSZGGJBCX-ULQDDVLXSA-N 0.000 description 7
- 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 7
- QFXVAFIHVWXXBJ-AVGNSLFASA-N Tyr-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O QFXVAFIHVWXXBJ-AVGNSLFASA-N 0.000 description 7
- CLEGSEJVGBYZBJ-MEYUZBJRSA-N Tyr-Thr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 CLEGSEJVGBYZBJ-MEYUZBJRSA-N 0.000 description 7
- JHDZONWZTCKTJR-KJEVXHAQSA-N Tyr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JHDZONWZTCKTJR-KJEVXHAQSA-N 0.000 description 7
- DBOXBUDEAJVKRE-LSJOCFKGSA-N Val-Asn-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N DBOXBUDEAJVKRE-LSJOCFKGSA-N 0.000 description 7
- LMSBRIVOCYOKMU-NRPADANISA-N Val-Gln-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N LMSBRIVOCYOKMU-NRPADANISA-N 0.000 description 7
- 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 7
- BZWUSZGQOILYEU-STECZYCISA-N Val-Ile-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BZWUSZGQOILYEU-STECZYCISA-N 0.000 description 7
- 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 7
- 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 7
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 7
- 238000009825 accumulation Methods 0.000 description 7
- 108010047495 alanylglycine Proteins 0.000 description 7
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 7
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 7
- 108010060035 arginylproline Proteins 0.000 description 7
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 108010037850 glycylvaline Proteins 0.000 description 7
- 108010054155 lysyllysine Proteins 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 6
- SKHCUBQVZJHOFM-NAKRPEOUSA-N Ala-Arg-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SKHCUBQVZJHOFM-NAKRPEOUSA-N 0.000 description 6
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 6
- ROLXPVQSRCPVGK-XDTLVQLUSA-N Ala-Glu-Tyr Chemical compound N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O ROLXPVQSRCPVGK-XDTLVQLUSA-N 0.000 description 6
- 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 6
- WESHVRNMNFMVBE-FXQIFTODSA-N Arg-Asn-Asp Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)CN=C(N)N WESHVRNMNFMVBE-FXQIFTODSA-N 0.000 description 6
- JTWOBPNAVBESFW-FXQIFTODSA-N Arg-Cys-Asp Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)CN=C(N)N JTWOBPNAVBESFW-FXQIFTODSA-N 0.000 description 6
- IGULQRCJLQQPSM-DCAQKATOSA-N Arg-Cys-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IGULQRCJLQQPSM-DCAQKATOSA-N 0.000 description 6
- VKCOHFFSTKCXEQ-OLHMAJIHSA-N Asn-Asn-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VKCOHFFSTKCXEQ-OLHMAJIHSA-N 0.000 description 6
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 6
- 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 6
- MYCSPQIARXTUTP-SRVKXCTJSA-N Asn-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)N)N MYCSPQIARXTUTP-SRVKXCTJSA-N 0.000 description 6
- UBGGJTMETLEXJD-DCAQKATOSA-N Asn-Leu-Met Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O UBGGJTMETLEXJD-DCAQKATOSA-N 0.000 description 6
- QXOPPIDJKPEKCW-GUBZILKMSA-N Asn-Pro-Arg Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O QXOPPIDJKPEKCW-GUBZILKMSA-N 0.000 description 6
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 6
- 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 6
- 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 6
- LIJXJYGRSRWLCJ-IHRRRGAJSA-N Asp-Phe-Arg Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LIJXJYGRSRWLCJ-IHRRRGAJSA-N 0.000 description 6
- GGBQDSHTXKQSLP-NHCYSSNCSA-N Asp-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N GGBQDSHTXKQSLP-NHCYSSNCSA-N 0.000 description 6
- XABFFGOGKOORCG-CIUDSAMLSA-N Cys-Asp-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O XABFFGOGKOORCG-CIUDSAMLSA-N 0.000 description 6
- 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 6
- VLOLPWWCNKWRNB-LOKLDPHHSA-N Gln-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O VLOLPWWCNKWRNB-LOKLDPHHSA-N 0.000 description 6
- 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 6
- VPKBCVUDBNINAH-GARJFASQSA-N Glu-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O VPKBCVUDBNINAH-GARJFASQSA-N 0.000 description 6
- PXHABOCPJVTGEK-BQBZGAKWSA-N Glu-Gln-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O PXHABOCPJVTGEK-BQBZGAKWSA-N 0.000 description 6
- 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 6
- 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 6
- ZAPFAWQHBOHWLL-GUBZILKMSA-N Glu-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N ZAPFAWQHBOHWLL-GUBZILKMSA-N 0.000 description 6
- CGWHAXBNGYQBBK-JBACZVJFSA-N Glu-Trp-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)N)C(O)=O)C1=CC=C(O)C=C1 CGWHAXBNGYQBBK-JBACZVJFSA-N 0.000 description 6
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 6
- 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 6
- 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 6
- FCKPEGOCSVZPNC-WHOFXGATSA-N Gly-Ile-Phe Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FCKPEGOCSVZPNC-WHOFXGATSA-N 0.000 description 6
- FXLVSYVJDPCIHH-STQMWFEESA-N Gly-Phe-Arg Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FXLVSYVJDPCIHH-STQMWFEESA-N 0.000 description 6
- WZSHYFGOLPXPLL-RYUDHWBXSA-N Gly-Phe-Glu Chemical compound NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCC(O)=O)C(O)=O WZSHYFGOLPXPLL-RYUDHWBXSA-N 0.000 description 6
- 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 6
- LLWQVJNHMYBLLK-CDMKHQONSA-N Gly-Thr-Phe Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LLWQVJNHMYBLLK-CDMKHQONSA-N 0.000 description 6
- PQKCQZHAGILVIM-NKIYYHGXSA-N His-Glu-Thr Chemical compound C[C@@H](O)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)Cc1cnc[nH]1)C(O)=O PQKCQZHAGILVIM-NKIYYHGXSA-N 0.000 description 6
- ZRSJXIKQXUGKRB-TUBUOCAGSA-N His-Ile-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZRSJXIKQXUGKRB-TUBUOCAGSA-N 0.000 description 6
- SGLXGEDPYJPGIQ-ACRUOGEOSA-N His-Phe-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)NC(=O)[C@H](CC3=CN=CN3)N SGLXGEDPYJPGIQ-ACRUOGEOSA-N 0.000 description 6
- WHKLDLQHSYAVGU-ACRUOGEOSA-N His-Phe-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WHKLDLQHSYAVGU-ACRUOGEOSA-N 0.000 description 6
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 6
- KIMHKBDJQQYLHU-PEFMBERDSA-N Ile-Glu-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KIMHKBDJQQYLHU-PEFMBERDSA-N 0.000 description 6
- WUKLZPHVWAMZQV-UKJIMTQDSA-N Ile-Glu-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N WUKLZPHVWAMZQV-UKJIMTQDSA-N 0.000 description 6
- 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 6
- KLBVGHCGHUNHEA-BJDJZHNGSA-N Ile-Leu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)O)N KLBVGHCGHUNHEA-BJDJZHNGSA-N 0.000 description 6
- IVXJIMGDOYRLQU-XUXIUFHCSA-N Ile-Pro-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O IVXJIMGDOYRLQU-XUXIUFHCSA-N 0.000 description 6
- KTNGVMMGIQWIDV-OSUNSFLBSA-N Ile-Pro-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O KTNGVMMGIQWIDV-OSUNSFLBSA-N 0.000 description 6
- 108010065920 Insulin Lispro Proteins 0.000 description 6
- 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 6
- DDEMUMVXNFPDKC-SRVKXCTJSA-N Leu-His-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CS)C(=O)O)N DDEMUMVXNFPDKC-SRVKXCTJSA-N 0.000 description 6
- 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 6
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-N 0.000 description 6
- 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 6
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe 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)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 6
- AXVIGSRGTMNSJU-YESZJQIVSA-N Leu-Tyr-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N AXVIGSRGTMNSJU-YESZJQIVSA-N 0.000 description 6
- DGWXCIORNLWGGG-CIUDSAMLSA-N Lys-Asn-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O DGWXCIORNLWGGG-CIUDSAMLSA-N 0.000 description 6
- 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 6
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 6
- GNLJXWBNLAIPEP-MELADBBJSA-N Lys-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCCCN)N)C(=O)O GNLJXWBNLAIPEP-MELADBBJSA-N 0.000 description 6
- GOVDTWNJCBRRBJ-DCAQKATOSA-N Lys-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GOVDTWNJCBRRBJ-DCAQKATOSA-N 0.000 description 6
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 6
- LBNFTWKGISQVEE-AVGNSLFASA-N Met-Leu-Met Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCSC LBNFTWKGISQVEE-AVGNSLFASA-N 0.000 description 6
- NKLDZIPTGKBDBB-HTUGSXCWSA-N Phe-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O NKLDZIPTGKBDBB-HTUGSXCWSA-N 0.000 description 6
- FMMIYCMOVGXZIP-AVGNSLFASA-N Phe-Glu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O FMMIYCMOVGXZIP-AVGNSLFASA-N 0.000 description 6
- ZIQQNOXKEFDPBE-BZSNNMDCSA-N Phe-Lys-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N ZIQQNOXKEFDPBE-BZSNNMDCSA-N 0.000 description 6
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 6
- 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 6
- LCUOTSLIVGSGAU-AVGNSLFASA-N Pro-His-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LCUOTSLIVGSGAU-AVGNSLFASA-N 0.000 description 6
- 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 6
- COAHUSQNSVFYBW-FXQIFTODSA-N Ser-Asn-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O COAHUSQNSVFYBW-FXQIFTODSA-N 0.000 description 6
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 6
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 6
- KCNSGAMPBPYUAI-CIUDSAMLSA-N Ser-Leu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KCNSGAMPBPYUAI-CIUDSAMLSA-N 0.000 description 6
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 6
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 6
- DKGRNFUXVTYRAS-UBHSHLNASA-N Ser-Ser-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DKGRNFUXVTYRAS-UBHSHLNASA-N 0.000 description 6
- MFEBUIFJVPNZLO-OLHMAJIHSA-N Thr-Asp-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O MFEBUIFJVPNZLO-OLHMAJIHSA-N 0.000 description 6
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 6
- 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 6
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 6
- 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 6
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 6
- 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 6
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 6
- 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 6
- 239000002253 acid Substances 0.000 description 6
- 108010047857 aspartylglycine Proteins 0.000 description 6
- 210000001772 blood platelet Anatomy 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 235000018417 cysteine Nutrition 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 108010025306 histidylleucine Proteins 0.000 description 6
- 102000057593 human F8 Human genes 0.000 description 6
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 6
- 108010000761 leucylarginine Proteins 0.000 description 6
- 108010064235 lysylglycine Proteins 0.000 description 6
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 6
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 6
- 108010070643 prolylglutamic acid Proteins 0.000 description 6
- 229940047431 recombinate Drugs 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 6
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 5
- 229930024421 Adenine Natural products 0.000 description 5
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 5
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 5
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 5
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 5
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004042 Fibroblast Growth Factor-23 Human genes 0.000 description 5
- 108090000569 Fibroblast Growth Factor-23 Proteins 0.000 description 5
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 5
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 5
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 5
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 5
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 5
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 5
- 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 5
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 5
- 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 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 5
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 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 5
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 5
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 5
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 5
- 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 5
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 5
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 5
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 5
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 5
- 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 5
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 5
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 5
- 229960000643 adenine Drugs 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 235000013601 eggs Nutrition 0.000 description 5
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 5
- 108010081551 glycylphenylalanine Proteins 0.000 description 5
- 210000002216 heart Anatomy 0.000 description 5
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- OZRFYUJEXYKQDV-UHFFFAOYSA-N 2-[[2-[[2-[(2-amino-3-carboxypropanoyl)amino]-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]butanedioic acid Chemical compound OC(=O)CC(N)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(=O)NC(CC(O)=O)C(O)=O OZRFYUJEXYKQDV-UHFFFAOYSA-N 0.000 description 4
- MFMDKJIPHSWSBM-GUBZILKMSA-N Ala-Lys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFMDKJIPHSWSBM-GUBZILKMSA-N 0.000 description 4
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 4
- 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 4
- 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 4
- WQSCVMQDZYTFQU-FXQIFTODSA-N Asn-Cys-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WQSCVMQDZYTFQU-FXQIFTODSA-N 0.000 description 4
- NNMUHYLAYUSTTN-FXQIFTODSA-N Asn-Gln-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O NNMUHYLAYUSTTN-FXQIFTODSA-N 0.000 description 4
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 4
- HJZLUGQGJWXJCJ-CIUDSAMLSA-N Asp-Pro-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O HJZLUGQGJWXJCJ-CIUDSAMLSA-N 0.000 description 4
- 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 4
- CVOZXIPULQQFNY-ZLUOBGJFSA-N Cys-Ala-Cys Chemical compound C[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O CVOZXIPULQQFNY-ZLUOBGJFSA-N 0.000 description 4
- ZIKWRNJXFIQECJ-CIUDSAMLSA-N Cys-Cys-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ZIKWRNJXFIQECJ-CIUDSAMLSA-N 0.000 description 4
- LKUCSUGWHYVYLP-GHCJXIJMSA-N Cys-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](CS)N LKUCSUGWHYVYLP-GHCJXIJMSA-N 0.000 description 4
- VXLXATVURDNDCG-CIUDSAMLSA-N Cys-Lys-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N VXLXATVURDNDCG-CIUDSAMLSA-N 0.000 description 4
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 4
- 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 4
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 4
- 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 4
- 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 4
- LLZXNUUIBOALNY-QWRGUYRKSA-N Gly-Leu-Lys Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN LLZXNUUIBOALNY-QWRGUYRKSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- WZBLRQQCDYYRTD-SIXJUCDHSA-N His-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=CN=CN3)N WZBLRQQCDYYRTD-SIXJUCDHSA-N 0.000 description 4
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 4
- 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 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FMEICTQWUKNAGC-YUMQZZPRSA-N Leu-Gly-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O FMEICTQWUKNAGC-YUMQZZPRSA-N 0.000 description 4
- GZRABTMNWJXFMH-UVOCVTCTSA-N Leu-Thr-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZRABTMNWJXFMH-UVOCVTCTSA-N 0.000 description 4
- XFOAWKDQMRMCDN-ULQDDVLXSA-N Lys-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CC1=CC=CC=C1 XFOAWKDQMRMCDN-ULQDDVLXSA-N 0.000 description 4
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 4
- HOYQLNNGMHXZDW-KKUMJFAQSA-N Phe-Glu-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O HOYQLNNGMHXZDW-KKUMJFAQSA-N 0.000 description 4
- 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 4
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 4
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-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]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 4
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 4
- CZCCVJUUWBMISW-FXQIFTODSA-N Pro-Ser-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O CZCCVJUUWBMISW-FXQIFTODSA-N 0.000 description 4
- GBUNEGKQPSAMNK-QTKMDUPCSA-N Pro-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@@H]2CCCN2)O GBUNEGKQPSAMNK-QTKMDUPCSA-N 0.000 description 4
- PGSWNLRYYONGPE-JYJNAYRXSA-N Pro-Val-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PGSWNLRYYONGPE-JYJNAYRXSA-N 0.000 description 4
- MESDJCNHLZBMEP-ZLUOBGJFSA-N Ser-Asp-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MESDJCNHLZBMEP-ZLUOBGJFSA-N 0.000 description 4
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 4
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 4
- 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 4
- HAUVENOGHPECML-BPUTZDHNSA-N Ser-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CO)=CNC2=C1 HAUVENOGHPECML-BPUTZDHNSA-N 0.000 description 4
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 4
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 4
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 4
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 4
- UMSZZGTXGKHTFJ-SRVKXCTJSA-N Tyr-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UMSZZGTXGKHTFJ-SRVKXCTJSA-N 0.000 description 4
- VXCAZHCVDBQMTP-NRPADANISA-N Val-Cys-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VXCAZHCVDBQMTP-NRPADANISA-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
- KDKLLPMFFGYQJD-CYDGBPFRSA-N Val-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N KDKLLPMFFGYQJD-CYDGBPFRSA-N 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000007975 buffered saline Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 108010085325 histidylproline Proteins 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 208000005368 osteomalacia Diseases 0.000 description 4
- 108010012581 phenylalanylglutamate Proteins 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108010031719 prolyl-serine Proteins 0.000 description 4
- 229940005657 pyrophosphoric acid Drugs 0.000 description 4
- 208000012201 sexual and gender identity disease Diseases 0.000 description 4
- 208000015891 sexual disease Diseases 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000011421 subcutaneous treatment Methods 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 3
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 3
- UWQJHXKARZWDIJ-ZLUOBGJFSA-N Ala-Ala-Cys Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(O)=O UWQJHXKARZWDIJ-ZLUOBGJFSA-N 0.000 description 3
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-N 0.000 description 3
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 3
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 3
- 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 3
- KQESEZXHYOUIIM-CQDKDKBSSA-N Ala-Lys-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KQESEZXHYOUIIM-CQDKDKBSSA-N 0.000 description 3
- 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 3
- 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 3
- BVBKBQRPOJFCQM-DCAQKATOSA-N Arg-Asn-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BVBKBQRPOJFCQM-DCAQKATOSA-N 0.000 description 3
- YUGFLWBWAJFGKY-BQBZGAKWSA-N Arg-Cys-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O YUGFLWBWAJFGKY-BQBZGAKWSA-N 0.000 description 3
- BBYTXXRNSFUOOX-IHRRRGAJSA-N Arg-Cys-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BBYTXXRNSFUOOX-IHRRRGAJSA-N 0.000 description 3
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-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
- STHNZYKCJHWULY-AVGNSLFASA-N Arg-Pro-His Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O STHNZYKCJHWULY-AVGNSLFASA-N 0.000 description 3
- 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 3
- MOGMYRUNTKYZFB-UNQGMJICSA-N Arg-Thr-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MOGMYRUNTKYZFB-UNQGMJICSA-N 0.000 description 3
- LFWOQHSQNCKXRU-UFYCRDLUSA-N Arg-Tyr-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 LFWOQHSQNCKXRU-UFYCRDLUSA-N 0.000 description 3
- VYLVOMUVLMGCRF-ZLUOBGJFSA-N Asn-Asp-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O VYLVOMUVLMGCRF-ZLUOBGJFSA-N 0.000 description 3
- RFLVTVBAESPKKR-ZLUOBGJFSA-N Asn-Cys-Cys Chemical compound N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O RFLVTVBAESPKKR-ZLUOBGJFSA-N 0.000 description 3
- ZPMNECSEJXXNBE-CIUDSAMLSA-N Asn-Cys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ZPMNECSEJXXNBE-CIUDSAMLSA-N 0.000 description 3
- 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 3
- 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 3
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 3
- XVBDDUPJVQXDSI-PEFMBERDSA-N Asn-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](CC(=O)N)N XVBDDUPJVQXDSI-PEFMBERDSA-N 0.000 description 3
- SPCONPVIDFMDJI-QSFUFRPTSA-N Asn-Ile-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O SPCONPVIDFMDJI-QSFUFRPTSA-N 0.000 description 3
- NLRJGXZWTKXRHP-DCAQKATOSA-N Asn-Leu-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NLRJGXZWTKXRHP-DCAQKATOSA-N 0.000 description 3
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 3
- FHETWELNCBMRMG-HJGDQZAQSA-N Asn-Leu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FHETWELNCBMRMG-HJGDQZAQSA-N 0.000 description 3
- WXVGISRWSYGEDK-KKUMJFAQSA-N Asn-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)N)N WXVGISRWSYGEDK-KKUMJFAQSA-N 0.000 description 3
- UYRPHDGXHKBZHJ-CIUDSAMLSA-N Asn-Met-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N UYRPHDGXHKBZHJ-CIUDSAMLSA-N 0.000 description 3
- 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 3
- SNYCNNPOFYBCEK-ZLUOBGJFSA-N Asn-Ser-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O SNYCNNPOFYBCEK-ZLUOBGJFSA-N 0.000 description 3
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 3
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 3
- NSTBNYOKCZKOMI-AVGNSLFASA-N Asn-Tyr-Glu Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O NSTBNYOKCZKOMI-AVGNSLFASA-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
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 3
- HMQDRBKQMLRCCG-GMOBBJLQSA-N Asp-Arg-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HMQDRBKQMLRCCG-GMOBBJLQSA-N 0.000 description 3
- KNMRXHIAVXHCLW-ZLUOBGJFSA-N Asp-Asn-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O KNMRXHIAVXHCLW-ZLUOBGJFSA-N 0.000 description 3
- AAIUGNSRQDGCDC-ZLUOBGJFSA-N Asp-Cys-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N)C(=O)O AAIUGNSRQDGCDC-ZLUOBGJFSA-N 0.000 description 3
- ACEDJCOOPZFUBU-CIUDSAMLSA-N Asp-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N ACEDJCOOPZFUBU-CIUDSAMLSA-N 0.000 description 3
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 3
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 3
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 3
- 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 3
- LBOVBQONZJRWPV-YUMQZZPRSA-N Asp-Lys-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LBOVBQONZJRWPV-YUMQZZPRSA-N 0.000 description 3
- RPUYTJJZXQBWDT-SRVKXCTJSA-N Asp-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](CC(=O)O)N RPUYTJJZXQBWDT-SRVKXCTJSA-N 0.000 description 3
- UAXIKORUDGGIGA-DCAQKATOSA-N Asp-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O UAXIKORUDGGIGA-DCAQKATOSA-N 0.000 description 3
- 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 3
- 206010010356 Congenital anomaly Diseases 0.000 description 3
- ZEXHDOQQYZKOIB-ACZMJKKPSA-N Cys-Glu-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZEXHDOQQYZKOIB-ACZMJKKPSA-N 0.000 description 3
- OTXLNICGSXPGQF-KBIXCLLPSA-N Cys-Ile-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTXLNICGSXPGQF-KBIXCLLPSA-N 0.000 description 3
- SSNJZBGOMNLSLA-CIUDSAMLSA-N Cys-Leu-Asn Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O SSNJZBGOMNLSLA-CIUDSAMLSA-N 0.000 description 3
- CIVXDCMSSFGWAL-YUMQZZPRSA-N Cys-Lys-Gly Chemical compound C(CCN)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CS)N CIVXDCMSSFGWAL-YUMQZZPRSA-N 0.000 description 3
- KGIHMGPYGXBYJJ-SRVKXCTJSA-N Cys-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CS KGIHMGPYGXBYJJ-SRVKXCTJSA-N 0.000 description 3
- CNAMJJOZGXPDHW-IHRRRGAJSA-N Cys-Pro-Phe Chemical compound N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O CNAMJJOZGXPDHW-IHRRRGAJSA-N 0.000 description 3
- RJPKQCFHEPPTGL-ZLUOBGJFSA-N Cys-Ser-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O RJPKQCFHEPPTGL-ZLUOBGJFSA-N 0.000 description 3
- HJXSYJVCMUOUNY-SRVKXCTJSA-N Cys-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N HJXSYJVCMUOUNY-SRVKXCTJSA-N 0.000 description 3
- 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 3
- 241000588724 Escherichia coli Species 0.000 description 3
- NKCZYEDZTKOFBG-GUBZILKMSA-N Gln-Gln-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NKCZYEDZTKOFBG-GUBZILKMSA-N 0.000 description 3
- DRDSQGHKTLSNEA-GLLZPBPUSA-N Gln-Glu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DRDSQGHKTLSNEA-GLLZPBPUSA-N 0.000 description 3
- MFJAPSYJQJCQDN-BQBZGAKWSA-N Gln-Gly-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O MFJAPSYJQJCQDN-BQBZGAKWSA-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
- SMLDOQHTOAAFJQ-WDSKDSINSA-N Gln-Gly-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SMLDOQHTOAAFJQ-WDSKDSINSA-N 0.000 description 3
- ZBKUIQNCRIYVGH-SDDRHHMPSA-N Gln-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZBKUIQNCRIYVGH-SDDRHHMPSA-N 0.000 description 3
- GURIQZQSTBBHRV-SRVKXCTJSA-N Gln-Lys-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GURIQZQSTBBHRV-SRVKXCTJSA-N 0.000 description 3
- 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 3
- DBNLXHGDGBUCDV-KKUMJFAQSA-N Gln-Phe-Met Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O DBNLXHGDGBUCDV-KKUMJFAQSA-N 0.000 description 3
- ZGHMRONFHDVXEF-AVGNSLFASA-N Gln-Ser-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZGHMRONFHDVXEF-AVGNSLFASA-N 0.000 description 3
- YRHZWVKUFWCEPW-GLLZPBPUSA-N Gln-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O YRHZWVKUFWCEPW-GLLZPBPUSA-N 0.000 description 3
- IIMZHVKZBGSEKZ-SZMVWBNQSA-N Gln-Trp-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O IIMZHVKZBGSEKZ-SZMVWBNQSA-N 0.000 description 3
- CVPXINNKRTZBMO-CIUDSAMLSA-N Glu-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)CN=C(N)N CVPXINNKRTZBMO-CIUDSAMLSA-N 0.000 description 3
- 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 3
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 3
- VAZZOGXDUQSVQF-NUMRIWBASA-N Glu-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)O VAZZOGXDUQSVQF-NUMRIWBASA-N 0.000 description 3
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 3
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 3
- 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 3
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 3
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-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)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 3
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 3
- 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 3
- MFNUFCFRAZPJFW-JYJNAYRXSA-N Glu-Lys-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFNUFCFRAZPJFW-JYJNAYRXSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- SYWCGQOIIARSIX-SRVKXCTJSA-N Glu-Pro-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O SYWCGQOIIARSIX-SRVKXCTJSA-N 0.000 description 3
- 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 3
- 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 3
- PYUCNHJQQVSPGN-BQBZGAKWSA-N Gly-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)CN=C(N)N PYUCNHJQQVSPGN-BQBZGAKWSA-N 0.000 description 3
- DJTXYXZNNDDEOU-WHFBIAKZSA-N Gly-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)C(=O)N DJTXYXZNNDDEOU-WHFBIAKZSA-N 0.000 description 3
- SUDUYJOBLHQAMI-WHFBIAKZSA-N Gly-Asp-Cys Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(O)=O SUDUYJOBLHQAMI-WHFBIAKZSA-N 0.000 description 3
- BEQGFMIBZFNROK-JGVFFNPUSA-N Gly-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)CN)C(=O)O BEQGFMIBZFNROK-JGVFFNPUSA-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
- XVYKMNXXJXQKME-XEGUGMAKSA-N Gly-Ile-Tyr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XVYKMNXXJXQKME-XEGUGMAKSA-N 0.000 description 3
- 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 3
- SJLKKOZFHSJJAW-YUMQZZPRSA-N Gly-Met-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)CN SJLKKOZFHSJJAW-YUMQZZPRSA-N 0.000 description 3
- 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 3
- ZLCLYFGMKFCDCN-XPUUQOCRSA-N Gly-Ser-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CO)NC(=O)CN)C(O)=O ZLCLYFGMKFCDCN-XPUUQOCRSA-N 0.000 description 3
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 3
- YDIDLLVFCYSXNY-RCOVLWMOSA-N Gly-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN YDIDLLVFCYSXNY-RCOVLWMOSA-N 0.000 description 3
- SOFSRBYHDINIRG-QTKMDUPCSA-N His-Arg-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N)O SOFSRBYHDINIRG-QTKMDUPCSA-N 0.000 description 3
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 3
- ZZLWLWSUIBSMNP-CIUDSAMLSA-N His-Asp-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZZLWLWSUIBSMNP-CIUDSAMLSA-N 0.000 description 3
- YOSQCYUFZGPIPC-PBCZWWQYSA-N His-Asp-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YOSQCYUFZGPIPC-PBCZWWQYSA-N 0.000 description 3
- CYHWWHKRCKHYGQ-GUBZILKMSA-N His-Cys-Glu Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N CYHWWHKRCKHYGQ-GUBZILKMSA-N 0.000 description 3
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 3
- NQKRILCJYCASDV-QWRGUYRKSA-N His-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 NQKRILCJYCASDV-QWRGUYRKSA-N 0.000 description 3
- ZFDKSLBEWYCOCS-BZSNNMDCSA-N His-Phe-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=CC=CC=C1 ZFDKSLBEWYCOCS-BZSNNMDCSA-N 0.000 description 3
- PGXZHYYGOPKYKM-IHRRRGAJSA-N His-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CCCCN)C(=O)O PGXZHYYGOPKYKM-IHRRRGAJSA-N 0.000 description 3
- FFKJUTZARGRVTH-KKUMJFAQSA-N His-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O FFKJUTZARGRVTH-KKUMJFAQSA-N 0.000 description 3
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 3
- SCHZQZPYHBWYEQ-PEFMBERDSA-N Ile-Asn-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N SCHZQZPYHBWYEQ-PEFMBERDSA-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
- NBJAAWYRLGCJOF-UGYAYLCHSA-N Ile-Asp-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N NBJAAWYRLGCJOF-UGYAYLCHSA-N 0.000 description 3
- PPSQSIDMOVPKPI-BJDJZHNGSA-N Ile-Cys-Leu Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)O PPSQSIDMOVPKPI-BJDJZHNGSA-N 0.000 description 3
- WZDCVAWMBUNDDY-KBIXCLLPSA-N Ile-Glu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)O)N WZDCVAWMBUNDDY-KBIXCLLPSA-N 0.000 description 3
- TVYWVSJGSHQWMT-AJNGGQMLSA-N Ile-Leu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N TVYWVSJGSHQWMT-AJNGGQMLSA-N 0.000 description 3
- FCWFBHMAJZGWRY-XUXIUFHCSA-N Ile-Leu-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N FCWFBHMAJZGWRY-XUXIUFHCSA-N 0.000 description 3
- PMMMQRVUMVURGJ-XUXIUFHCSA-N Ile-Leu-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O PMMMQRVUMVURGJ-XUXIUFHCSA-N 0.000 description 3
- UIEZQYNXCYHMQS-BJDJZHNGSA-N Ile-Lys-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)O)N UIEZQYNXCYHMQS-BJDJZHNGSA-N 0.000 description 3
- XDUVMJCBYUKNFJ-MXAVVETBSA-N Ile-Lys-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N XDUVMJCBYUKNFJ-MXAVVETBSA-N 0.000 description 3
- FHPZJWJWTWZKNA-LLLHUVSDSA-N Ile-Phe-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N FHPZJWJWTWZKNA-LLLHUVSDSA-N 0.000 description 3
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 3
- YCKPUHHMCFSUMD-IUKAMOBKSA-N Ile-Thr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YCKPUHHMCFSUMD-IUKAMOBKSA-N 0.000 description 3
- YBKKLDBBPFIXBQ-MBLNEYKQSA-N Ile-Thr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)O)N YBKKLDBBPFIXBQ-MBLNEYKQSA-N 0.000 description 3
- 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 3
- XIRYQRLFHWWWTC-QEJZJMRPSA-N Leu-Ala-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XIRYQRLFHWWWTC-QEJZJMRPSA-N 0.000 description 3
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 3
- VIWUBXKCYJGNCL-SRVKXCTJSA-N Leu-Asn-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 VIWUBXKCYJGNCL-SRVKXCTJSA-N 0.000 description 3
- POJPZSMTTMLSTG-SRVKXCTJSA-N Leu-Asn-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N POJPZSMTTMLSTG-SRVKXCTJSA-N 0.000 description 3
- CLVUXCBGKUECIT-HJGDQZAQSA-N Leu-Asp-Thr 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)O)C(O)=O CLVUXCBGKUECIT-HJGDQZAQSA-N 0.000 description 3
- QLQHWWCSCLZUMA-KKUMJFAQSA-N Leu-Asp-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QLQHWWCSCLZUMA-KKUMJFAQSA-N 0.000 description 3
- IIKJNQWOQIWWMR-CIUDSAMLSA-N Leu-Cys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)N IIKJNQWOQIWWMR-CIUDSAMLSA-N 0.000 description 3
- VPKIQULSKFVCSM-SRVKXCTJSA-N Leu-Gln-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VPKIQULSKFVCSM-SRVKXCTJSA-N 0.000 description 3
- 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 3
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 3
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 3
- XBCWOTOCBXXJDG-BZSNNMDCSA-N Leu-His-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 XBCWOTOCBXXJDG-BZSNNMDCSA-N 0.000 description 3
- 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 3
- WXUOJXIGOPMDJM-SRVKXCTJSA-N Leu-Lys-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O WXUOJXIGOPMDJM-SRVKXCTJSA-N 0.000 description 3
- 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 3
- NHRINZSPIUXYQZ-DCAQKATOSA-N Leu-Met-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)O)N NHRINZSPIUXYQZ-DCAQKATOSA-N 0.000 description 3
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 3
- FYPWFNKQVVEELI-ULQDDVLXSA-N Leu-Phe-Val Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 FYPWFNKQVVEELI-ULQDDVLXSA-N 0.000 description 3
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 3
- YUTNOGOMBNYPFH-XUXIUFHCSA-N Leu-Pro-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YUTNOGOMBNYPFH-XUXIUFHCSA-N 0.000 description 3
- 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 3
- 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 3
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 3
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 3
- 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 3
- SUYRAPCRSCCPAK-VFAJRCTISA-N Leu-Trp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SUYRAPCRSCCPAK-VFAJRCTISA-N 0.000 description 3
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 3
- 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 3
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 3
- HGZHSNBZDOLMLH-DCAQKATOSA-N Lys-Asn-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N HGZHSNBZDOLMLH-DCAQKATOSA-N 0.000 description 3
- OVIVOCSURJYCTM-GUBZILKMSA-N Lys-Asp-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OVIVOCSURJYCTM-GUBZILKMSA-N 0.000 description 3
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 3
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 3
- 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 3
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 3
- 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 3
- VLMNBMFYRMGEMB-QWRGUYRKSA-N Lys-His-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CNC=N1 VLMNBMFYRMGEMB-QWRGUYRKSA-N 0.000 description 3
- ZMMDPRTXLAEMOD-BZSNNMDCSA-N Lys-His-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZMMDPRTXLAEMOD-BZSNNMDCSA-N 0.000 description 3
- AHFOKDZWPPGJAZ-SRVKXCTJSA-N Lys-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N AHFOKDZWPPGJAZ-SRVKXCTJSA-N 0.000 description 3
- MTBBHUKKPWKXBT-ULQDDVLXSA-N Lys-Met-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MTBBHUKKPWKXBT-ULQDDVLXSA-N 0.000 description 3
- 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 3
- 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 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
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 3
- ZUGVARDEGWMMLK-SRVKXCTJSA-N Lys-Ser-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN ZUGVARDEGWMMLK-SRVKXCTJSA-N 0.000 description 3
- UIJVKVHLCQSPOJ-XIRDDKMYSA-N Lys-Ser-Trp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O UIJVKVHLCQSPOJ-XIRDDKMYSA-N 0.000 description 3
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 3
- YCJCEMKOZOYBEF-OEAJRASXSA-N Lys-Thr-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YCJCEMKOZOYBEF-OEAJRASXSA-N 0.000 description 3
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 3
- SUZVLFWOCKHWET-CQDKDKBSSA-N Lys-Tyr-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O SUZVLFWOCKHWET-CQDKDKBSSA-N 0.000 description 3
- DCHHUGLTVLJYKA-FXQIFTODSA-N Met-Asn-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O DCHHUGLTVLJYKA-FXQIFTODSA-N 0.000 description 3
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 3
- JYPITOUIQVSCKM-IHRRRGAJSA-N Met-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCSC)N JYPITOUIQVSCKM-IHRRRGAJSA-N 0.000 description 3
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 3
- RMLWDZINJUDMEB-IHRRRGAJSA-N Met-Tyr-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N RMLWDZINJUDMEB-IHRRRGAJSA-N 0.000 description 3
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 3
- LGBVMDMZZFYSFW-HJWJTTGWSA-N Phe-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](CC1=CC=CC=C1)N LGBVMDMZZFYSFW-HJWJTTGWSA-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
- 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 3
- BFYHIHGIHGROAT-HTUGSXCWSA-N Phe-Glu-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BFYHIHGIHGROAT-HTUGSXCWSA-N 0.000 description 3
- SFKOEHXABNPLRT-KBPBESRZSA-N Phe-His-Gly Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)NCC(O)=O SFKOEHXABNPLRT-KBPBESRZSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- HBXAOEBRGLCLIW-AVGNSLFASA-N Phe-Ser-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HBXAOEBRGLCLIW-AVGNSLFASA-N 0.000 description 3
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 3
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 3
- MHNBYYFXWDUGBW-RPTUDFQQSA-N Phe-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CC=CC=C2)N)O MHNBYYFXWDUGBW-RPTUDFQQSA-N 0.000 description 3
- 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 3
- SSSFPISOZOLQNP-GUBZILKMSA-N Pro-Arg-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSFPISOZOLQNP-GUBZILKMSA-N 0.000 description 3
- 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 3
- INXAPZFIOVGHSV-CIUDSAMLSA-N Pro-Asn-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 INXAPZFIOVGHSV-CIUDSAMLSA-N 0.000 description 3
- XKHCJJPNXFBADI-DCAQKATOSA-N Pro-Asp-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O XKHCJJPNXFBADI-DCAQKATOSA-N 0.000 description 3
- SNIPWBQKOPCJRG-CIUDSAMLSA-N Pro-Gln-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O SNIPWBQKOPCJRG-CIUDSAMLSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- XQSREVQDGCPFRJ-STQMWFEESA-N Pro-Gly-Phe Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XQSREVQDGCPFRJ-STQMWFEESA-N 0.000 description 3
- 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 3
- FKYKZHOKDOPHSA-DCAQKATOSA-N Pro-Leu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FKYKZHOKDOPHSA-DCAQKATOSA-N 0.000 description 3
- JFBJPBZSTMXGKL-JYJNAYRXSA-N Pro-Met-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JFBJPBZSTMXGKL-JYJNAYRXSA-N 0.000 description 3
- JIWJRKNYLSHONY-KKUMJFAQSA-N Pro-Phe-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JIWJRKNYLSHONY-KKUMJFAQSA-N 0.000 description 3
- 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 3
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 3
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 3
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 3
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 3
- FNGOXVQBBCMFKV-CIUDSAMLSA-N Pro-Ser-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O FNGOXVQBBCMFKV-CIUDSAMLSA-N 0.000 description 3
- 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 3
- YHUBAXGAAYULJY-ULQDDVLXSA-N Pro-Tyr-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O YHUBAXGAAYULJY-ULQDDVLXSA-N 0.000 description 3
- OQSGBXGNAFQGGS-CYDGBPFRSA-N Pro-Val-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OQSGBXGNAFQGGS-CYDGBPFRSA-N 0.000 description 3
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 3
- OHKLFYXEOGGGCK-ZLUOBGJFSA-N Ser-Asp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OHKLFYXEOGGGCK-ZLUOBGJFSA-N 0.000 description 3
- SFZKGGOGCNQPJY-CIUDSAMLSA-N Ser-Asp-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N SFZKGGOGCNQPJY-CIUDSAMLSA-N 0.000 description 3
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 3
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 3
- ZHYMUFQVKGJNRM-ZLUOBGJFSA-N Ser-Cys-Asn Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC(N)=O ZHYMUFQVKGJNRM-ZLUOBGJFSA-N 0.000 description 3
- SWIQQMYVHIXPEK-FXQIFTODSA-N Ser-Cys-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O SWIQQMYVHIXPEK-FXQIFTODSA-N 0.000 description 3
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 3
- DGHFNYXVIXNNMC-GUBZILKMSA-N Ser-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](CO)N DGHFNYXVIXNNMC-GUBZILKMSA-N 0.000 description 3
- OHKFXGKHSJKKAL-NRPADANISA-N Ser-Glu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OHKFXGKHSJKKAL-NRPADANISA-N 0.000 description 3
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 3
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 3
- QGAHMVHBORDHDC-YUMQZZPRSA-N Ser-His-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CN=CN1 QGAHMVHBORDHDC-YUMQZZPRSA-N 0.000 description 3
- DOSZISJPMCYEHT-NAKRPEOUSA-N Ser-Ile-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O DOSZISJPMCYEHT-NAKRPEOUSA-N 0.000 description 3
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 3
- OQSQCUWQOIHECT-YJRXYDGGSA-N Ser-Tyr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OQSQCUWQOIHECT-YJRXYDGGSA-N 0.000 description 3
- SGZVZUCRAVSPKQ-FXQIFTODSA-N Ser-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N SGZVZUCRAVSPKQ-FXQIFTODSA-N 0.000 description 3
- 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 3
- ZLNWJMRLHLGKFX-SVSWQMSJSA-N Thr-Cys-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZLNWJMRLHLGKFX-SVSWQMSJSA-N 0.000 description 3
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 3
- QQWNRERCGGZOKG-WEDXCCLWSA-N Thr-Gly-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O QQWNRERCGGZOKG-WEDXCCLWSA-N 0.000 description 3
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 3
- NZRUWPIYECBYRK-HTUGSXCWSA-N Thr-Phe-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O NZRUWPIYECBYRK-HTUGSXCWSA-N 0.000 description 3
- VEIKMWOMUYMMMK-FCLVOEFKSA-N Thr-Phe-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VEIKMWOMUYMMMK-FCLVOEFKSA-N 0.000 description 3
- MEBDIIKMUUNBSB-RPTUDFQQSA-N Thr-Phe-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MEBDIIKMUUNBSB-RPTUDFQQSA-N 0.000 description 3
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 3
- 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 3
- GFRIEEKFXOVPIR-RHYQMDGZSA-N Thr-Pro-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O GFRIEEKFXOVPIR-RHYQMDGZSA-N 0.000 description 3
- DOBIBIXIHJKVJF-XKBZYTNZSA-N Thr-Ser-Gln Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O DOBIBIXIHJKVJF-XKBZYTNZSA-N 0.000 description 3
- XEVHXNLPUBVQEX-DVJZZOLTSA-N Thr-Trp-Gly Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N)O XEVHXNLPUBVQEX-DVJZZOLTSA-N 0.000 description 3
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 3
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 3
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 3
- MDDYTWOFHZFABW-SZMVWBNQSA-N Trp-Gln-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 MDDYTWOFHZFABW-SZMVWBNQSA-N 0.000 description 3
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 3
- NJNCVQYFNKZMAH-JYBASQMISA-N Trp-Thr-Cys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CS)C(O)=O)=CNC2=C1 NJNCVQYFNKZMAH-JYBASQMISA-N 0.000 description 3
- YCQKQFKXBPJXRY-PMVMPFDFSA-N Trp-Tyr-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CCCCN)C(=O)O)N YCQKQFKXBPJXRY-PMVMPFDFSA-N 0.000 description 3
- RWTFCAMQLFNPTK-UMPQAUOISA-N Trp-Val-Thr Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)=CNC2=C1 RWTFCAMQLFNPTK-UMPQAUOISA-N 0.000 description 3
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 3
- NGALWFGCOMHUSN-AVGNSLFASA-N Tyr-Gln-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NGALWFGCOMHUSN-AVGNSLFASA-N 0.000 description 3
- PMDWYLVWHRTJIW-STQMWFEESA-N Tyr-Gly-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PMDWYLVWHRTJIW-STQMWFEESA-N 0.000 description 3
- 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 3
- GITNQBVCEQBDQC-KKUMJFAQSA-N Tyr-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O GITNQBVCEQBDQC-KKUMJFAQSA-N 0.000 description 3
- 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 3
- XGZBEGGGAUQBMB-KJEVXHAQSA-N Tyr-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC2=CC=C(C=C2)O)N)O XGZBEGGGAUQBMB-KJEVXHAQSA-N 0.000 description 3
- HRHYJNLMIJWGLF-BZSNNMDCSA-N Tyr-Ser-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 HRHYJNLMIJWGLF-BZSNNMDCSA-N 0.000 description 3
- 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 3
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 3
- HSCJRCZFDFQWRP-JZMIEXBBSA-N UDP-alpha-D-glucose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-JZMIEXBBSA-N 0.000 description 3
- HSCJRCZFDFQWRP-UHFFFAOYSA-N Uridindiphosphoglukose Natural products OC1C(O)C(O)C(CO)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-UHFFFAOYSA-N 0.000 description 3
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 3
- 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 3
- 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 3
- YDPFWRVQHFWBKI-GVXVVHGQSA-N Val-Glu-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N YDPFWRVQHFWBKI-GVXVVHGQSA-N 0.000 description 3
- ROLGIBMFNMZANA-GVXVVHGQSA-N Val-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N ROLGIBMFNMZANA-GVXVVHGQSA-N 0.000 description 3
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 3
- CHWRZUGUMAMTFC-IHRRRGAJSA-N Val-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CNC=N1 CHWRZUGUMAMTFC-IHRRRGAJSA-N 0.000 description 3
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-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](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 3
- JAKHAONCJJZVHT-DCAQKATOSA-N Val-Lys-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N JAKHAONCJJZVHT-DCAQKATOSA-N 0.000 description 3
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 3
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 3
- LTTQCQRTSHJPPL-ZKWXMUAHSA-N Val-Ser-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N LTTQCQRTSHJPPL-ZKWXMUAHSA-N 0.000 description 3
- 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 3
- HWNYVQMOLCYHEA-IHRRRGAJSA-N Val-Ser-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N HWNYVQMOLCYHEA-IHRRRGAJSA-N 0.000 description 3
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 3
- MIAZWUMFUURQNP-YDHLFZDLSA-N Val-Tyr-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N MIAZWUMFUURQNP-YDHLFZDLSA-N 0.000 description 3
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 3
- 208000005475 Vascular calcification Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 108010005233 alanylglutamic acid Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 108010068380 arginylarginine Proteins 0.000 description 3
- 229960005261 aspartic acid Drugs 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 108010004073 cysteinylcysteine Proteins 0.000 description 3
- 108010016616 cysteinylglycine Proteins 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000028208 end stage renal disease Diseases 0.000 description 3
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 3
- 108010089804 glycyl-threonine Proteins 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108010015796 prolylisoleucine Proteins 0.000 description 3
- 108010053725 prolylvaline Proteins 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 3
- 108010080629 tryptophan-leucine Proteins 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 2
- XFBOJHLYDJZYSP-UHFFFAOYSA-N 2,8-dioxoadenine Chemical class N1C(=O)N=C2NC(=O)NC2=C1N XFBOJHLYDJZYSP-UHFFFAOYSA-N 0.000 description 2
- SBGXWWCLHIOABR-UHFFFAOYSA-N Ala Ala Gly Ala Chemical compound CC(N)C(=O)NC(C)C(=O)NCC(=O)NC(C)C(O)=O SBGXWWCLHIOABR-UHFFFAOYSA-N 0.000 description 2
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 2
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 2
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 2
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 2
- 208000037157 Azotemia Diseases 0.000 description 2
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 2
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 2
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 2
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 2
- 101000986621 Homo sapiens ATP-binding cassette sub-family C member 6 Proteins 0.000 description 2
- 101000812677 Homo sapiens Nucleotide pyrophosphatase Proteins 0.000 description 2
- 101000653784 Homo sapiens Protein S100-A12 Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 2
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 2
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 2
- 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
- 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
- YNNPKXBBRZVIRX-IHRRRGAJSA-N Lys-Arg-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O YNNPKXBBRZVIRX-IHRRRGAJSA-N 0.000 description 2
- 102100039306 Nucleotide pyrophosphatase Human genes 0.000 description 2
- KNYPNEYICHHLQL-ACRUOGEOSA-N Phe-Leu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 KNYPNEYICHHLQL-ACRUOGEOSA-N 0.000 description 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 2
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 2
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 2
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 2
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 2
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 2
- 102000002070 Transferrins Human genes 0.000 description 2
- 108010015865 Transferrins Proteins 0.000 description 2
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 2
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 2
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 2
- 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 2
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 2
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000018678 bone mineralization Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000037219 healthy weight Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 108010053037 kyotorphin Proteins 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010091078 rigin Proteins 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000011125 single therapy Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 108010020532 tyrosyl-proline Proteins 0.000 description 2
- 208000009852 uremia Diseases 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102100029457 Adenine phosphoribosyltransferase Human genes 0.000 description 1
- 108010024223 Adenine phosphoribosyltransferase Proteins 0.000 description 1
- 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 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- MIPWEZAIMPYQST-FXQIFTODSA-N Ala-Cys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O MIPWEZAIMPYQST-FXQIFTODSA-N 0.000 description 1
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 1
- QHASENCZLDHBGX-ONGXEEELSA-N Ala-Gly-Phe Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QHASENCZLDHBGX-ONGXEEELSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 241000024188 Andala Species 0.000 description 1
- 241000208340 Araliaceae Species 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
- GHNDBBVSWOWYII-LPEHRKFASA-N Arg-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GHNDBBVSWOWYII-LPEHRKFASA-N 0.000 description 1
- XVLLUZMFSAYKJV-GUBZILKMSA-N Arg-Asp-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XVLLUZMFSAYKJV-GUBZILKMSA-N 0.000 description 1
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 1
- AGVNTAUPLWIQEN-ZPFDUUQYSA-N Arg-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](CCCN=C(N)N)N AGVNTAUPLWIQEN-ZPFDUUQYSA-N 0.000 description 1
- OOIMKQRCPJBGPD-XUXIUFHCSA-N Arg-Ile-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O OOIMKQRCPJBGPD-XUXIUFHCSA-N 0.000 description 1
- GNYUVVJYGJFKHN-RVMXOQNASA-N Arg-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N GNYUVVJYGJFKHN-RVMXOQNASA-N 0.000 description 1
- 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 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
- WCZXPVPHUMYLMS-VEVYYDQMSA-N Arg-Thr-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O WCZXPVPHUMYLMS-VEVYYDQMSA-N 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- XWGJDUSDTRPQRK-ZLUOBGJFSA-N Asn-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O XWGJDUSDTRPQRK-ZLUOBGJFSA-N 0.000 description 1
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 1
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 1
- KHCNTVRVAYCPQE-CIUDSAMLSA-N Asn-Lys-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O KHCNTVRVAYCPQE-CIUDSAMLSA-N 0.000 description 1
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 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
- RDRMWJBLOSRRAW-BYULHYEWSA-N Asp-Asn-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O RDRMWJBLOSRRAW-BYULHYEWSA-N 0.000 description 1
- IJHUZMGJRGNXIW-CIUDSAMLSA-N Asp-Glu-Arg Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IJHUZMGJRGNXIW-CIUDSAMLSA-N 0.000 description 1
- BIVYLQMZPHDUIH-WHFBIAKZSA-N Asp-Gly-Cys Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)C(=O)O BIVYLQMZPHDUIH-WHFBIAKZSA-N 0.000 description 1
- RQYMKRMRZWJGHC-BQBZGAKWSA-N Asp-Gly-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)O)N RQYMKRMRZWJGHC-BQBZGAKWSA-N 0.000 description 1
- KHGPWGKPYHPOIK-QWRGUYRKSA-N Asp-Gly-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KHGPWGKPYHPOIK-QWRGUYRKSA-N 0.000 description 1
- YRZIYQGXTSBRLT-AVGNSLFASA-N Asp-Phe-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O YRZIYQGXTSBRLT-AVGNSLFASA-N 0.000 description 1
- BWJZSLQJNBSUPM-FXQIFTODSA-N Asp-Pro-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O BWJZSLQJNBSUPM-FXQIFTODSA-N 0.000 description 1
- ZQFRDAZBTSFGGW-SRVKXCTJSA-N Asp-Ser-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZQFRDAZBTSFGGW-SRVKXCTJSA-N 0.000 description 1
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 1
- QPDUWAUSSWGJSB-NGZCFLSTSA-N Asp-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N QPDUWAUSSWGJSB-NGZCFLSTSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100021961 Bis(5'-adenosyl)-triphosphatase ENPP4 Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- VNLYIYOYUNGURO-ZLUOBGJFSA-N Cys-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N VNLYIYOYUNGURO-ZLUOBGJFSA-N 0.000 description 1
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 1
- GCDLPNRHPWBKJJ-WDSKDSINSA-N Cys-Gly-Glu Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O GCDLPNRHPWBKJJ-WDSKDSINSA-N 0.000 description 1
- KKUVRYLJEXJSGX-MXAVVETBSA-N Cys-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CS)N KKUVRYLJEXJSGX-MXAVVETBSA-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
- 101001117086 Dictyostelium discoideum cAMP/cGMP-dependent 3',5'-cAMP/cGMP phosphodiesterase A Proteins 0.000 description 1
- 102100036093 Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 Human genes 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- LJEPDHWNQXPXMM-NHCYSSNCSA-N Gln-Arg-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O LJEPDHWNQXPXMM-NHCYSSNCSA-N 0.000 description 1
- CRRFJBGUGNNOCS-PEFMBERDSA-N Gln-Asp-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CRRFJBGUGNNOCS-PEFMBERDSA-N 0.000 description 1
- JKPGHIQCHIIRMS-AVGNSLFASA-N Gln-Asp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N JKPGHIQCHIIRMS-AVGNSLFASA-N 0.000 description 1
- QFTRCUPCARNIPZ-XHNCKOQMSA-N Gln-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)N)N)C(=O)O QFTRCUPCARNIPZ-XHNCKOQMSA-N 0.000 description 1
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 1
- 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 1
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 1
- LWYUQLZOIORFFJ-XKBZYTNZSA-N Glu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O LWYUQLZOIORFFJ-XKBZYTNZSA-N 0.000 description 1
- JXYMPBCYRKWJEE-BQBZGAKWSA-N Gly-Arg-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O JXYMPBCYRKWJEE-BQBZGAKWSA-N 0.000 description 1
- GGEJHJIXRBTJPD-BYPYZUCNSA-N Gly-Asn-Gly Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GGEJHJIXRBTJPD-BYPYZUCNSA-N 0.000 description 1
- TZOVVRJYUDETQG-RCOVLWMOSA-N Gly-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN TZOVVRJYUDETQG-RCOVLWMOSA-N 0.000 description 1
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 1
- GDOZQTNZPCUARW-YFKPBYRVSA-N Gly-Gly-Glu Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O GDOZQTNZPCUARW-YFKPBYRVSA-N 0.000 description 1
- 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 1
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 1
- 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 1
- YHYDTTUSJXGTQK-UWVGGRQHSA-N Gly-Met-Leu Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(C)C)C(O)=O YHYDTTUSJXGTQK-UWVGGRQHSA-N 0.000 description 1
- YLEIWGJJBFBFHC-KBPBESRZSA-N Gly-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 YLEIWGJJBFBFHC-KBPBESRZSA-N 0.000 description 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- 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
- LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
- 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 1
- RHRLHXQWHCNJKR-PMVVWTBXSA-N Gly-Thr-His Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 RHRLHXQWHCNJKR-PMVVWTBXSA-N 0.000 description 1
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 1
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 1
- JHVCZQFWRLHUQR-DCAQKATOSA-N His-Arg-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N JHVCZQFWRLHUQR-DCAQKATOSA-N 0.000 description 1
- PGTISAJTWZPFGN-PEXQALLHSA-N His-Gly-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O PGTISAJTWZPFGN-PEXQALLHSA-N 0.000 description 1
- SAPLASXFNUYUFE-CQDKDKBSSA-N His-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CN=CN2)N SAPLASXFNUYUFE-CQDKDKBSSA-N 0.000 description 1
- SVVULKPWDBIPCO-BZSNNMDCSA-N His-Phe-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O SVVULKPWDBIPCO-BZSNNMDCSA-N 0.000 description 1
- 101000897056 Homo sapiens Bis(5'-adenosyl)-triphosphatase ENPP4 Proteins 0.000 description 1
- 101000876377 Homo sapiens Ectonucleotide pyrophosphatase/phosphodiesterase family member 7 Proteins 0.000 description 1
- FZWVCYCYWCLQDH-NHCYSSNCSA-N Ile-Leu-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N FZWVCYCYWCLQDH-NHCYSSNCSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010009595 Inorganic Pyrophosphatase Proteins 0.000 description 1
- 102100027050 Inorganic pyrophosphatase Human genes 0.000 description 1
- 206010048858 Ischaemic cardiomyopathy Diseases 0.000 description 1
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 1
- 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
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-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
- 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 1
- 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 1
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 1
- RTIRBWJPYJYTLO-MELADBBJSA-N Leu-Lys-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N RTIRBWJPYJYTLO-MELADBBJSA-N 0.000 description 1
- MUCIDQMDOYQYBR-IHRRRGAJSA-N Leu-Pro-His Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N MUCIDQMDOYQYBR-IHRRRGAJSA-N 0.000 description 1
- 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 1
- ABHIXYDMILIUKV-CIUDSAMLSA-N Lys-Asn-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ABHIXYDMILIUKV-CIUDSAMLSA-N 0.000 description 1
- DEFGUIIUYAUEDU-ZPFDUUQYSA-N Lys-Asn-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DEFGUIIUYAUEDU-ZPFDUUQYSA-N 0.000 description 1
- 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
- GPJGFSFYBJGYRX-YUMQZZPRSA-N Lys-Gly-Asp Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O GPJGFSFYBJGYRX-YUMQZZPRSA-N 0.000 description 1
- KKFVKBWCXXLKIK-AVGNSLFASA-N Lys-His-Glu Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCCCN)N KKFVKBWCXXLKIK-AVGNSLFASA-N 0.000 description 1
- JYXBNQOKPRQNQS-YTFOTSKYSA-N Lys-Ile-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JYXBNQOKPRQNQS-YTFOTSKYSA-N 0.000 description 1
- MGKFCQFVPKOWOL-CIUDSAMLSA-N Lys-Ser-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N MGKFCQFVPKOWOL-CIUDSAMLSA-N 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- FJVJLMZUIGMFFU-BQBZGAKWSA-N Met-Asp-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O FJVJLMZUIGMFFU-BQBZGAKWSA-N 0.000 description 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
- KQBJYJXPZBNEIK-DCAQKATOSA-N Met-Glu-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQBJYJXPZBNEIK-DCAQKATOSA-N 0.000 description 1
- DJDFBVNNDAUPRW-GUBZILKMSA-N Met-Glu-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O DJDFBVNNDAUPRW-GUBZILKMSA-N 0.000 description 1
- 101001051972 Mus musculus Fibroblast growth factor 23 Proteins 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 108010047562 NGR peptide Proteins 0.000 description 1
- 101150071357 NPP2 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000008021 Nucleoside-Triphosphatase Human genes 0.000 description 1
- 108010075285 Nucleoside-Triphosphatase Proteins 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- KYYMILWEGJYPQZ-IHRRRGAJSA-N Phe-Glu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KYYMILWEGJYPQZ-IHRRRGAJSA-N 0.000 description 1
- AAERWTUHZKLDLC-IHRRRGAJSA-N Phe-Pro-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O AAERWTUHZKLDLC-IHRRRGAJSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- 101100080097 Phytophthora capsici NLP2 gene Proteins 0.000 description 1
- LXVLKXPFIDDHJG-CIUDSAMLSA-N Pro-Glu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O LXVLKXPFIDDHJG-CIUDSAMLSA-N 0.000 description 1
- ZTVCLZLGHZXLOT-ULQDDVLXSA-N Pro-Glu-Trp Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O ZTVCLZLGHZXLOT-ULQDDVLXSA-N 0.000 description 1
- 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 1
- 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 1
- FYPGHGXAOZTOBO-IHRRRGAJSA-N Pro-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@@H]2CCCN2 FYPGHGXAOZTOBO-IHRRRGAJSA-N 0.000 description 1
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 1
- XQPHBAKJJJZOBX-SRVKXCTJSA-N Pro-Lys-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O XQPHBAKJJJZOBX-SRVKXCTJSA-N 0.000 description 1
- CDGABSWLRMECHC-IHRRRGAJSA-N Pro-Lys-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O CDGABSWLRMECHC-IHRRRGAJSA-N 0.000 description 1
- PUQRDHNIOONJJN-AVGNSLFASA-N Pro-Lys-Met Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O PUQRDHNIOONJJN-AVGNSLFASA-N 0.000 description 1
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 1
- AJJDPGVVNPUZCR-RHYQMDGZSA-N Pro-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1)O AJJDPGVVNPUZCR-RHYQMDGZSA-N 0.000 description 1
- VDHGTOHMHHQSKG-JYJNAYRXSA-N Pro-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O VDHGTOHMHHQSKG-JYJNAYRXSA-N 0.000 description 1
- 101710167959 Putative UTP-glucose-1-phosphate uridylyltransferase Proteins 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 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 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
- KJMOINFQVCCSDX-XKBZYTNZSA-N Ser-Gln-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KJMOINFQVCCSDX-XKBZYTNZSA-N 0.000 description 1
- PVDTYLHUWAEYGY-CIUDSAMLSA-N Ser-Glu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PVDTYLHUWAEYGY-CIUDSAMLSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- IXCHOHLPHNGFTJ-YUMQZZPRSA-N Ser-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CO)N IXCHOHLPHNGFTJ-YUMQZZPRSA-N 0.000 description 1
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- FHXGMDRKJHKLKW-QWRGUYRKSA-N Ser-Tyr-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 FHXGMDRKJHKLKW-QWRGUYRKSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 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 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
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- CJEHCEOXPLASCK-MEYUZBJRSA-N Thr-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CC=C(O)C=C1 CJEHCEOXPLASCK-MEYUZBJRSA-N 0.000 description 1
- PRONOHBTMLNXCZ-BZSNNMDCSA-N Tyr-Leu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PRONOHBTMLNXCZ-BZSNNMDCSA-N 0.000 description 1
- VTCKHZJKWQENKX-KBPBESRZSA-N Tyr-Lys-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O VTCKHZJKWQENKX-KBPBESRZSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- 102100038834 UTP-glucose-1-phosphate uridylyltransferase Human genes 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
- 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 1
- UGFMVXRXULGLNO-XPUUQOCRSA-N Val-Ser-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O UGFMVXRXULGLNO-XPUUQOCRSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- HXXFSFRBOHSIMQ-VFUOTHLCSA-N alpha-D-glucose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O HXXFSFRBOHSIMQ-VFUOTHLCSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- -1 asparagicacid residue Compound Chemical class 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229950010772 glucose-1-phosphate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 201000005991 hyperphosphatemia Diseases 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 208000038009 orphan disease Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000018883 protein targeting Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000246 remedial effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 102220080600 rs797046116 Human genes 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011550 stock solution Substances 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000004231 tunica media Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/04—Phosphoric diester hydrolases (3.1.4)
- C12Y301/04001—Phosphodiesterase I (3.1.4.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y306/00—Hydrolases acting on acid anhydrides (3.6)
- C12Y306/01—Hydrolases acting on acid anhydrides (3.6) in phosphorus-containing anhydrides (3.6.1)
- C12Y306/01009—Nucleotide diphosphatase (3.6.1.9), i.e. nucleotide-pyrophosphatase
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
本发明提供了一种治疗NPP1缺陷或NPP1相关疾病的方法,所述NPP1缺陷或NPP1相关疾病诸如特发性婴儿型动脉钙化(idiopathic infantile arterial calcification)(IIAC)、弹性假黄色瘤(pseudoxanthoma elasticum)、慢性肾脏疾病中的血管钙化(VCCKD)、胰岛素耐受、低磷酸血症佝偻病(hypophosphatemic rickets)、心肌缺血(myocardial ischemia)、关节钙化(joint calcification)、血管样条纹症(angioid streaks)和脊柱后纵韧带骨化(ossification of the posterior longitudinal ligament of the spine)。本发明提供了一种用于通过施用可溶性NPP1以产生血清焦磷酸盐水平的瞬时增加来治疗组织钙化的方法。
Description
相关申请
本申请要求于2014年12月19日提交的美国临时申请第62/094,943号、和于2015年11月2日提交的美国临时申请第62/249,781号的权益。以上申请的整体教导通过引用并入本文。
对以电子形式提交的序列表的引用
随本申请提交的以ASCII文本文件的电子形式提交的序列表(名称:081245-0208_ascii.txt;大小:88,556字节;且创建日期为:2015年12月15日)的内容通过引用以其整体并入本文。
发明背景
血管钙化的特征可以在于形成非常小的、分散的羟基磷灰石(HA)晶体和血管组织诸如动脉中的大的钙化沉积物。(Amann,K.Clin J Am Soc Nephrol 2008,3,1599-605)。细胞外焦磷酸盐(PPi)为抑制HA形成的关键内源性血管钙化抑制物。(Lomashvili,K.A.等,JAm Soc Nephrol 2004,15,1392-1401;Fleisch,H.等,Nature 1966,212,901-903)。
外核苷酸焦磷酸酶焦磷酸化酶(NPP1)为切割ATP以产生细胞外焦磷酸盐(PPi)的外切酶。焦磷酸盐为羟基磷灰石形成的有效抑制物,并且在正常条件下起抑制血管钙化作用。
在人类中NPP1缺陷导致循环PPi水平降低,并且已被牵涉在状况诸如动脉钙化和婴儿期广泛性动脉钙化(generalized arterial calcification of infancy)(GACI)中。(Rutsch,F.等,Am J Pathol 2001,158,543-554)。当喂食高磷酸盐饮食时,缺少NPP1(Enpp1-/-)的小鼠也具有降低的PPi水平,并表现出与NPP1缺陷的人类相似的表型。(Harmey,D.等,Am J Pathol 2004,164,1199-1209)。血管钙化也为慢性肾脏疾病(CKD)和终末期肾脏疾病(ESRD)受试者中公认且常见的并发症,并且与增加的发病率和死亡率相关。(Giachelli,C.J Am Soc Nephrol 2004,15,2959-64;Raggi,P.等,J Am Coll Cardiol2002,39,695-701)。
外核苷酸焦磷酸酶/磷酸二酯酶1(NPP1/ENPP1/PC-1)缺陷为由NPP1,一种II型跨膜糖蛋白,中的突变引起的罕见疾病。NPP1切割多种底物,包括核苷酸和核苷酸糖的磷酸二酯键以及核苷酸和核苷酸糖的焦磷酸键。NPP1缺陷与特发性婴儿型动脉钙化(idiopathicinfantile arterial calcification)(IIAC)、胰岛素耐受、低磷酸血症佝偻病(hypophosphatemic rickets)、和脊柱后纵韧带骨化(ossification of the posteriorlongitudinal ligament of the spine)相关。
IIAC,一种罕见的常染色体隐性的且几乎总为致命的紊乱,特征在于肌肉动脉的内部弹性层(internal elastic lamina)的钙化和由于肌内膜增殖(myointimalproliferation)引起的狭窄。全世界已报道了多于160例IIAC。该疾病的症状最常出现于婴儿期早期,而且该疾病在到6个月龄时为致命的,一般因为缺血性心肌病,以及包括肾动脉狭窄在内的阻塞性动脉病变(obstructive arteriopathy)的其他并发症。
尽管NPP1蛋白的缺陷已牵涉在如IIAC这样的严重疾病中,由于异常的骨代谢;低水平的循环和局部产生的磷酸盐产生物的抑制物;或受损的肾脏排泄,对于受到由高的钙和磷总体负荷引起的疾病和其他钙化疾病影响的患者,目前尚无可用的治疗。
目前用于预防血管钙化的治疗选择方案具有有限的功效和不期望的和/或不可接受的副作用。例如,功效需要非常大量的外源PPi,并且羟基磷灰石形成的其他抑制物抑制骨钙化且可以导致骨软化。特别地,发现外源PPi的直接施用防止尿毒症动物模型中的钙化。(O’Neil,W.C.等,Kidney Int 2011,79,512-517;Riser,B.L.等,Nephrol Dial Transp2011,26,3349-3357)。但是,由于短的PPi半衰期,这种方法要求高剂量的PPi,并且导致超生理血浆水平的PPi,导致局部刺激。为PPi的不可水解类似物的双膦酸盐已用于例如在动物模型中治疗血管钙化。(Fleisch,H.等,Europ J Clin Invest 1970,1,12-18;Price,P.A.等,Arteriosclerosis Throm and Vas Bio 2001,21,817-824;Price,P.A.等,KidneyInt 2006,70,1577-1583;Lomashvili,K.A.等,Kidney Int 2009,75,617-625)。然而,双膦酸盐也抑制骨形成。双膦酸盐可以延迟但不能阻止患有GACI的受试者中的钙化(Rutsch,F.等,Circ Cardiovasc Genet 2008,1,133-140),并且如在动物中导致骨软化。(Otero,J.E.,等,J Bone Miner Res 2013,28,419-430)。
Braddock,D.等(WO 2014/126965A2)公开了用于通过施用NPP1治疗病理性钙化和骨化的组合物和方法。Quinn,A.等(WO 2012/125182A1)公开了治疗包括GACI、动脉钙化、胰岛素耐受、低磷酸血症佝偻病和脊柱后纵韧带骨化的状况的NPP1融合蛋白胰岛素耐受。
尽管在该领域有相当多的研究,对有效抑制血管钙化的优选地不导致骨软化的新疗法仍存在持续需求。对用于治疗IIAC、慢性肾脏疾病中的血管钙化(VCCKD)、弹性假黄色瘤(PXE)、胰岛素耐受、低磷酸血症佝偻病和脊柱后纵韧带骨化的有效和安全的药物也存在需求。
发明概述
本发明涉及缺少N-末端胞质和跨膜结构域的分离的重组人类可溶性NPP1及其融合蛋白用于治疗NPP1缺陷或特征在于钙和其他矿物质的沉积物的积累的其他进行性紊乱的用途。
本发明的蛋白可以出乎意料地用于在具有NPP1活性缺陷或表现出骨、关节、心脏、血管、眼睛和/或皮肤中钙沉积物的积累的受试者中恢复血液NPP1活性并恢复焦磷酸盐的正常水平。
更具体地,本发明的NPP1蛋白和NPP1融合蛋白可以用于治疗具有NPP1缺陷或与低水平焦磷酸盐相关的其他疾病或紊乱的受试者,NPP1缺陷或与低水平焦磷酸盐相关的其他疾病或紊乱包括但不限于,特发性婴儿型动脉钙化(IIAC,也称为广泛性婴儿动脉钙化)、慢性肾脏疾病中的血管钙化(VCCKD)、弹性假黄色瘤(PXE)、胰岛素耐受、低磷酸血症佝偻病、关节钙化、心肌缺血、和脊柱后纵韧带骨化。特征在于动脉和/或结缔组织中的钙和其他矿物质的沉积物的累积的任何进行性紊乱都在本发明的范围内。
在一些方面,本发明涉及一种降低有相应需要的受试者中组织钙化,优选地血管钙化的方法。该方法包括将两个或更多个剂量的治疗有效量的包含可溶性外核苷酸焦磷酸酶磷酸二酯酶(NPP1)的组合物施用至患有低血浆焦磷酸盐(PPi)或升高的无机磷酸盐(Pi)的受试者。每一个剂量包含足以实现受试者中血浆PPi的瞬时增加的量的可溶性NPP1。血浆PPi的瞬时增加的特征在于峰值PPi水平为正常血浆PPi水平的至少约40%,并且在施用剂量之后约48小时内回复至基线PPi水平。剂量之间的时间段为至少2天。
血浆PPi的瞬时增加被维持至少约4小时,优选地至少约6小时、至少约8小时、至少约10小时或至少约12小时。
组织钙化可以为血管钙化,诸如静脉钙化或动脉钙化,并且钙化可以为内膜的或内侧的。
需要疗法的受试者可以具有NPP1缺陷、慢性肾脏疾病(CKD)、终末期肾脏疾病(ESRD)、婴儿期广泛性动脉钙化(GACI)、心血管紊乱、II型糖尿病、动脉粥样硬化或弹性假黄色瘤(PXE)。当受试者具有低血浆PPi时,受试者中血浆焦磷酸盐(PPi)的预处理水平比正常血浆PPi水平的低至少约40%,且受试者为人类。当受试者具有高水平的Pi时,受试者中Pi的预处理水平通常为正常血浆Pi水平的至少约110%。
在每一个剂量中施用的sNPP1的量可以为约1.0mg/kg至约5.0mg/kg NPP1或约1.0mg/kg至约10.0mg/kg NPP1。在NPP1剂量之间的时间段为至少2天,并且可以更长,例如至少3天、至少1周、2周或1个月。sNPP1可以以任何合适的方式,诸如静脉内、皮下或腹膜内被施用。
在优选的方面,NPP1融合蛋白被施用。优选的融合蛋白包含NPP1组分和免疫球蛋白的Fc区以及任选地靶向部分。优选的靶向部分为Asp10。用于根据本文公开的方法施用的特别优选的NPP1融合蛋白具有SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12的氨基酸序列。
本发明的其他特征和优势将从以下详述和权利要求变得明显。
附图简述
图1为野生型NPP1蛋白的氨基酸序列(SEQ ID NO:1)。胞质和跨膜区被加下划线。潜在的N-糖基化位点呈粗体。呈粗体的氨基酸基序“PSCAKE”(SEQ ID NO:17)为包含半胱氨酸富集区的可溶性NPP1的开始。
图2为包含半胱氨酸富集区、催化区和c-末端区的sNPP1的氨基酸序列(SEQ IDNO:2)。
图3为sNPP1-Fc融合蛋白的氨基酸序列(SEQ ID NO:3)。
图4为sNPP1-Fc-D10的氨基酸序列(SEQ ID NO:4)。Fc序列被加下划线。D10(SEQID NO:18)靶向部分呈粗体。
图5阐释了在sNPP1-Fc或sNPP1-Fc-D10静脉内(注射后1小时)和皮下(注射后4小时)施用之后野生型小鼠的血液中的焦磷酸盐水平。
图6阐释了用sNPP1-Fc-D10处理预防Enpp1(-/-)小鼠中的主动脉钙化。在21天的时间段内,每隔一天用媒介物或6mg/kg sNPP1-Fc-D10皮下处理Enpp1(-/-)小鼠。示出了雄性和雌性的主动脉钙水平。
图7阐释了用6mg/kg sNPP1-Fc-D10静脉内处理的Enpp1(-/-)小鼠中的血液PPi和酶促活性水平。在0小时、4小时、24小时、48小时和72小时的时间点收集血浆,并且分析其NPP1活性(虚线)和PPi水平(实线)。野生型PPi水平被确定为2.18μM(数据未示出)。从顶部至底部的虚线显示野生型、杂合Enpp1(+/-)和纯合Enpp1(-/-)asj小鼠的PPi水平(Li等,2013)。sNPP1-Fc的谱(profiles)与sNPP1-Fc-D10的谱相似。
图8阐释了与媒介物处理的小鼠相比用5mg/kg sNPP1-Fc处理的Enpp1asj纯合雄性小鼠的增加的存活率。将野生型和Enpp1asj小鼠在出生时开始置于高磷、低镁饮食。在14天龄时开始每隔一天皮下给药媒介物或sNPP1-Fc(5mg/kg)。卡普兰-迈耶存活率曲线(Kaplan-Meier survival curve)显示,>50%的as j小鼠在6周之前死亡,且所有动物到9周时均死亡。相比之下,50%的sNPP1-Fc处理的动物在过去的7周存活,并且在9周时仍然活着。
图9A和9B阐释了与媒介物处理的小鼠(图9A)相比,用5mg/kg sNPP1-Fc处理的Enpp1asj雄性小鼠(图9B)的增加的体重增加百分比。将野生型和Enpp1asj小鼠在出生时开始置于高磷、低镁饮食。在14天龄时开始每隔一天皮下注射媒介物或sNPP1-Fc(5mg/kg)。绘制两至九周龄野生型(实线)和Enpp1asj(圆)小鼠的体重增加百分比。媒介物组中的所有Enpp1asj动物在9周时均死亡(空心圆)(上图)。相比之下,在9周结束时,sNPP1-Fc处理组中的5只Enpp1asj小鼠活着(实心圆)且5只死亡(空心圆)。
图10A-10C为野生型(图10A,顶部)、媒介物处理的Enpp1asj(图10B,中部)、sNPP1-Fc处理的(5mg/Kg)Enpp1asj(图10C,顶部)小鼠的照片。
图11阐释了媒介物处理的野生型、媒介物处理的Enpp1asj/asj、和sNPP1-Fc处理的(5mg/Kg)Enpp1as/asj小鼠中成纤维细胞生长因子23的水平。
图12A-12H为可溶性NPP1化合物、融合伴侣和融合蛋白的氨基酸序列。图12A示出了包含SEQ ID NO:1的从107至925的氨基酸的可溶性NPP1的氨基酸序列(SEQ ID NO:5)。图12B示出了包含SEQ ID NO:1的从187至925的氨基酸的可溶性NPP1的氨基酸序列(SEQ IDNO:6)。图12C示出了包含铰链区的人类IgG1的Fc区的氨基酸序列(SEQ ID NO:7)。图12D示出了包含部分铰链区的人类IgG1的Fc的氨基酸序列(SEQ ID NO:8)。图12E示出了NPP1-Fc融合蛋白的氨基酸序列(SEQ ID NO:9)。NPP1组分包含SEQ ID NO:5,且Fc序列包含铰链区。图12F示出了NPP1-Fc融合蛋白的氨基酸序列(SEQ ID NO:10)。可溶性NPP1包含SEQ ID NO:5,且Fc序列包含部分铰链区。图12G示出了NPP1-Fc融合蛋白的氨基酸序列(SEQ ID NO:11)。可溶性NPP1包含SEQ ID NO:6,且Fc序列包含铰链区。图12H示出了NPP1-Fc融合蛋白的氨基酸序列(SEQ ID NO:12)。可溶性NPP1包含SEQ ID NO:6,且Fc序列包含部分铰链区。
图13A-13C为薄层色谱的放射自显影图,其阐释了重组NPP1在体外和体内的活性。图13A:将100nM ATP与130ug/ml sNPP1-Fc-D10在37℃孵育1小时。图13B:将100nM ATP与来自野生型小鼠(WT)、Enpp1-/-小鼠和在IV注射重组NPP1(6mg/kg)2小时之后的Enpp1-/-小鼠的血浆孵育。图13C:将100nM ATP与来自野生型小鼠(WT)、Enpp1-/-小鼠和在IV注射重组NPP1(6mg/kg)2小时之后的Enpp1-/-小鼠的主动脉孵育。Pi:正磷酸盐;ATP:腺苷三磷酸;PPi:焦磷酸盐。
图14A和14B为柱状图,其阐释了在皮下注射重组NPP1(5mg/kg)之后Enpp1(-/-)小鼠中的血浆NPP1活性(图14A,顶部)和血浆焦磷酸盐浓度(图14B,底部)的时程。
图15为散点图,其阐释了在皮下注射重组NPP1(5mg/kg)(圆)之后在多个时间点的Enpp1(-/-)小鼠和野生型小鼠(正方形)的血浆NPP1活性和血浆焦磷酸盐(PPi)之间的关系。
图16A-16C为柱状图,其阐释了人类血液中焦磷酸盐的合成。图16A:从同一血液样品获得的肝素化的血液或血浆。图16B:将离心的有血沉棕黄层(所有细胞)或没有血沉棕黄层(红细胞)的血细胞取出,悬浮于HEPES缓冲盐水中。图16C:将分离的白细胞或血小板悬浮于HEPES缓冲盐水中。将样品在37℃下与或不与重组NPP1(145ug/ml)孵育2小时。
图17为柱状图,其阐释了重组NPP1对Enpp1(-/-)小鼠主动脉钙化的影响。在喂食高磷酸盐饮食的小鼠中,每隔48小时皮下注射重组NPP1(6mg/kg)。每一个柱代表具有下面给定周龄的单个动物。M:雄性对;F:雌性对。虚线指示来自野生型同窝小鼠的主动脉的平均钙含量。
图18为柱状图,其阐释了重组NPP1对患有肾衰竭的尿毒症大鼠中主动脉钙化的影响。在喂食高腺嘌呤饮食的尿毒症大鼠中每周5个剂量持续21天皮下注射sNPP1-Fc-D10或对照(5mg/kg)。每一个柱代表约4个月龄的单个动物。
发明详述
定义
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域内普通技术人员通常的理解相同的意思。尽管与本文描述的那些相似或等效的任何方法和材料都可以用于实践或测试本发明,但描述了优选的方法和材料。
当提及可测量值诸如量,时间持续时间等时,如本文使用的“约”意指包括指定值±20%或±10%、更优选地±5%、甚至更优选地±1%、以及仍更优选地±0.1%的变化,因为此类变化适于进行所公开的方法。
术语“改变的PPi:Pi比率”指血浆中PPi与血清中Pi的比率,其比该类型受试者(例如人类)的正常PPi:Pi比率高至少10%或低至少20%。改变的PPi:Pi比率可由于血浆PPi的水平低于正常水平或血清Pi的水平高于正常水平存在。PPi:Pi的比率被表示为([PPi]/[Pi])*1000,并且人类的正常比率为约1.75。
如本文使用的,关于NPP1蛋白,术语“片段”指全长NPP1的子序列。蛋白或肽的“片段”可以是至少约20个氨基酸长度;例如,至少约50个氨基酸长度;至少约100个氨基酸长度;至少约200个氨基酸长度;至少约300个氨基酸长度;或至少约400个氨基酸长度(以及之间的任何整数值)。片段的大小范围可以从四个氨基酸残基至整个氨基酸序列减去一个氨基酸。因此,“包含SEQ ID NO:1的氨基酸序列的至少一部分”的蛋白包括全长NPP1及其片段。
如本文使用的术语“高血清Pi”指受试者的血清中无机磷酸盐(Pi)水平,该无机磷酸盐(Pi)水平为该类型受试者(例如人类)的正常Pi水平的至少110%。优选地,受试者的血清中的Pi水平为该类型受试者的正常Pi水平的至少约120%、至少约150%、至少约200%或至少约300%。据报道,人类的正常Pi水平为1.5±0.5毫摩尔(Rutsch,F.等,CircCardiovasc Genet 1:133-140(2008))。
“分离的”或“纯化的”可溶性NPP1蛋白或其生物活性片段或融合蛋白基本上不含来自NPP1蛋白、生物活性片段或NPP1融合蛋白所来源自的细胞或组织来源的细胞材料或其他污染蛋白,或者当被化学合成时基本上不含化学前体或其他化学物质。语言“基本上不含细胞材料”包括NPP1蛋白、生物活性片段或NPP1融合蛋白的制备物,其中蛋白与该蛋白所分离自或重组产生自的细胞的细胞组分分离。在一个实施方案中,语言“基本上不含细胞材料”包括具有以下的PP1蛋白、生物活性片段或NPP1融合蛋白的制备物:小于约30%(按干重计)的非NPP1蛋白/片段/融合蛋白(本文也称为“污染蛋白”),更优选地小于约20%的非NPP1蛋白/片段/融合蛋白,仍更优选地小于约10%的非NPP1蛋白/片段/融合蛋白,以及最优选地小于约5%的非NPP1蛋白/片段/融合蛋白。当重组产生NPP1蛋白、其融合蛋白或生物活性片段时,其还优选地基本上不含培养基,即培养基代表小于约20%、更优选地小于约10%、以及最优选地少于约5%的蛋白制剂的体积。
如本文使用的术语“低血浆PPi”指受试者的血浆中焦磷酸盐(PPi)水平,该焦磷酸盐(PPi)水平不超过该类型受试者(例如人类)的正常PPi水平的50%。优选地,受试者的血浆中的PPi水平不超过该类型受试者的正常PPi水平的约40%、约30%、约20%或约10%。据报道,人类的正常PPi水平为2.63±0.47微摩尔。(O’Neill等,Nephrol Dial Transplant2010,25,187-191)。可以使用合适的已知方法,诸如尿苷-二磷酸葡萄糖(UDPG)方法以酶促方式定量焦磷酸盐。(Ryan,L.M.等,Arthritis Rheum 1979,22,886-91)。
范围:贯穿本公开内容,本发明的多个方面可以以范围格式呈现。应当理解,以范围格式的描述仅仅是为了方便和简洁,并且不应被解释为对本发明的范围的僵化限制。因此,范围的描述应该被认为已具体公开了所有可能的子范围以及在该范围内的单独数值。例如,范围的描述诸如从1至6应该被认为已具体公开了子范围诸如从1至3、从1至4、从1至5、从2至4、从2至6、从3至6等等,以及在该范围内的单独数字,例如1、2、2.7、3、4、5、5.3和6。无论范围的广度如何,这都适用。
如本文使用的,术语“受试者”包括哺乳动物和非哺乳动物。哺乳动物的实例包括,但不限于,人类、黑猩猩、猿猴、牛(cattle)、马、绵羊、山羊、猪(swine)、兔、狗、猫、大鼠、小鼠、豚鼠(guinea pig)等。非哺乳动物的实例包括但不限于鸟、鱼等。
如本文使用的,术语“治疗有效量”指无毒但足够量的剂(例如sNPP1蛋白),其与未接受此类量的相应受试者相比,导致改进的治疗、愈合、预防、或疾病、紊乱或副作用的改善,或者疾病或紊乱的进展速率的降低。该术语在其范围内还包括有效提高正常生理功能的量。
术语“治疗”包括以治愈、愈合、减轻、缓解、改变、补救(remedy)、改善、预防、改进或影响疾病或紊乱的目的将本发明的NPP1蛋白、片段和融合蛋白应用或施用至受试者,或者将本发明的NPP1蛋白、片段和融合蛋白应用或施用至具有以下的受试者:NPP1-相关疾病或紊乱或与低水平血液焦磷酸盐相关的其他疾病或紊乱或者特征在于钙和其他矿物质的沉积物的积累(矿化)的其他进行性紊乱。术语“治疗”指在治疗或改善损伤、病理或状况方面成功的任何象征,包括任何客观或主观参数,著如症状的减少;缓和;减弱或者使损伤、病理或状况对受试者更耐受;退化或衰退的速率减慢;使退化的最终点不那么虚弱;或改进受试者的身体或心里健康(mental well-being)。治疗可以是治疗性的或预防性的。症状的治疗或改善可以基于客观或主观参数;包括身体检查的结果。
治疗方法
本发明涉及缺少N-末端部分(即,缺少胞质和跨膜结构域)的分离的重组人可溶性NPP1(“sNPP1”)及其融合蛋白用于治疗NPP1相关疾病和紊乱的用途。本发明的蛋白可以出乎意料地用于体内增加NPP1活性,并增加或恢复受试者中的血液焦磷酸盐(PPi)的正常水平。本发明的蛋白还可以用于防止关节、肾脏、心脏(例如,主动脉)、动脉、血管或脊柱后纵韧带中的钙的沉积物的积累。
受试者可以是以下的人类患者:具有NPP1活性缺陷(NPP1缺陷)表现出低水平焦磷酸盐、罹患与低水平焦磷酸盐相关的疾病或紊乱、或罹患特征在于弹性纤维中钙和其他矿物质的沉积物的积累(矿化)的进行性紊乱。矿化可以发生于心脏、动脉、血管、肾脏、脊柱韧带、皮肤、眼睛和消化道。
更具体地,本发明的NPP1蛋白和NPP1融合蛋白可以用于治疗具有NPP1相关疾病或紊乱的受试者,所述NPP1相关疾病或紊乱包括但不限于,特发性婴儿型动脉钙化(IIAC)、胰岛素耐受、低磷酸血症佝偻病、和脊柱后纵韧带骨化、诸如慢性肾脏疾病中的血管钙化(VCCKD)、心肌缺血、关节钙化、血管样条纹症和弹性假黄色瘤(PXE)的其他疾病。
可溶性NPP1蛋白、其片段和NPP1融合蛋白可以用于治疗受试者中多种的状况。例如,可以通过在受试者诸如哺乳动物,例如,人类患者中降低和/或消除一种或更多种钙化结构和/或预防形成钙化结构而改进的状况的治疗在本发明的范围内。
在一个特别有用的实施方案中,待治疗的状况为广泛性动脉钙化(也称为婴儿期特发性动脉钙化和婴儿期动脉介质钙化(arterial media calcification of infancy))。
在其他实施方案中,还可以使用本文描述的方法治疗状况诸如弹性假黄色瘤、慢性肾脏疾病中的血管钙化、胰岛素耐受、低磷酸血症佝偻病、或脊柱后纵韧带骨化。
通常,施用至受试者的融合蛋白的剂量将根据已知的因素而变化,所述已知的因素诸如接受者的年龄、健康和体重、并发治疗的类型、治疗频率等。通常,活性成分(即,融合蛋白)的剂量可以在约0.0001至约50毫克/千克体重之间。施用的精确剂量、频率和治疗的时间跨度可以由施用治疗蛋白领域的熟练医师来确定。
本发明的优选的实施方案涉及一种用于治疗NPP1相关疾病或其他钙化疾病的方法,所述方法包括将治疗有效量的分离的可溶性NPP1蛋白(sNPP1)、生物活性片段或NPP1融合蛋白施用至受试者的步骤。如本文定义的,蛋白的治疗有效量(即有效剂量)范围为从约0.001mg/kg至50mg/kg体重。技术人员将理解,某些因素可能影响有效治疗受试者所要求的剂量,该某些因素包括但不限于疾病的严重程度、先前的治疗、受试者的一般健康和/或年龄以及存在的其他疾病。此外,用治疗有效量的蛋白治疗受试者可以包括单一治疗,或者优选地可以包括一系列治疗。还将理解,用于治疗的蛋白的有效剂量可以在特定治疗过程中增加或减少。
如本文定义的,蛋白或多肽的治疗有效量(即有效剂量)范围为从约0.001mg/kg至50mg/kg体重、优选地约0.01mg/kg至25mg/kg体重、更优选地约0.1mg/kg至20mg/kg体重、以及甚至更优选地约1mg/kg至10mg/kg、2mg/kg至9mg/kg、3mg/kg至8mg/kg、4mg/kg至7mg/kg或5mg/kg至6mg/kg体重。技术人员将理解,某些因素可能影响有效治疗受试者所要求的剂量,该某些因素包括但不限于疾病或紊乱的严重程度、先前的治疗、受试者的一般健康和/或年龄以及存在的其他疾病。此外,用治疗有效量的蛋白、多肽或抗体治疗受试者可以包括单一治疗,或者优选地可以包括一系列治疗。
在优选的实例中,在约0.1mg/kg至20mg/kg体重之间的范围内,每周一次、每周两次、约10天一次、约12天一次、约14天一次、约17天一次、约20天一次、约25天中一次、或约30天一次。还将理解,用于治疗的可溶性sNPP1蛋白、其生物活性片段或融合蛋白的有效剂量可以在特定治疗过程中增加或减少。
本发明提供了治疗有效剂量的sNPP1、其生物活性片段或融合蛋白,其将在每5天一次和每30天一次之间被施用至患者,持续由医学科学领域技术从业者确定的时间段。在一个实施方案中,该时间段将是患者寿命的剩余部分。在一个实施方案中,给药频率为在每5天一次和每25天一次之间。在一个实施方案中,给药频率为在每5天一次和每21天一次之间。在另一个实施方案中,给药频率为在每7天一次和每14天一次之间。sNPP1、其生物活性片段或融合蛋白可以被每5天一次、每6天一次、每7天一次、每8天一次、每9天一次、每10天一次、每11天一次、每12天一次、每13天一次、或每14天一次施用。在一些实施方案中,约每周一次施用sNPP1、其生物活性片段或融合蛋白。在其他实施方案中,约两周一次施用sNPP1、其生物活性片段或融合蛋白。在一个实施方案中,给药频率为约30天一次。
在一个实施方案中,患者小于2岁。在一些实施方案中,约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约1mg、约2mg、约3mg、约5mg、约10mg、约15mg、约20mg、约25mg、约30mg、约35mg、约40mg、或约45mg的sNPP1、生物活性片段或融合蛋白被施用至患有NPP1缺陷或其他钙化疾病的患者。在一些实施方案中,约0.5mg至约30mg、约0.5mg至约20mg、约0.5mg至约10mg、或约0.5mg至约5mg被施用至患者。
在一个实施方案中,每周一次将约1mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约2mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约3mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约4mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约5mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约6mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约7mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约8mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约9mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。在一个实施方案中,每周一次将约10mg/kg的sNPP1、生物活性片段或融合蛋白施用至患者。
在一些实施方案中,患者的血液PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约1%、约2%、约3%、约5%、约10%、约15%、约20%、约30%、约40%、约50%、约60%、约70%、或约80%。在一个实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约50%或更少。在一个实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约40%或更少。在一些实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约30%或更少。在一些实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常水平PPi的约30%或更少。在一些实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约20%或更少。在一些实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约10%或更少。在一些实施方案中,患者中的PPi水平在治疗之前为正常人类个体中观察到的正常PPi水平的约5%或更少。在一些实施方案中,患者在治疗之前未显示可测量的PPi。
sNPP1、生物活性片段或融合蛋白可以通过例如皮下注射、肌内注射和静脉内(IV)输注或注射施用。
在一个实施方案中,sNPP1、生物活性片段或融合蛋白通过任何有用的方法通过IV输注静脉内施用。在一个实例中,sNPP1、生物活性片段或融合蛋白可以通过外周线通过静脉内输注施用。在另一个实例中,sNPP1、生物活性片段或融合蛋白可以通过外周插入的中心导管通过静脉内输注施用。
在另一个实施方案中,sNPP1、生物活性片段或融合蛋白通过IV注射静脉内施用。
在另一个实施方案中,sNPP1、生物活性片段或融合蛋白可以经由腹膜内注射施用。
在另一个实施方案中,sNPP1、生物活性片段或融合蛋白可以通过皮下注射施用。
在另一个实施方案中,sNPP1、生物活性片段或融合蛋白可以通过肌内注射施用。
在仍另一个实施方案中,sNPP1、生物活性片段或融合蛋白经由治疗蛋白的药学上可接受的胶囊施用。例如,胶囊可以是肠溶包衣的明胶胶囊。
在一个实施方案中,方法包括单独地或与其他剂组合地施用本发明的可溶性NPP1蛋白或NPP1融合蛋白。在一个实施方案中,方法包括施用本发明的NPP1蛋白或NPP1融合蛋白作为疗法以补偿具有NPP1缺陷或其他相关疾病或紊乱的受试者中的降低的或异常的NPP1表达或活性。
在一个实施方案中,分离的sNPP1蛋白、片段和融合蛋白可以在用剂之前、之后或与剂同时施用,或者可以与其他已知疗法共施用。将本发明的分离的sNPP1蛋白、片段和融合蛋白与其他治疗剂共施用可以提供两种经由产生增加的治疗效果的不同机制起作用的剂。此类共施用可以解决由于对药物的耐受性的发展而产生的问题。
在特定方面,本公开内容涉及一种用于降低需要其的受试者中血管钙化的方法。该方法基于出乎意料的发现,NPP1的可溶性形式可以被施用至具有低血浆PPi水平(抑制物或组织钙化)或高血清Pi水平的动物,引起动物中血浆PPi的瞬时增加,并且血浆PPi的瞬时增加可以抑制动物中的血管钙化。由于血浆PPi的增加是瞬时的,疗法可以被定制为抑制不希望的或病理性的组织钙化,诸如血管钙化,而不抑制骨钙化或诱发骨软化。
一般来讲,本公开内容涉及一种用于通过将两个或更多个剂量的可溶性NPP1(sNPP1)施用至受试者来降低有相应需要的受试者中的组织钙化(例如,血管钙化)的方法。每一个剂量包含足以实现受试者中血浆PPi的瞬时增加的量的可溶性NPP1,优选地在施用该剂量之后约48小时内返回至基线PPi水平。每一个剂量的施用之间的时间段通常为至少2天。
有相应需要的受试者可以为任何年龄和性别,并且优选地具有低血浆PPi或高血清Pi(例如,导致改变的PPi:Pi比率)。低血浆PPi可以是由于,例如,先天性NPP1缺陷,诸如编码NPP1的基因的导致降低的活性NPP1的表达或降低的酶促活性的突变(与NPP1缺陷和常染色体隐性低磷酸血症佝偻病相关),以及编码MRP6的基因的导致不存在或无功能的MRP6蛋白的突变(与弹性假黄色瘤相关)。低血浆PPi或高血清Pi也常见于患有慢性肾脏疾病、终末期肾脏疾病/衰竭、糖尿病以及其他状况的患者。因此,需要疗法的受试者可以具有慢性肾脏疾病(CKD)、终末期肾脏疾病(ESRD)、婴儿期广泛性动脉钙化(GACI)、II型糖尿病、常染色体隐性低磷酸血症佝偻病、心血管紊乱、动脉粥样硬化和/或弹性假黄色瘤(PXE)。受试者通常为人类,但也可以为任何其他合适的哺乳动物或非哺乳动物。
组织钙化为一种进行性过程,并且生而患有先天性NPP1缺陷的个体可能在几年内不显示组织钙化。通过尽早开始疗法,可以在此类受试者中降低和/或最小化钙化是可能的。在患有不由种系突变引起的低血浆PPi水平或患有高血清Pi水平(例如,具有改变的血浆PPi:Pi比率)的患者中,疗法应该在尽快可行的情况下(即,在诊断为状况诸如慢性肾脏疾病(CKD)或终末期肾脏疾病(ESRD)之后不久)开始。在某些实施方案中,待治疗的受试者可以在1个月龄和24个月龄之间、小于1岁、小于2岁、小于3岁、小于4岁或小于5岁。
被施用至受试者的每一个剂量的sNPP1包含足以实现血浆PPi瞬时增加的量的sNPP1。优选地,瞬时增加的特征在于峰值PPi水平为正常血浆PPi水平的至少约40%、正常血浆PPi水平的至少约50%、正常血浆PPi水平的至少约60%、正常血浆PPi水平的至少约70%、正常血浆PPi水平的至少约80%、在正常血浆PPi水平的约40%和100%之间、在正常血浆PPi水平的约50%和100%之间、在正常血浆PPi水平的约60%和100%之间、在正常血浆PPi水平的约70%和100%之间、在正常血浆PPi水平的约80%和100%之间、或在正常血浆PPi水平的约100%至200%之间。
优选地,血浆PPi在施用sNPP1之后的瞬时增加被维持至少约4小时、至少约6小时、至少约8小时、至少约10小时或至少约12小时。另外,优选的是,在施用剂量之后约48小时内、在施用剂量之后约3天内或在施用剂量之后约4天内,血浆PPi的瞬时增加返回至受试者的基线PPi水平。
受试者中的低血浆PPi在治疗之前为正常受试者(例如,人类)中观察到的正常PPi水平的约50%或更少,优选地40%或更少。在一些方面,受试者中的PPi水平在治疗之前为正常PPi水平的约30%或更少。在其他方面,受试者中的PPi水平在治疗之前为正常PPi水平的约20%或更少。在一些其他方面,受试者中的PPi水平在治疗之前为正常水平的约10%或更少。在一些方面,受试者在治疗之前可能没有可测量的PPi。
受试者中的高血清Pi在治疗之前为正常受试者(例如,人类)中观察到的正常Pi水平的约110%或更多,优选地125%或更多。在一些方面,受试者中的Pi水平在治疗之前为正常PPi水平的约150%或更多。在其他方面,受试者中的Pi水平在治疗之前为正常PPi水平的约200%或更多。在一些其他方面,受试者中的Pi水平在治疗之前为正常水平的约300%或更多。不希望受限于任何特定的理论,认为诱发血清PPi的瞬时增加可以补偿升高的血浆Pi水平,并且瞬时恢复正常或接近正常的PPi:Pi比率,从而抑制由高于正常水平的血清Pi促进的组织钙化。
足以实现血浆PPi的瞬时增加的sNPP1的量可以由具有普通技术的临床医师容易地确定,例如通过施用预期产生血浆PPi的瞬时增加的剂量,确定瞬时增加是否发生,以及然后对剂量进行适当的调整。施用的量将受到一些常规因素的影响,所述常规因素包括使用的特定sNPP1、受试者的年龄、健康和体重、受试者对药物的敏感性以及其他相关因素。通常,每剂量中待施用的sNPP1的量为在约0.001毫克/千克体重和约50毫克/千克体重之间,其中1mg/kg至5mg/kg、1mg/kg至10mg/kg、1mg/kg至20mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、11mg/kg、12mg/kg、13mg/kg、14mg/kg、15mg/kg、16mg/kg、17mg/kg、18mg/kg、19mg/kg、或20mg/kg是优选的。施用的精确剂量、频率和治疗的时间跨度可以由施用治疗蛋白领域的技术医师来确定。
在一些优选的实施方案中,每一个剂量包含约1.0mg至约5.0mg sNPP1/Kg体重、约1.0mg至约10.0mg sNPP1/Kg体重或约1.0mg至约20.0mg sNPP1/Kg体重。
剂量之间的时间段被选择以允许受试者的血清PPi水平返回至基线水平,并且为至少2天(48小时),但可以根据需要或指示更长。例如,剂量之间的时间段可以为3天、4天、5天、6天、1周、10天、12天、2周、3周或约1个月。
通常,期望在诊断为低血浆PPi、高血清Pi或NPP1缺陷之后,在尽快可行的情况下,根据本文描述的方法开始疗法。生而患有先天性NPP1缺陷的受试者可能在几年内不显示组织钙化。通过尽早开始疗法,可以在此类受试者中降低和/或最小化钙化是可能的。在患有不由种系突变引起的低血浆PPi水平或患有高血清Pi的患者中,在诊断为状况诸如慢性肾脏疾病(CKD)或终末期肾脏疾病(ESRD)之后,疗法应该在尽快可行的情况下开始。
方法提供了降低患有低血浆PPi或患有高血清Pi的受试者包括患有改变的PPi与Pi比率的那些受试者中的组织钙化(例如血管钙化)的有效方式。组织钙化优选地为血管钙化,其优选地为动脉钙化,但也可以为静脉钙化。血管钙化可以为内膜的或内侧的。待被根据本文描述的方法治疗的受试者可以具有NPP1缺陷、广泛性动脉钙化(GACI),也称为婴儿期特发性动脉钙化和婴儿期动脉介质钙化。待治疗的受试者还可以具有心血管紊乱,诸如冠状动脉疾病和/或动脉粥样硬化。待治疗的受试者可以具有慢性肾脏疾病(CKD)或终末期肾脏疾病(ESRD)。待治疗的患者可以具有糖尿病(例如II型糖尿病)。待治疗的受试者可以具有弹性假黄色瘤(PXE)。
sNPP1可以通过任何合适的方法或施用途径,诸如胃肠外、口服或通过吸入施用。肠胃外施用诸如静脉内注射或输注、皮下注射、腹膜内注射或肌内注射是优选的。
如果需要,sNPP1可以与一种或更多种共治疗剂一起施用。对于共疗法,sNPP1和一种或更多种另外的治疗剂被施用,使得在受试者中它们的单独的药理活性存在实质重叠。因此,可以在施用sNPP1之前、与之同时或之后施用任何共治疗剂。共疗法可以提供两种经由产生增加的治疗效果的不同机制起作用的剂。
除了导致血清PPi的瞬时增加以外,认为根据本文描述的方法施用sNPP1可以改变受试者中某些蛋白的水平。例如,不希望受限于任何特定的理论,认为根据本文描述的方法施用sNPP1可以减少受试者中骨桥蛋白、护骨蛋白和成纤维细胞生长因子23(FGF-23)的水平。因此,除了血浆PPi和血清Pi水平以外,这些蛋白的水平也可以用于监测疗法并定制给药。
sNPP1
本发明采用为NPP1的生物活性NPP1结构域的可溶性NPP1(即,包含天然存在的NPP1对于焦磷酸酶和/或磷酸二酯酶活性的至少一个细胞外催化结构域的NPP1组分)。本发明的可溶性NPP1蛋白至少包含实现焦磷酸酶和/或磷酸二酯酶活性必需的NPP1结构域。
在一个实施方案中,可溶性NPP1、其片段和融合蛋白可以形成功能性同型二聚体或单体。在优选的实施方案中,可以测定可溶性NPP1蛋白或其NPP1融合蛋白的焦磷酸酶活性以及增加体内焦磷酸盐水平的能力。
本发明的优选的可溶性NPP1蛋白和NPP1融合蛋白在体内(例如,人类)为酶促活性的。在一个实施方案中,可溶性蛋白包含与以下序列具有至少60%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%的序列同一性的氨基酸序列:
PSCAKEVKSCKGRCFERTFGNCRCDAACVELGNCCLDYQETCIEPEHIWTCNKFRCGEKRLTRSLCACSDDCKDKGDCCINYSSVCQGEKSWVEEPCESINEPQCPAGFETPPTLLFSLDGFRAEYLHTWGGLLPVISKLKKCGTYTKNMRPVYPTKTFPNHYSIVTGLYPESHGIIDNKMYDPKMNASFSLKSKEKFNPEWYKGEPIWVTAKYQGLKSGTFFWPGSDVEINGIFPDIYKMYNGSVPFEERILAVLQWLQLPKDERPHFYTLYLEEPDSSGHSYGPVSSEVIKALQRVDGMVGMLMDGLKELNLHRCLNLILISDHGMEQGSCKKYIYLNKYLGDVKNIKVIYGPAARLRPSDVPDKYYSFNYEGIARNLSCREPNQHFKPYLKHFLPKRLHFAKSDRIEPLTFYLDPQWQLALNPSERKYCGSGFHGSDNVFSNMQALFVGYGPGFKHGIEADTFENIEVYNLMCDLLNLTPAPNNGTHGSLNHLLKNPVYTPKHPKEVHPLVQCPFTRNPRDNLGCSCNPSILPIEDFQTQFNLTVAEEKIIKHETLPYGRPRVLQKENTICLLSQHQFMSGYSQDILMPLWTSYTVDRNDSFSTEDFSNCLYQDFRIPLSPVHKCSFYKNNTKVSYGFLSPPQLNKNSSGIYSEALLTTNIVPMYQSFQVIWRYFHDTLLRKYAEERNGVNVVSGPVFDFDYDGRCDSLENLRQKRRVIRNQEILIPTHFFIVLTSCKDTSQTPLHCENLDTLAFILPHRTDNSESCVHGKHDSSWVEELLMLHRARITDVEHITGLSFYQQRKEPVSDILKLKTHLPTFSQED(SEQ ID NO:2)
任何期望的酶促活性形式的可溶性NPP1可以用于本文描述的方法中。酶促活性的sNPP1可以增加合适的酶促测定中的PPi水平,并且可以测定焦磷酸酶活性、磷酸二酯酶活性或焦磷酸酶和磷酸二酯酶活性。通常,sNPP1至少包含缺少天然存在的跨膜NPP1的N-末端胞质和跨膜结构域的NPP1组分。在优选的方面,NPP1组分包含天然存在的人类NPP1的半胱氨酸富集区(SEQ ID NO:1的氨基酸99-204)和催化区(SEQ ID NO:1的氨基酸205-591)。通常,NPP1组分还包括C-末端区(SEQ ID NO:1的氨基酸592至925),并且具有SEQ ID NO:2的氨基酸序列。然而,如果需要,C-末端区可以被截短。因此,优选的NPP1组分包括人类NPP1的半胱氨酸富集区和催化区(SEQ ID NO:1的氨基酸99-591)或者人类NPP1的半胱氨酸富集区、催化区和C-末端区(SEQ ID NO:2)。其他优选的NPP1组分仅包含半胱氨酸富集结构域的一部分,并且具有SEQ ID NO:1的氨基酸107至925或SEQ ID NO:1的氨基酸187至925的氨基酸序列。
NPP1的半胱氨酸富集区(即,SEQ ID NO:1的氨基酸99至204)可以促进sNPP1的二聚化。sNPP1,包括融合蛋白,可以呈功能性同型二聚体的单体的形式。
NPP1组分的氨基酸序列可以为天然存在的NPP1序列的变体,条件是NPP1组分为酶促活性的。NPP1变体为酶促活性的,并且与人类NPP1的相应部分(例如,在半胱氨酸富集区、催化区、c-末端区、半胱氨酸富集区加上催化区、半胱氨酸富集区加上催化区加上c-末端区的长度内)具有至少80%、至少85%、至少90%、至少95%、更优选地至少96%的氨基酸序列同一性。优选的NPP1变体与以下具有至少90%、优选地至少95%、更优选地至少97%的氨基酸序列同一性:(i)SEQ ID NO:1的残基205-591的氨基酸序列、(ii)SEQ ID NO:1的残基99-591的氨基酸序列、(iii)SEQ ID NO:1的残基99-925的氨基酸序列、(iv)SEQ ID NO:1的残基107-925的氨基酸序列,或(v)SEQ ID NO:1的残基187-925的氨基酸序列。氨基酸变化的合适位置从NPP1结构研究和NPP1中疾病相关突变分析可熟知。例如,以下氨基酸的取代发生在降低NPP1酶促活性的某些疾病相关突变中,并且应避免在这些位置处的氨基酸的变化:Ser216、Gly242、Pro250、Gly266、Pro305、Arg349、Tyr371、Arg456、Tyr471、His500、Ser504、Tyr513、Asp538、Tyr570、Lys579、Gly586;Tyr659、Glu668、Cys726、Arg774、His777、Asn792、Asp804、Arg821、Arg888、和Tyr901。(参见,例如,Jansen,S.等,Structure 20:1948-1959(2012).)。
在一个实施方案中,可溶性NPP1蛋白可以为与融合伴侣重组融合或化学键合(例如,共价键、离子键、疏水键和范德瓦耳斯力)的融合蛋白。在另一个实施方案中,融合蛋白与SEQ ID NO:3或SEQ ID NO:4具有至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、或99%的序列同一性。
为了确定两个氨基酸序列的同一性百分比,出于最佳比较目的将序列对齐(例如,为最佳对齐,可以引入空位到第一和第二氨基酸序列中或第一和第二核酸序列中的一个或两者中,并且出于比较目的非同源序列可被忽略)。在优选的实施方案中,出于比较目的而比对的参考序列的长度为参考序列的长度的至少30%、优选地至少40%、更优选地至少50%、甚至更优选地至少60%、以及甚至更优选地至少70%、80%、或90%(例如,SEQ IDNO:2的sNPP1氨基酸序列;SEQ ID NO:1的氨基酸107-925或SEQ ID NO:1的氨基酸187-925)。然后将在相应氨基酸位置处的氨基酸残基或核苷酸进行比较。当在第一序列中的位置被与在第二序列中相应位置处的相同的氨基酸残基或核苷酸占据时,则分子在该位置处相同(如本文使用的,氨基酸等同于氨基酸或核酸“同源性”)。两个序列之间的同一性百分比为考虑到两个序列的最佳对齐所需要被引入的空位的数目和每一个空位的长度的情况下序列所共享的相同位置的数目的函数。
序列的比较和两个序列之间的同一性百分比的确定可以使用数学算法来完成。在优选的实施方案中,两个氨基酸序列之间的同一性百分比如下来确定:使用已被并入GCG软件包中的GAP程序(在www.gcg.com可得)的Needleman和Wunsch(J Mol Biol 1970,48,444-453)算法,使用Blosum 62矩阵或PAM250矩阵以及16、14、12、10、8、6或4的空位权重和1、2、3、4、5或6的长度权重。在另一个实施方案中,两个氨基酸之间的同一性百分比如下来确定:使用已被并入ALIGN程序(2.0版或2.0U版)的E.Meyers和W.Miller(CABIOS,1989,4,11-17)的算法,使用PAM120权重残基表、12的空位长度罚分和4的空位罚分。
sNPP1可以由如本文描述的NPP1组分组成或基本上由如本文描述的NPP1组分组成。可选择地,sNPP1可以呈包含NPP1组分和一种或更多种被称为融合伴侣的其他多肽(任选地在每一种情况下通过合适的接头)的融合蛋白的形式,或者可以呈NPP1组分和另一种分子(例如,PEG)之间的缀合的形式。当sNPP1呈融合蛋白的形式时,每一个融合伴侣优选地位于NPP1组分的c-末端。不希望受限于任何特定的理论,认为包含含半胱氨酸富集区和催化区的NPP1组分和位于NPP1组分的c-末端的一种或更多种融合蛋白的融合蛋白优于NPP1融合蛋白的其他结构,因为它们可以以足够的水平表达并且足够稳定地被用作治疗蛋白。
任何合适的融合伴侣可以被包含在融合蛋白中。有利地,本领域熟知的许多融合伴侣可以提供某些优势,诸如降低的聚集和免疫原性、增加的溶解度、改进的表达和/或稳定性、以及改进的药代动力学和/或药效学性能。参见,例如,Strohl,W.R.BioDrugs 29:215-239(2015)。例如,熟知,白蛋白、白蛋白片段或白蛋白变体(例如,人类血清白蛋白及其片段或变体)可以被并入融合蛋白中,并且使得此类融合蛋白可以容易地纯化、稳定并具有改进的血浆半衰期。可以在sNPP1融合蛋白中使用的合适的白蛋白、白蛋白片段和白蛋白变体被公开在例如WO 2005/077042A2和WO 03/076567A2中,它们的每一个通过引用以其整体并入本文。还已知与人类转铁蛋白的融合改进半衰期。参见,例如,Kim BJ等,J PharmacolExpr Ther 334(3):682-692(2010);和WO 2000/020746。也可以使用与白蛋白或转铁蛋白结合的肽,诸如抗体或抗体片段。参见,例如,EP 0486525 B1、US 6,267,964 B1、WO 04/001064A2、WO 02/076489A1、WO 01/45746、WO 2006/004603、和WO 2008/028977。类似地,免疫球蛋白Fc融合蛋白为熟知的。参见,例如,Czajkowsky DM等,EMBO Mol Med 4(10):1015-1028(2012),美国专利第7,902,151号;和美国专利第7,858,297号,它们的整体教导通过引用以其整体并入本文。融合蛋白还可以包括CTP序列(还参见Fares等,Endocrinol 2010,151,4410-4417;Fares等,Proc Natl Acad Sci 1992,89,4304-4308;和Furuhashi等,MolEndocrinol 1995,9,54-63)。优选地,融合伴侣为免疫球蛋白的Fc(例如,Fc或人类IgG1)。Fc可以包括人类IgG1的CH1、CH2和CH3,以及如果需要,任选地人类IgG1铰链区(EPKSCDKTHTCPPCP(SEQ ID NO:13))或人类IgG1铰链区的一部分(例如,DKTHTCPPCP(SEQID NO:14)或PKSCDKTHTCPPCP(SEQ ID NO:15))。在一些融合蛋白中,如果需要,Fc可以包括人类IgG1的CH2和CH3、或人类IgG2或人类IgG4的Fc。
优选地,sNPP1融合蛋白包含NPP1组分和增加融合蛋白的半衰期的肽,最优选地免疫球蛋白的Fc(例如,Fc或人类IgG1)。如本文使用的,“增加融合蛋白的半衰期的蛋白”指这样的蛋白,其当与可溶性NPP1或生物活性片段融合时,与单独的可溶性NPP1多肽或单独的NPP1生物活性片段的半衰期相比,将可溶性NPP1多肽或生物活性片段的半衰期增加。
在一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了50%。在另一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了60%。在另一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了70%。在另一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了80%。在另一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了90%。
在另一个实施方案中,与单独的NPP1多肽或生物活性片段的半衰期相比,NPP1融合蛋白的半衰期被增加了2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍或10倍。确定蛋白或融合蛋白的半衰期的方法为本领域熟知的。例如,Zhou等人,Determining Protein Half-Lives,Methods in Molecular Biology 2004,284,67-77公开了许多用于测试蛋白的半衰期的方法。如果需要,融合蛋白可以与聚合物缀合,或延长半衰期的其他合适的化合物诸如聚乙二醇(PEG)可以与NPP1融合蛋白缀合。
在一个实施方案中,增加融合蛋白的半衰期的肽为CTP序列(还参见,Fares等,2010,Endocrinol.,151(9):4410-4417;Fares等,1992,Proc.Natl.Acad.Sci,89(10):4304-4308;和Furuhashi等,1995,Molec.Endocrinol.,9(1):54-63)。
在另一个实施方案中,增加融合蛋白的半衰期的肽为Ig的Fc结构域。
还可以选择融合伴侣以将融合蛋白靶向具有临床或生物重要性的期望位点(例如,钙化位点)。例如,在美国专利第7,323,542号中描述了对骨具有高亲和力的肽,其整体教导通过引用并入本文。可以增加蛋白对钙化位点的靶向的肽可以包含至少约4个酸性氨基酸,例如谷氨酸或天冬氨酸,的连续链段。通常,将融合蛋白靶向钙化位点的肽将包含在4个至20个之间的连续的酸性氨基酸,例如4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个或20个选自谷氨酸和天冬氨酸的连续的氨基酸。肽可以仅由谷氨酸残基组成、仅由天冬氨酸残基组成,或者为谷氨酸残基和天冬氨酸残基的混合物。用于靶向钙化位点的特别优选的部分为Asp10(SEQ ID NO:18)。
在一个实施方案中,本发明的NPP1融合蛋白包含NPP1多肽和增加蛋白对钙化位点的靶向的部分,诸如酸性氨基酸,例如谷氨酸或天冬氨酸,的连续链段。
用于在融合蛋白中使用的合适的肽接头为熟知的,并且通常采取柔性延伸构象,并且不干扰NPP1组分或融合伴侣的功能。肽接头序列可以包含以任何组合的Gly、His、Asn和Ser残基。有用的肽接头包括,但不限于,聚-Gly、聚-His、聚-Asn或聚-Ser。其他近中性氨基酸,诸如Thr和Ala也可以用于接头序列中。可以作为接头被有用地采用的氨基酸序列包括以下中公开的那些:Maratea等,Gene 1985,40,39-46;Murphy等,Proc Natl Acad SciUSA 1986,83,8258-8262;美国专利第4,935,233号和美国专利第4,751,180号。其他合适的接头可以从天然存在的蛋白,诸如免疫球蛋白的铰链区获得。优选的合成的接头为(Gly4Ser)n,其中n为1、2、3、4、5、6、7、8、9或10(SEQ ID NO:19)。优选地,n为3或4。例如,在一些实施方案中,接头为(Gly4Ser)3(SEQ ID NO:16),并且融合蛋白包含具有氨基酸序列GlyGlyGlyGlySerGlyGlyGlyGlySerGlyGlyGlyGlySer(SEQ ID NO:16)的接头。通常,接头的长度为从1个至约50个氨基酸残基,或长度为1个至约25个氨基酸。接头的长度通常在约8个至约20个氨基酸之间。
优选的NPP1融合蛋白从N-末端至C-末端包含NPP1组分、任选地接头、免疫球蛋白的Fc区(例如,任选地包括铰链或其部分的人类IgG1Fc)、任选地第二接头以及任选地靶向部分。因此,Fc区和任选的靶向部分(当存在时)各自位于NPP1组分的C-末端。NPP1组分优选地包含NPP1的半胱氨酸富集区和催化结构域,缺少N-末端胞质和跨膜结构域,并且任选地包含C-末端区。
优选的融合蛋白从N-末端至C-末端包含NPP1组分和人类免疫球蛋白的Fc区,所述NPP1组分包含人类NPP1的半胱氨酸富集结构域、催化结构域和C-末端区;所述人类免疫球蛋白的Fc区包括铰链。优选地,Fc区来自人类IgG1。在特定实施方案中,融合蛋白与SEQ IDNO:3具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列同一性。这种类型的优选的融合蛋白具有SEQ ID NO:3的氨基酸序列。
另一个优选的融合蛋白从N-末端至C-末端包含NPP1组分、接头(例如,(Gly4Ser)3(SEQ ID NO:16))和人类免疫球蛋白的Fc区,所述NPP1组分包含人类NPP1的半胱氨酸富集结构域、催化结构域和C-末端区;所述人类免疫球蛋白的Fc区包括铰链。优选地,Fc区来自人类IgG1。
另一个优选的融合蛋白从N-末端至C-末端包含NPP1组分、人类免疫球蛋白的Fc区和将所述融合蛋白靶向钙化位点的部分,所述NPP1组分包含人类NPP1的半胱氨酸富集结构域、催化结构域和C-末端区;所述人类免疫球蛋白的Fc区包括铰链或其部分。优选地,Fc区来自人类IgG1。优选地,将融合蛋白靶向钙化位点的部分为Asp10(SEQ ID NO:18)。更优选地,Fc区来自人类IgG1,并且将融合蛋白靶向钙化位点的部分为Asp10(SEQ ID NO:18)。在特定实施方案中,融合蛋白与SEQ ID NO:4具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列同一性。这种类型的优选的融合蛋白具有SEQ ID NO:4的氨基酸序列。
另一个优选的融合蛋白从N-末端至C-末端包含NPP1组分、接头(例如,(Gly4Ser)3(SEQ ID NO:16))、人类免疫球蛋白的Fc区和将所述融合蛋白靶向钙化位点的部分,所述NPP1组分包含人类NPP1的半胱氨酸富集结构域、催化结构域和C-末端区;所述人类免疫球蛋白的Fc区包括铰链或其部分。优选地,Fc区来自人类IgG1。优选地,将融合蛋白靶向钙化位点的部分为Asp10(SEQ ID NO:18)。更优选地,Fc区来自人类IgG1,并且将融合蛋白靶向钙化位点的部分为Asp10(SEQ ID NO:18)。
另一个优选的融合蛋白从N-末端至C-末端包含NPP1组分、任选地接头(例如,(Gly4Ser)3(SEQ ID NO:16))、人类免疫球蛋白的Fc区,所述NPP1组分包含人类NPP1的半胱氨酸富集结构域的一部分、催化结构域和c-末端区;所述人类免疫球蛋白的Fc区包括铰链或其部分。优选地,Fc区来自人类IgG1。在特定实施方案中,融合蛋白与SEQ ID NO:9、SEQID NO:10、SEQ ID NO:11、或SEQ ID NO:12具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列同一性。这种类型的优选的融合蛋白具有SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、或SEQ ID NO:12的氨基酸序列。
在特别优选的方面,根据本文描述的方法施用SEQ ID NO:3的融合蛋白。在其他特别优选的方面,根据本文描述的方法施用SEQ ID NO:4的融合蛋白。在其他特别优选的方面,根据本文描述的方法施用SEQ ID NO:9的融合蛋白。在其他特别优选的方面,根据本文描述的方法施用SEQ ID NO:10的融合蛋白。在其他特别优选的方面,根据本文描述的方法施用SEQ ID NO:11的融合蛋白。在其他特别优选的方面,根据本文描述的方法施用SEQ IDNO:12的融合蛋白。
本发明的融合蛋白可以使用本领域熟知的标准方法(包括重组技术或化学缀合)制备。可用于分离和表征本发明的核酸和蛋白的技术为本领域技术人员熟知的,并且可以参考标准分子生物学和生物化学手册以选择合适的方案用于使用,而无需过度的实验。参见,例如,Sambrook等,1989,“Molecular Cloning:A Laboratory Manual”,第2版,ColdSpring Harbor,其的内容通过引用以其整体并入本文。
分离的重组人类sNPP1、其片段和融合蛋白可以在任何有用的蛋白表达系统中产生,所述任何有用的蛋白表达系统包括,但不限于,细胞培养物(例如,CHO细胞、COS细胞、HEK203)、细菌诸如大肠杆菌(Escherichia coli)(E.coli)和转基因动物,包括,但不限于哺乳动物和鸟类(例如,鸡、鹌鹑、鸭和火鸡)。为了表达,编码sNPP1的构建体并且包含合适的信号序列(例如,来自人类Ig重链、NPP2、NPP4、NPP7或例如人类血清白蛋白),该信号序列与sNPP1的序列符合读框的并且可操作地连接至合适的表达控制元件。
包括融合蛋白的sNPP1及其生理上可接受的盐形式通常被配制为用于根据本文描述的方法施用的药物组合物。药物组合物通常包含药学上可接受的载体或赋形剂。通过熟知的常规方法来配制包含此类载体的组合物,包括复合分子(composite molecule)(参见,例如,Remington’s Pharmaceutical Sciences,第14版,Mack Publishing Co.,Easton,PA),其整体教导通过引用并入本文。载体可以包括稀释剂。在一个实施方案中,药物载体可以是液体,并且融合蛋白可以呈溶液的形式。药物载体可以是蜡、脂肪或醇。在另一个实施方案中,药学上可接受的载体可以为粉末、冻干的粉末或片剂的形式的固体。在一个实施方案中,载体可以包含脂质体或微胶囊。药物组合物可以呈用稀释剂重建后用于注射的无菌冻干粉末的形式。稀释剂可以为注射用水、抑菌性注射用水或无菌盐水。冻干的粉末可以通过将融合蛋白的溶液冷冻干燥以产生干燥形式的蛋白来生产。如本领域已知的,冻干的蛋白通常具有增加的稳定性和比液体蛋白溶液长的保质期。
实施例
本发明通过以下实施例进一步示例。实施例仅用于说明目的,并不意图,也不应该被解释为以任何方式限制本发明。
方法
动物:
使用6周龄野生型雄性C57Bl/6J小鼠。这些小鼠的平均体重范围为21-22g。以5mg/kg的浓度通过皮下(SC)或静脉内(IV)注射用sNPP1-Fc[1.04mg/ml]或sNPP1-Fc-D10[1.03mg/ml]给药小鼠。表1.
使用两种不同品系的缺少NPP1的小鼠。Enpp1-/-小鼠先前在Lomashvili,K.A.等,Kidney Int 2014,85,1351-1356中被描述。为加快动脉钙化,将饮食补充有1.5%磷酸盐(最终磷含量:2%),按比例使用NaH2PO4和Na2HPO4的混合物,以产生如先前描述的中性pH。(O’Neill,W.C.等,Kidney Int 2011,79,512-517)。
慢性肾脏疾病(CKD)模型:野生型sprague dawley大鼠用于CKD模型研究。将大鼠喂食包含0.25%-0.75%腺嘌呤和高水平磷(0.75%-0.9%磷对比于正常食物(normalchow)中的0.4%)的饮食。过量的膳食腺嘌呤使正常的腺嘌呤磷酸核糖转移酶补救途径处于饱和,且腺嘌呤改为被代谢为2,8-二羟基腺嘌呤,2,8-二羟基腺嘌呤由于其低溶解度在肾小管中沉淀并形成晶体。这些晶体在肾脏中引起肾小管损伤、炎症、阻塞和纤维化,并且导致与人类CKD一致的表型。所造成的肾脏损害和肾衰竭导致受损的磷酸盐排泄,导致异常高的血清Pi水平和紊乱的矿物质代谢,诸如广泛性软组织钙化。饮食中高磷水平加速动脉钙化。高腺嘌呤饮食的大鼠发展尿毒症、高磷血症、继发性甲状旁腺功能亢进症、肾性骨营养不良症和血管钙化。
血浆制备:
将血液通过心脏穿刺收集,并且立即混合(9:1体积:体积血液至110mM柠檬酸溶液)。血清收集导致从血小板释放过量的焦磷酸盐(PPi),并且EDTA对凝血的抑制可能干扰测定。将柠檬酸化血液的管摇晃数分钟,并且然后以2,000xg离心10-15min。收集顶层血浆(100-300μl),并且将约200μl添加至10kDa微量离心浓缩器(centricon)。然后将这些管以12,000xg离心10min以使血浆脱蛋白。在离心之后,将流通液收集到新管中。将血浆和脱蛋白的样品在-20℃冷冻直到分析。
荧光PPi测定:
:该测定采用发荧光的PPi传感器,其具有成比例地取决于PPi浓度的荧光强度。将10kDa过滤的样品(4μl)添加至46μl测定缓冲液中。将PPi传感器储备溶液(200X)在测定缓冲液中稀释,并且将其50μl添加至样品中。在室温孵育20min之后,读取固体黑色96孔板的荧光(Ex/Em=316/456nm)。
测定:
如先前描述测量NPP1活性。(Villa-Bellosta,R.等,Am J Physiol Heart CircPhysiol 2011,301,H61-H68)。简言之,将血浆添加至20体积的包含200nM ATP和1.5uCi[32P]ATP/ml的生理缓冲液中在37℃持续10分钟。然后通过聚乙烯亚胺纤维素上的薄层色谱分离反应物,并且产生的PPi的量通过放射自显影的光密度法确定。使用通过30kD截留(cut-off)的过滤器新鲜过滤的血浆和基于通过UDP葡萄糖焦磷酸化酶将PPi和UDP-葡萄糖转化为UTP和葡糖-1-磷酸的酶测定,如先前描述的测量血浆PPi(Lomashvili,K.A等,Kidney Int 2014,85,1351-1356)。所有使用的水均用羟基磷灰石预处理以去除污染的PPi。如先前描述的,主动脉钙在干主动脉的HCl酸提取物中以量热法测量。(Lomashvili,K.A.等,Kidney Int 2014,85,1351-1356)。将钙含量归一化为干重,并且在减去正常小鼠主动脉的钙含量之后确定钙化的分数下降。
血细胞分级分离:
为了制备白细胞和血小板,将新鲜抽取的肝素化人类血液在室温以250g离心15分钟。将血浆取出并以2200g离心12分钟以获得血小板。将来自第一次离心的沉淀物重新悬浮于生理盐水至原使的血液体积,并在冰上添加4体积的裂解缓冲液(155mmol/L氯化铵;10mmol/L碳酸氢钠;0.1mmol/L EDTA,pH 7.4),持续5-10分钟。在离心并去除上清液之后重复此操作,在最终离心之后产生纯化的白细胞。
统计分析:
连续变量被表示为平均值±标准误差,其中差异由学生t检验确定。在对数转化之后分析主动脉钙含量。
实施例I
背景:进行实验以确定是否存在用sNPP1变体给药的野生型小鼠的PPi水平的增加。为此,对于单次静脉注射疗法选择1小时时间点并且对于单次皮下注射疗法选择4小时时间点。通过abcam PPi荧光测定法确定PPi水平的估计值。
结果:将来自1min读数(总共9个读数)的原始数据平均,并转化为正常血浆(WT)的%。表2
表2
空白 | 空白 | 缓冲液 | 缓冲液 | WT1 | WT2 | IV Fc-1 | IV Fc-2 | IV D10-1 | IV D10-2 | sc Fc-1 | sc Fc-2 | sc D10-1 | sc D10-2 | |
1 | 0.4 | 0.4 | 32.6 | 31.1 | 36.2 | 40.2 | 37.9 | 48.0 | 51.0 | 40.6 | 47.0 | 45.9 | 463 | 47.3 |
2 | 0.4 | 0.4 | 31.5 | 30.1 | 36.3 | 40.8 | 37.2 | 46.7 | 50.8 | 39.0 | 46.5 | 44.6 | 46.7 | 47.3 |
3 | 0.4 | 0.4 | 31.5 | 31.1 | 35.5 | 40.8 | 37.0 | 45.7 | 51.0 | 38.8 | 46.2 | 44.1 | 46.0 | 46.2 |
4 | 0.4 | 0.4 | 31.1 | 31.3 | 35.5 | 40.4 | 37.0 | 46.0 | 49.5 | 38.8 | 46.6 | 45.3 | 45.6 | 46.2 |
5 | 0.4 | 0.4 | 31.2 | 29.9 | 35.5 | 39.7 | 35.4 | 45.7 | 50.3 | 38.6 | 46.3 | 43.7 | 46.4 | 46.4 |
6 | 0.3 | 0.4 | 31.0 | 29.8 | 35.4 | 40.2 | 36.0 | 44.7 | 50.9 | 39.0 | 45.7 | 44.2 | 44.4 | 44.8 |
7 | 0.4 | 0.4 | 30.7 | 31.2 | 34.2 | 39.6 | 35.1 | 45.5 | 50.9 | 38.6 | 45.8 | 43.5 | 45.5 | 45.7 |
8 | 0.4 | 0.4 | 32.0 | 29.4 | 34.9 | 40.8 | 35.5 | 45.4 | 50.4 | 37.7 | 45.0 | 43.6 | 46.1 | 44.5 |
9 | 0.4 | 0.3 | 31.0 | 29.6 | 34.3 | 38.9 | 35.6 | 45.3 | 51.3 | 37.1 | 45.7 | 43.4 | 44.8 | 45.1 |
平均值 | 0.4 | 0.4 | 31.4 | 30.4 | 35.3 | 40.1 | 36.3 | 45.9 | 50.7 | 38.7 | 46.1 | 44.2 | 45.7 | 45.9 |
在野生型小鼠中静脉内或皮下注射sNPP1蛋白变体(5mg/kg)显示出PPi浓度高于正常血浆水平的增加,如图5中示出的。图5阐释了在sNPP1-Fc或sNPP1-Fc-D10静脉内(注射后1小时)和皮下(注射后4小时)施用之后野生型小鼠的血液中的焦磷酸盐水平
实施例II
在21天的时间段内,每隔一天用媒介物或6mg/kg sNPP1-Fc-D10皮下处理Enpp1(-/-)敲除的小鼠。示出了雄性和雌性的主动脉钙水平。图6示出了用sNPP1-Fc-D10处理有效预防Enpp1(-/-)小鼠中的主动脉钙化。
实施例III
用6mg/kg sNPP1-Fc-D10静脉内处理Enpp1(-/-)敲除的小鼠,以确定血液PPi和酶促活性水平。如图7中示出的,在0小时、4小时、24小时、48小时和72小时的时间点收集血浆,并且分析其NPP1活性(虚线)和PPi水平(实线)。野生型PPi水平被确定为2.18μM(数据未示出)。从顶部至底部的虚线显示野生型、杂合Enpp1(+/-)和纯合Enpp1(-/-)小鼠的PPi水平(Li等,2013)。sNPP1-Fc的谱与sNPP1-Fc-D10的相似。
实施例IV
将野生型和Enpp1asj小鼠在出生时开始置于高磷、低镁饮食。在14天龄开始每隔一天皮下给药媒介物或sNPP1-Fc(5mg/kg)。卡普兰-迈耶存活曲线显示,>50%的asj小鼠在6周之前死亡,且所有动物到9周时均死亡。相比之下,50%的sNPP1-Fc处理的动物在过去的7周存活,并且在9周时仍然活着。图8阐释了与媒介物处理的小鼠相比用5mg/kg sNPP1-Fc处理的Enpp1asj纯合雄性小鼠的增加的存活率。
实施例V
将野生型和Enpp1asj小鼠在出生时开始置于高磷、低镁饮食,并且在14天龄开始每隔一天用媒介物或sNPP1-Fc(5mg/kg)进行皮下处理,以确定生长速率。如图9A和9B中示出的,从两至九周龄绘制野生型(实线)和Enpp1asj(圆)小鼠的体重增加百分比。图9A和9B阐释了与媒介物处理的小鼠相比,用5mg/kg sNPP1-Fc处理的Enpp1asj雄性小鼠的增加的体重增加百分比。媒介物组中的所有Enpp1asj动物在9周时均死亡(空心圆)(上图)。相比之下,在9周结束时,sNPP1-Fc处理组中的5只Enpp1asj小鼠活着(实心圆)且5只死亡(空心圆)。图10A-10C阐释了野生型(图10A,顶部)、媒介物处理的Enpp1asj(图10B,中部)、sNPP1-Fc处理的(5mg/Kg)Enpp1asj(图10C,顶部)小鼠的照片。
实施例VI
在野生型和Enpp1asj雄性小鼠中测量FGF-23(成纤维细胞生长因子23),磷酸盐代谢的生物标志物。将野生型和Enpp1asj小鼠在出生时开始置于高磷、低镁饮食(TD.00442,Harlan)。在18天龄开始每隔一天皮下给药媒介物或sNPP1-Fc-D10(5mg/kg)。将所有血清在给药24小时之后收集,并使用小鼠FGF-23ELISA试剂盒(Kainos Laboratories Inc.,Tokyo,Japan)进行分析。在Enpp1+/+-媒介物(黑色实线)、Enpp1asj/asj-媒介物(黑色点线)、和Enpp1asj/asj–sNPP1-Fc-D10(灰色实线)小鼠中FGF-23水平在开始处理前在基线(第0天),以及和处理过程期间被测量。
在疾病进展过程期间(到第9天[27天龄]),Enpp1asj/asj小鼠中FGF-23水平升高。然而,到处理的第17天与媒介物处理组相比,用5mg/kg的sNPP1-Fc-D10处理的Enpp1asj/asj小鼠显示出降低的FGF-23水平。*,p<0.05,通过单因素ANOVA或学生t检验。图11阐释了媒介物处理的Enpp1asj(中部)、sNPP1-Fc处理的(5mg/Kg)Enpp1asj(底部)小鼠的成纤维细胞生长因子的水平。
实施例VII体外和体内活性
重组sNPP1-Fc-D10在体外将ATP完全水解为PPi,而不将PPi水解为正磷酸盐,如图13A中示出的。
血浆中的酶活性示于图13B中。在野生型小鼠的血浆中存在显著的活性,其中在10分钟内将略多于三分之一的ATP转化为PPi,相应于7.6±1.0nmol/h/ml的活性。剩余的经由核苷酸三磷酸酶转化为正磷酸盐。来自Enpp1-/-小鼠的血浆基本上不含NPP1,其中少量的PPi代表PPi污染[32P]ATP。在静脉内注射NPP1(5mg/kg)之后2小时,活性显著增加至10.3±0.3nmol/h/ml,并且这伴随着血浆PPi从0.07±0.02增加至1.00±0.14uM,相比之下在野生型小鼠中水平为2.39±0.37uM。
NPP1活性在来自野生型或Enpp1-/-小鼠的主动脉中未被检测到,并且在注射NPP1之后未增加,如图13C中示出的。在施用重组NPP1之后,在肝脏中也未检测到活性。
在将5mg/kg皮下注射到Enpp1-/-小鼠中之后的血浆NPP1活性和PPi浓度的时程示于图14中。NPP1活性和PPi浓度在注射之后12小时达到峰值,水平分别为野生型同窝小鼠中的那些水平的195%和41%。水平迅速降低,并且在24小时之后是基本不可检测到的。
皮下注射sNPP1-Fc-D10(5mg/kg)显示了血浆PPi水平和血浆NPP1活性之间的相关性,如图15中示出的。血浆PPi与血浆NPP1的相关性表明PPi在循环中产生。这通过将新鲜人类血液与重组NPP1孵育,并且然后测量血浆中的PPi来检查。使用人类血液是因为可从小鼠获得有限量的血液。计算添加至血液中的NPP1的量,以产生与在小鼠中注射之后实现的水平相似的水平。
图16A阐释了当添加至全血2小时而不是当添加至单独的血浆时,重组NPP1的施用增加血浆PPi,这表明了细胞要求。为了检查红细胞对比于其他细胞的作用,将血液离心并取出血浆,有或没有血沉棕黄层剩余。然后添加HEPES缓冲盐水以恢复原使的血细胞比容。如图16B中示出的,产生仅在保留血沉棕黄层时发生,表明要求白细胞或血小板而不是红细胞。在HEPES缓冲盐水中孵育分离的白细胞或血小板表明,仅仅在白细胞中,出现了响应于外源NPP1的释放的或产生的PPi而非合成。
实施例VIII治疗模型
A.NPP1缺陷
将成年的Enpp1-/-小鼠置于高磷酸盐饮食中,并且如图17中示出的,每隔一天用媒介物或sNPP1-Fc-D10(6mg/kg)皮下处理,以确定重组NPP1对动脉钙化的影响。将每一只处理的小鼠与接受相同体积的单独的媒介物的相同性别和相似年龄的小鼠配对。在18天之后,媒介物处理的小鼠中平均主动脉钙含量为61±30nmol/mg,且用重组NPP1处理的小鼠中的为8.8±1.0nmol/mg(p=0.016)。野生型同窝小鼠中的含量为6.3±3.4nmol/mg(n=16)。在8个对照主动脉(80±37nmol/mg)中的6个中以及在仅一个处理的主动脉(15nmol/mg)中含量升高(高于野生型同窝小鼠2个标准差)。在对照主动脉中存在钙化的对中,这代表91%±2%的钙化减少。
为了确定在多次注射之后是否存在NPP1随时间的任何积累,在处死(注射之后24小时)时测量血浆NPP1活性和PPi,且两者均是不可检测的。在单独的Enpp1-/-小鼠组中,在每隔一天3次注射重组NPP1之后,主动脉NPP1活性是不可检测到的。
B.慢性肾脏疾病
该实施例公开了在尿毒症大鼠模型中sNPP1-Fc-D10治疗慢性肾脏疾病(CKD)的疗效。为了确定重组NPP1对患有肾衰竭的尿毒症大鼠中动脉钙化的影响,给尿毒症大鼠喂食高腺嘌呤饮食,并且每周5个剂量用对照或sNPP1-Fc-D10(5mg/kg)进行皮下注射,如图18中示出的。在治疗21天之后,对照处理的大鼠中平均主动脉钙含量为25.7±4.9nmol/mg,且用重组NPP1处理的大鼠中的为7.0±1.0nmol/mg(p=0.0068)。正常主动脉钙含量为5nmol/mg。
实施例VII和VIII证明了sNPP1的活性和sNPP1在外核苷酸焦磷酸酶焦磷酸化酶缺陷和慢性肾脏疾病模型中的有效用途。这些实施例表明PPi的瞬时增加足以有效治疗血管钙化和NPP1缺陷。
等同物
尽管已经参考本发明的示例性实施方案具体示出和描述了本发明,但是本领域技术人员将会理解,可以在其中进行形式和细节的多种改变而不偏离所附权利要求书所涵盖的本发明的范围。
序列表
<110> 阿雷克森制药公司
<120> 治疗组织钙化的方法
<130> 081245-0208
<140>
<141>
<150> 62/249,781
<151> 2015-11-02
<150> 62/094,943
<151> 2014-12-19
<160> 19
<170> PatentIn version 3.5
<210> 1
<211> 925
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Met Glu Arg Asp Gly Cys Ala Gly Gly Gly Ser Arg Gly Gly Glu Gly
1 5 10 15
Gly Arg Ala Pro Arg Glu Gly Pro Ala Gly Asn Gly Arg Asp Arg Gly
20 25 30
Arg Ser His Ala Ala Glu Ala Pro Gly Asp Pro Gln Ala Ala Ala Ser
35 40 45
Leu Leu Ala Pro Met Asp Val Gly Glu Glu Pro Leu Glu Lys Ala Ala
50 55 60
Arg Ala Arg Thr Ala Lys Asp Pro Asn Thr Tyr Lys Val Leu Ser Leu
65 70 75 80
Val Leu Ser Val Cys Val Leu Thr Thr Ile Leu Gly Cys Ile Phe Gly
85 90 95
Leu Lys Pro Ser Cys Ala Lys Glu Val Lys Ser Cys Lys Gly Arg Cys
100 105 110
Phe Glu Arg Thr Phe Gly Asn Cys Arg Cys Asp Ala Ala Cys Val Glu
115 120 125
Leu Gly Asn Cys Cys Leu Asp Tyr Gln Glu Thr Cys Ile Glu Pro Glu
130 135 140
His Ile Trp Thr Cys Asn Lys Phe Arg Cys Gly Glu Lys Arg Leu Thr
145 150 155 160
Arg Ser Leu Cys Ala Cys Ser Asp Asp Cys Lys Asp Lys Gly Asp Cys
165 170 175
Cys Ile Asn Tyr Ser Ser Val Cys Gln Gly Glu Lys Ser Trp Val Glu
180 185 190
Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln Cys Pro Ala Gly Phe Glu
195 200 205
Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr
210 215 220
Leu His Thr Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys Lys
225 230 235 240
Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro Thr Lys Thr
245 250 255
Phe Pro Asn His Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His
260 265 270
Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe
275 280 285
Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu
290 295 300
Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe
305 310 315 320
Phe Trp Pro Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile
325 330 335
Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala
340 345 350
Val Leu Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe Tyr
355 360 365
Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser Gly His Ser Tyr Gly Pro
370 375 380
Val Ser Ser Glu Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val
385 390 395 400
Gly Met Leu Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu
405 410 415
Asn Leu Ile Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys Lys
420 425 430
Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys
435 440 445
Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp
450 455 460
Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys
465 470 475 480
Arg Glu Pro Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe Leu Pro
485 490 495
Lys Arg Leu His Phe Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe
500 505 510
Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys
515 520 525
Tyr Cys Gly Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met
530 535 540
Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly Ile Glu
545 550 555 560
Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu
565 570 575
Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asn
580 585 590
His Leu Leu Lys Asn Pro Val Tyr Thr Pro Lys His Pro Lys Glu Val
595 600 605
His Pro Leu Val Gln Cys Pro Phe Thr Arg Asn Pro Arg Asp Asn Leu
610 615 620
Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr
625 630 635 640
Gln Phe Asn Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr
645 650 655
Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys
660 665 670
Leu Leu Ser Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile Leu
675 680 685
Met Pro Leu Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp Ser Phe Ser
690 695 700
Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln Asp Phe Arg Ile Pro Leu
705 710 715 720
Ser Pro Val His Lys Cys Ser Phe Tyr Lys Asn Asn Thr Lys Val Ser
725 730 735
Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile
740 745 750
Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser
755 760 765
Phe Gln Val Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr
770 775 780
Ala Glu Glu Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe Asp
785 790 795 800
Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln Lys
805 810 815
Arg Arg Val Ile Arg Asn Gln Glu Ile Leu Ile Pro Thr His Phe Phe
820 825 830
Ile Val Leu Thr Ser Cys Lys Asp Thr Ser Gln Thr Pro Leu His Cys
835 840 845
Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu Pro His Arg Thr Asp Asn
850 855 860
Ser Glu Ser Cys Val His Gly Lys His Asp Ser Ser Trp Val Glu Glu
865 870 875 880
Leu Leu Met Leu His Arg Ala Arg Ile Thr Asp Val Glu His Ile Thr
885 890 895
Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser Asp Ile Leu
900 905 910
Lys Leu Lys Thr His Leu Pro Thr Phe Ser Gln Glu Asp
915 920 925
<210> 2
<211> 827
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的
多肽
<400> 2
Pro Ser Cys Ala Lys Glu Val Lys Ser Cys Lys Gly Arg Cys Phe Glu
1 5 10 15
Arg Thr Phe Gly Asn Cys Arg Cys Asp Ala Ala Cys Val Glu Leu Gly
20 25 30
Asn Cys Cys Leu Asp Tyr Gln Glu Thr Cys Ile Glu Pro Glu His Ile
35 40 45
Trp Thr Cys Asn Lys Phe Arg Cys Gly Glu Lys Arg Leu Thr Arg Ser
50 55 60
Leu Cys Ala Cys Ser Asp Asp Cys Lys Asp Lys Gly Asp Cys Cys Ile
65 70 75 80
Asn Tyr Ser Ser Val Cys Gln Gly Glu Lys Ser Trp Val Glu Glu Pro
85 90 95
Cys Glu Ser Ile Asn Glu Pro Gln Cys Pro Ala Gly Phe Glu Thr Pro
100 105 110
Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr Leu His
115 120 125
Thr Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys Lys Cys Gly
130 135 140
Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro Thr Lys Thr Phe Pro
145 150 155 160
Asn His Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His Gly Ile
165 170 175
Ile Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe Ser Leu
180 185 190
Lys Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu Pro Ile
195 200 205
Trp Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe Phe Trp
210 215 220
Pro Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile Tyr Lys
225 230 235 240
Met Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala Val Leu
245 250 255
Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe Tyr Thr Leu
260 265 270
Tyr Leu Glu Glu Pro Asp Ser Ser Gly His Ser Tyr Gly Pro Val Ser
275 280 285
Ser Glu Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val Gly Met
290 295 300
Leu Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu Asn Leu
305 310 315 320
Ile Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys Lys Lys Tyr
325 330 335
Ile Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys Val Ile
340 345 350
Tyr Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp Lys Tyr
355 360 365
Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys Arg Glu
370 375 380
Pro Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe Leu Pro Lys Arg
385 390 395 400
Leu His Phe Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe Tyr Leu
405 410 415
Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys Tyr Cys
420 425 430
Gly Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met Gln Ala
435 440 445
Leu Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly Ile Glu Ala Asp
450 455 460
Thr Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu Leu Asn
465 470 475 480
Leu Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asn His Leu
485 490 495
Leu Lys Asn Pro Val Tyr Thr Pro Lys His Pro Lys Glu Val His Pro
500 505 510
Leu Val Gln Cys Pro Phe Thr Arg Asn Pro Arg Asp Asn Leu Gly Cys
515 520 525
Ser Cys Asn Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr Gln Phe
530 535 540
Asn Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr Leu Pro
545 550 555 560
Tyr Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys Leu Leu
565 570 575
Ser Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile Leu Met Pro
580 585 590
Leu Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp Ser Phe Ser Thr Glu
595 600 605
Asp Phe Ser Asn Cys Leu Tyr Gln Asp Phe Arg Ile Pro Leu Ser Pro
610 615 620
Val His Lys Cys Ser Phe Tyr Lys Asn Asn Thr Lys Val Ser Tyr Gly
625 630 635 640
Phe Leu Ser Pro Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile Tyr Ser
645 650 655
Glu Ala Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser Phe Gln
660 665 670
Val Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr Ala Glu
675 680 685
Glu Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe Asp Phe Asp
690 695 700
Tyr Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln Lys Arg Arg
705 710 715 720
Val Ile Arg Asn Gln Glu Ile Leu Ile Pro Thr His Phe Phe Ile Val
725 730 735
Leu Thr Ser Cys Lys Asp Thr Ser Gln Thr Pro Leu His Cys Glu Asn
740 745 750
Leu Asp Thr Leu Ala Phe Ile Leu Pro His Arg Thr Asp Asn Ser Glu
755 760 765
Ser Cys Val His Gly Lys His Asp Ser Ser Trp Val Glu Glu Leu Leu
770 775 780
Met Leu His Arg Ala Arg Ile Thr Asp Val Glu His Ile Thr Gly Leu
785 790 795 800
Ser Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser Asp Ile Leu Lys Leu
805 810 815
Lys Thr His Leu Pro Thr Phe Ser Gln Glu Asp
820 825
<210> 3
<211> 1058
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述: 合成的
多肽
<400> 3
Pro Ser Cys Ala Lys Glu Val Lys Ser Cys Lys Gly Arg Cys Phe Glu
1 5 10 15
Arg Thr Phe Gly Asn Cys Arg Cys Asp Ala Ala Cys Val Glu Leu Gly
20 25 30
Asn Cys Cys Leu Asp Tyr Gln Glu Thr Cys Ile Glu Pro Glu His Ile
35 40 45
Trp Thr Cys Asn Lys Phe Arg Cys Gly Glu Lys Arg Leu Thr Arg Ser
50 55 60
Leu Cys Ala Cys Ser Asp Asp Cys Lys Asp Lys Gly Asp Cys Cys Ile
65 70 75 80
Asn Tyr Ser Ser Val Cys Gln Gly Glu Lys Ser Trp Val Glu Glu Pro
85 90 95
Cys Glu Ser Ile Asn Glu Pro Gln Cys Pro Ala Gly Phe Glu Thr Pro
100 105 110
Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr Leu His
115 120 125
Thr Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys Lys Cys Gly
130 135 140
Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro Thr Lys Thr Phe Pro
145 150 155 160
Asn His Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His Gly Ile
165 170 175
Ile Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe Ser Leu
180 185 190
Lys Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu Pro Ile
195 200 205
Trp Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe Phe Trp
210 215 220
Pro Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile Tyr Lys
225 230 235 240
Met Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala Val Leu
245 250 255
Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe Tyr Thr Leu
260 265 270
Tyr Leu Glu Glu Pro Asp Ser Ser Gly His Ser Tyr Gly Pro Val Ser
275 280 285
Ser Glu Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val Gly Met
290 295 300
Leu Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu Asn Leu
305 310 315 320
Ile Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys Lys Lys Tyr
325 330 335
Ile Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys Val Ile
340 345 350
Tyr Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp Lys Tyr
355 360 365
Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys Arg Glu
370 375 380
Pro Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe Leu Pro Lys Arg
385 390 395 400
Leu His Phe Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe Tyr Leu
405 410 415
Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys Tyr Cys
420 425 430
Gly Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met Gln Ala
435 440 445
Leu Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly Ile Glu Ala Asp
450 455 460
Thr Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu Leu Asn
465 470 475 480
Leu Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asn His Leu
485 490 495
Leu Lys Asn Pro Val Tyr Thr Pro Lys His Pro Lys Glu Val His Pro
500 505 510
Leu Val Gln Cys Pro Phe Thr Arg Asn Pro Arg Asp Asn Leu Gly Cys
515 520 525
Ser Cys Asn Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr Gln Phe
530 535 540
Asn Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr Leu Pro
545 550 555 560
Tyr Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys Leu Leu
565 570 575
Ser Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile Leu Met Pro
580 585 590
Leu Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp Ser Phe Ser Thr Glu
595 600 605
Asp Phe Ser Asn Cys Leu Tyr Gln Asp Phe Arg Ile Pro Leu Ser Pro
610 615 620
Val His Lys Cys Ser Phe Tyr Lys Asn Asn Thr Lys Val Ser Tyr Gly
625 630 635 640
Phe Leu Ser Pro Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile Tyr Ser
645 650 655
Glu Ala Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser Phe Gln
660 665 670
Val Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr Ala Glu
675 680 685
Glu Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe Asp Phe Asp
690 695 700
Tyr Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln Lys Arg Arg
705 710 715 720
Val Ile Arg Asn Gln Glu Ile Leu Ile Pro Thr His Phe Phe Ile Val
725 730 735
Leu Thr Ser Cys Lys Asp Thr Ser Gln Thr Pro Leu His Cys Glu Asn
740 745 750
Leu Asp Thr Leu Ala Phe Ile Leu Pro His Arg Thr Asp Asn Ser Glu
755 760 765
Ser Cys Val His Gly Lys His Asp Ser Ser Trp Val Glu Glu Leu Leu
770 775 780
Met Leu His Arg Ala Arg Ile Thr Asp Val Glu His Ile Thr Gly Leu
785 790 795 800
Ser Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser Asp Ile Leu Lys Leu
805 810 815
Lys Thr His Leu Pro Thr Phe Ser Gln Glu Asp Pro Lys Ser Cys Asp
820 825 830
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
835 840 845
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
850 855 860
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
865 870 875 880
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
885 890 895
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
900 905 910
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
915 920 925
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
930 935 940
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
945 950 955 960
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
965 970 975
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
980 985 990
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
995 1000 1005
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
1010 1015 1020
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
1025 1030 1035
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
1040 1045 1050
Leu Ser Pro Gly Lys
1055
<210> 4
<211> 1068
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 4
Pro Ser Cys Ala Lys Glu Val Lys Ser Cys Lys Gly Arg Cys Phe Glu
1 5 10 15
Arg Thr Phe Gly Asn Cys Arg Cys Asp Ala Ala Cys Val Glu Leu Gly
20 25 30
Asn Cys Cys Leu Asp Tyr Gln Glu Thr Cys Ile Glu Pro Glu His Ile
35 40 45
Trp Thr Cys Asn Lys Phe Arg Cys Gly Glu Lys Arg Leu Thr Arg Ser
50 55 60
Leu Cys Ala Cys Ser Asp Asp Cys Lys Asp Lys Gly Asp Cys Cys Ile
65 70 75 80
Asn Tyr Ser Ser Val Cys Gln Gly Glu Lys Ser Trp Val Glu Glu Pro
85 90 95
Cys Glu Ser Ile Asn Glu Pro Gln Cys Pro Ala Gly Phe Glu Thr Pro
100 105 110
Pro Thr Leu Leu Phe Ser Leu Asp Gly Phe Arg Ala Glu Tyr Leu His
115 120 125
Thr Trp Gly Gly Leu Leu Pro Val Ile Ser Lys Leu Lys Lys Cys Gly
130 135 140
Thr Tyr Thr Lys Asn Met Arg Pro Val Tyr Pro Thr Lys Thr Phe Pro
145 150 155 160
Asn His Tyr Ser Ile Val Thr Gly Leu Tyr Pro Glu Ser His Gly Ile
165 170 175
Ile Asp Asn Lys Met Tyr Asp Pro Lys Met Asn Ala Ser Phe Ser Leu
180 185 190
Lys Ser Lys Glu Lys Phe Asn Pro Glu Trp Tyr Lys Gly Glu Pro Ile
195 200 205
Trp Val Thr Ala Lys Tyr Gln Gly Leu Lys Ser Gly Thr Phe Phe Trp
210 215 220
Pro Gly Ser Asp Val Glu Ile Asn Gly Ile Phe Pro Asp Ile Tyr Lys
225 230 235 240
Met Tyr Asn Gly Ser Val Pro Phe Glu Glu Arg Ile Leu Ala Val Leu
245 250 255
Gln Trp Leu Gln Leu Pro Lys Asp Glu Arg Pro His Phe Tyr Thr Leu
260 265 270
Tyr Leu Glu Glu Pro Asp Ser Ser Gly His Ser Tyr Gly Pro Val Ser
275 280 285
Ser Glu Val Ile Lys Ala Leu Gln Arg Val Asp Gly Met Val Gly Met
290 295 300
Leu Met Asp Gly Leu Lys Glu Leu Asn Leu His Arg Cys Leu Asn Leu
305 310 315 320
Ile Leu Ile Ser Asp His Gly Met Glu Gln Gly Ser Cys Lys Lys Tyr
325 330 335
Ile Tyr Leu Asn Lys Tyr Leu Gly Asp Val Lys Asn Ile Lys Val Ile
340 345 350
Tyr Gly Pro Ala Ala Arg Leu Arg Pro Ser Asp Val Pro Asp Lys Tyr
355 360 365
Tyr Ser Phe Asn Tyr Glu Gly Ile Ala Arg Asn Leu Ser Cys Arg Glu
370 375 380
Pro Asn Gln His Phe Lys Pro Tyr Leu Lys His Phe Leu Pro Lys Arg
385 390 395 400
Leu His Phe Ala Lys Ser Asp Arg Ile Glu Pro Leu Thr Phe Tyr Leu
405 410 415
Asp Pro Gln Trp Gln Leu Ala Leu Asn Pro Ser Glu Arg Lys Tyr Cys
420 425 430
Gly Ser Gly Phe His Gly Ser Asp Asn Val Phe Ser Asn Met Gln Ala
435 440 445
Leu Phe Val Gly Tyr Gly Pro Gly Phe Lys His Gly Ile Glu Ala Asp
450 455 460
Thr Phe Glu Asn Ile Glu Val Tyr Asn Leu Met Cys Asp Leu Leu Asn
465 470 475 480
Leu Thr Pro Ala Pro Asn Asn Gly Thr His Gly Ser Leu Asn His Leu
485 490 495
Leu Lys Asn Pro Val Tyr Thr Pro Lys His Pro Lys Glu Val His Pro
500 505 510
Leu Val Gln Cys Pro Phe Thr Arg Asn Pro Arg Asp Asn Leu Gly Cys
515 520 525
Ser Cys Asn Pro Ser Ile Leu Pro Ile Glu Asp Phe Gln Thr Gln Phe
530 535 540
Asn Leu Thr Val Ala Glu Glu Lys Ile Ile Lys His Glu Thr Leu Pro
545 550 555 560
Tyr Gly Arg Pro Arg Val Leu Gln Lys Glu Asn Thr Ile Cys Leu Leu
565 570 575
Ser Gln His Gln Phe Met Ser Gly Tyr Ser Gln Asp Ile Leu Met Pro
580 585 590
Leu Trp Thr Ser Tyr Thr Val Asp Arg Asn Asp Ser Phe Ser Thr Glu
595 600 605
Asp Phe Ser Asn Cys Leu Tyr Gln Asp Phe Arg Ile Pro Leu Ser Pro
610 615 620
Val His Lys Cys Ser Phe Tyr Lys Asn Asn Thr Lys Val Ser Tyr Gly
625 630 635 640
Phe Leu Ser Pro Pro Gln Leu Asn Lys Asn Ser Ser Gly Ile Tyr Ser
645 650 655
Glu Ala Leu Leu Thr Thr Asn Ile Val Pro Met Tyr Gln Ser Phe Gln
660 665 670
Val Ile Trp Arg Tyr Phe His Asp Thr Leu Leu Arg Lys Tyr Ala Glu
675 680 685
Glu Arg Asn Gly Val Asn Val Val Ser Gly Pro Val Phe Asp Phe Asp
690 695 700
Tyr Asp Gly Arg Cys Asp Ser Leu Glu Asn Leu Arg Gln Lys Arg Arg
705 710 715 720
Val Ile Arg Asn Gln Glu Ile Leu Ile Pro Thr His Phe Phe Ile Val
725 730 735
Leu Thr Ser Cys Lys Asp Thr Ser Gln Thr Pro Leu His Cys Glu Asn
740 745 750
Leu Asp Thr Leu Ala Phe Ile Leu Pro His Arg Thr Asp Asn Ser Glu
755 760 765
Ser Cys Val His Gly Lys His Asp Ser Ser Trp Val Glu Glu Leu Leu
770 775 780
Met Leu His Arg Ala Arg Ile Thr Asp Val Glu His Ile Thr Gly Leu
785 790 795 800
Ser Phe Tyr Gln Gln Arg Lys Glu Pro Val Ser Asp Ile Leu Lys Leu
805 810 815
Lys Thr His Leu Pro Thr Phe Ser Gln Glu Asp Pro Lys Ser Cys Asp
820 825 830
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala
835 840 845
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
850 855 860
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
865 870 875 880
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
885 890 895
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
900 905 910
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
915 920 925
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
930 935 940
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
945 950 955 960
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
965 970 975
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
980 985 990
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
995 1000 1005
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
1010 1015 1020
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
1025 1030 1035
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
1040 1045 1050
Leu Ser Pro Gly Lys Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp
1055 1060 1065
<210> 5
<211> 819
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 5
Ser Cys Lys Gly Arg Cys Phe Glu Arg Thr Phe Gly Asn Cys Arg Cys
1 5 10 15
Asp Ala Ala Cys Val Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln Glu
20 25 30
Thr Cys Ile Glu Pro Glu His Ile Trp Thr Cys Asn Lys Phe Arg Cys
35 40 45
Gly Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp Cys
50 55 60
Lys Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln Gly
65 70 75 80
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
85 90 95
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
100 105 110
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
115 120 125
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
130 135 140
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
145 150 155 160
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
165 170 175
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
180 185 190
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
195 200 205
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
210 215 220
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
225 230 235 240
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
245 250 255
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
260 265 270
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
275 280 285
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
290 295 300
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
305 310 315 320
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
325 330 335
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
340 345 350
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
355 360 365
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
370 375 380
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
385 390 395 400
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
405 410 415
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
420 425 430
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
435 440 445
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
450 455 460
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
465 470 475 480
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
485 490 495
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
500 505 510
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
515 520 525
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
530 535 540
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
545 550 555 560
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
565 570 575
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
580 585 590
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
595 600 605
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
610 615 620
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
625 630 635 640
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
645 650 655
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
660 665 670
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
675 680 685
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
690 695 700
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
705 710 715 720
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
725 730 735
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
740 745 750
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
755 760 765
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
770 775 780
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
785 790 795 800
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
805 810 815
Gln Glu Asp
<210> 6
<211> 739
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 6
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
1 5 10 15
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
20 25 30
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
35 40 45
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
50 55 60
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
65 70 75 80
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
85 90 95
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
100 105 110
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
115 120 125
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
130 135 140
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
145 150 155 160
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
165 170 175
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
180 185 190
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
195 200 205
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
210 215 220
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
225 230 235 240
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
245 250 255
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
260 265 270
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
275 280 285
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
290 295 300
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
305 310 315 320
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
325 330 335
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
340 345 350
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
355 360 365
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
370 375 380
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
385 390 395 400
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
405 410 415
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
420 425 430
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
435 440 445
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
450 455 460
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
465 470 475 480
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
485 490 495
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
500 505 510
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
515 520 525
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
530 535 540
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
545 550 555 560
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
565 570 575
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
580 585 590
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
595 600 605
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
610 615 620
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
625 630 635 640
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
645 650 655
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
660 665 670
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
675 680 685
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
690 695 700
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
705 710 715 720
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
725 730 735
Gln Glu Asp
<210> 7
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 7
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 8
<211> 227
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 8
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 9
<211> 1051
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 9
Ser Cys Lys Gly Arg Cys Phe Glu Arg Thr Phe Gly Asn Cys Arg Cys
1 5 10 15
Asp Ala Ala Cys Val Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln Glu
20 25 30
Thr Cys Ile Glu Pro Glu His Ile Trp Thr Cys Asn Lys Phe Arg Cys
35 40 45
Gly Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp Cys
50 55 60
Lys Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln Gly
65 70 75 80
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
85 90 95
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
100 105 110
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
115 120 125
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
130 135 140
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
145 150 155 160
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
165 170 175
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
180 185 190
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
195 200 205
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
210 215 220
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
225 230 235 240
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
245 250 255
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
260 265 270
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
275 280 285
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
290 295 300
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
305 310 315 320
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
325 330 335
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
340 345 350
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
355 360 365
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
370 375 380
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
385 390 395 400
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
405 410 415
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
420 425 430
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
435 440 445
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
450 455 460
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
465 470 475 480
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
485 490 495
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
500 505 510
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
515 520 525
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
530 535 540
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
545 550 555 560
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
565 570 575
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
580 585 590
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
595 600 605
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
610 615 620
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
625 630 635 640
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
645 650 655
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
660 665 670
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
675 680 685
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
690 695 700
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
705 710 715 720
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
725 730 735
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
740 745 750
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
755 760 765
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
770 775 780
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
785 790 795 800
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
805 810 815
Gln Glu Asp Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
820 825 830
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
835 840 845
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
850 855 860
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
865 870 875 880
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
885 890 895
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
900 905 910
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
915 920 925
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
930 935 940
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
945 950 955 960
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
965 970 975
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
980 985 990
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
995 1000 1005
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
1010 1015 1020
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
1025 1030 1035
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1040 1045 1050
<210> 10
<211> 1046
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 10
Ser Cys Lys Gly Arg Cys Phe Glu Arg Thr Phe Gly Asn Cys Arg Cys
1 5 10 15
Asp Ala Ala Cys Val Glu Leu Gly Asn Cys Cys Leu Asp Tyr Gln Glu
20 25 30
Thr Cys Ile Glu Pro Glu His Ile Trp Thr Cys Asn Lys Phe Arg Cys
35 40 45
Gly Glu Lys Arg Leu Thr Arg Ser Leu Cys Ala Cys Ser Asp Asp Cys
50 55 60
Lys Asp Lys Gly Asp Cys Cys Ile Asn Tyr Ser Ser Val Cys Gln Gly
65 70 75 80
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
85 90 95
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
100 105 110
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
115 120 125
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
130 135 140
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
145 150 155 160
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
165 170 175
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
180 185 190
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
195 200 205
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
210 215 220
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
225 230 235 240
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
245 250 255
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
260 265 270
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
275 280 285
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
290 295 300
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
305 310 315 320
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
325 330 335
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
340 345 350
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
355 360 365
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
370 375 380
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
385 390 395 400
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
405 410 415
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
420 425 430
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
435 440 445
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
450 455 460
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
465 470 475 480
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
485 490 495
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
500 505 510
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
515 520 525
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
530 535 540
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
545 550 555 560
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
565 570 575
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
580 585 590
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
595 600 605
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
610 615 620
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
625 630 635 640
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
645 650 655
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
660 665 670
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
675 680 685
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
690 695 700
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
705 710 715 720
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
725 730 735
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
740 745 750
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
755 760 765
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
770 775 780
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
785 790 795 800
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
805 810 815
Gln Glu Asp Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
820 825 830
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
835 840 845
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
850 855 860
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
865 870 875 880
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
885 890 895
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
900 905 910
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
915 920 925
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
930 935 940
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
945 950 955 960
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
965 970 975
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
980 985 990
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
995 1000 1005
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
1010 1015 1020
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
1025 1030 1035
Ser Leu Ser Leu Ser Pro Gly Lys
1040 1045
<210> 11
<211> 971
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 11
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
1 5 10 15
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
20 25 30
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
35 40 45
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
50 55 60
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
65 70 75 80
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
85 90 95
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
100 105 110
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
115 120 125
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
130 135 140
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
145 150 155 160
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
165 170 175
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
180 185 190
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
195 200 205
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
210 215 220
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
225 230 235 240
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
245 250 255
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
260 265 270
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
275 280 285
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
290 295 300
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
305 310 315 320
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
325 330 335
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
340 345 350
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
355 360 365
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
370 375 380
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
385 390 395 400
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
405 410 415
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
420 425 430
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
435 440 445
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
450 455 460
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
465 470 475 480
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
485 490 495
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
500 505 510
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
515 520 525
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
530 535 540
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
545 550 555 560
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
565 570 575
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
580 585 590
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
595 600 605
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
610 615 620
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
625 630 635 640
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
645 650 655
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
660 665 670
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
675 680 685
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
690 695 700
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
705 710 715 720
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
725 730 735
Gln Glu Asp Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
740 745 750
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
755 760 765
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
770 775 780
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
785 790 795 800
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
805 810 815
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
820 825 830
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
835 840 845
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
850 855 860
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
865 870 875 880
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
885 890 895
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
900 905 910
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
915 920 925
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
930 935 940
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
945 950 955 960
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
965 970
<210> 12
<211> 966
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<400> 12
Glu Lys Ser Trp Val Glu Glu Pro Cys Glu Ser Ile Asn Glu Pro Gln
1 5 10 15
Cys Pro Ala Gly Phe Glu Thr Pro Pro Thr Leu Leu Phe Ser Leu Asp
20 25 30
Gly Phe Arg Ala Glu Tyr Leu His Thr Trp Gly Gly Leu Leu Pro Val
35 40 45
Ile Ser Lys Leu Lys Lys Cys Gly Thr Tyr Thr Lys Asn Met Arg Pro
50 55 60
Val Tyr Pro Thr Lys Thr Phe Pro Asn His Tyr Ser Ile Val Thr Gly
65 70 75 80
Leu Tyr Pro Glu Ser His Gly Ile Ile Asp Asn Lys Met Tyr Asp Pro
85 90 95
Lys Met Asn Ala Ser Phe Ser Leu Lys Ser Lys Glu Lys Phe Asn Pro
100 105 110
Glu Trp Tyr Lys Gly Glu Pro Ile Trp Val Thr Ala Lys Tyr Gln Gly
115 120 125
Leu Lys Ser Gly Thr Phe Phe Trp Pro Gly Ser Asp Val Glu Ile Asn
130 135 140
Gly Ile Phe Pro Asp Ile Tyr Lys Met Tyr Asn Gly Ser Val Pro Phe
145 150 155 160
Glu Glu Arg Ile Leu Ala Val Leu Gln Trp Leu Gln Leu Pro Lys Asp
165 170 175
Glu Arg Pro His Phe Tyr Thr Leu Tyr Leu Glu Glu Pro Asp Ser Ser
180 185 190
Gly His Ser Tyr Gly Pro Val Ser Ser Glu Val Ile Lys Ala Leu Gln
195 200 205
Arg Val Asp Gly Met Val Gly Met Leu Met Asp Gly Leu Lys Glu Leu
210 215 220
Asn Leu His Arg Cys Leu Asn Leu Ile Leu Ile Ser Asp His Gly Met
225 230 235 240
Glu Gln Gly Ser Cys Lys Lys Tyr Ile Tyr Leu Asn Lys Tyr Leu Gly
245 250 255
Asp Val Lys Asn Ile Lys Val Ile Tyr Gly Pro Ala Ala Arg Leu Arg
260 265 270
Pro Ser Asp Val Pro Asp Lys Tyr Tyr Ser Phe Asn Tyr Glu Gly Ile
275 280 285
Ala Arg Asn Leu Ser Cys Arg Glu Pro Asn Gln His Phe Lys Pro Tyr
290 295 300
Leu Lys His Phe Leu Pro Lys Arg Leu His Phe Ala Lys Ser Asp Arg
305 310 315 320
Ile Glu Pro Leu Thr Phe Tyr Leu Asp Pro Gln Trp Gln Leu Ala Leu
325 330 335
Asn Pro Ser Glu Arg Lys Tyr Cys Gly Ser Gly Phe His Gly Ser Asp
340 345 350
Asn Val Phe Ser Asn Met Gln Ala Leu Phe Val Gly Tyr Gly Pro Gly
355 360 365
Phe Lys His Gly Ile Glu Ala Asp Thr Phe Glu Asn Ile Glu Val Tyr
370 375 380
Asn Leu Met Cys Asp Leu Leu Asn Leu Thr Pro Ala Pro Asn Asn Gly
385 390 395 400
Thr His Gly Ser Leu Asn His Leu Leu Lys Asn Pro Val Tyr Thr Pro
405 410 415
Lys His Pro Lys Glu Val His Pro Leu Val Gln Cys Pro Phe Thr Arg
420 425 430
Asn Pro Arg Asp Asn Leu Gly Cys Ser Cys Asn Pro Ser Ile Leu Pro
435 440 445
Ile Glu Asp Phe Gln Thr Gln Phe Asn Leu Thr Val Ala Glu Glu Lys
450 455 460
Ile Ile Lys His Glu Thr Leu Pro Tyr Gly Arg Pro Arg Val Leu Gln
465 470 475 480
Lys Glu Asn Thr Ile Cys Leu Leu Ser Gln His Gln Phe Met Ser Gly
485 490 495
Tyr Ser Gln Asp Ile Leu Met Pro Leu Trp Thr Ser Tyr Thr Val Asp
500 505 510
Arg Asn Asp Ser Phe Ser Thr Glu Asp Phe Ser Asn Cys Leu Tyr Gln
515 520 525
Asp Phe Arg Ile Pro Leu Ser Pro Val His Lys Cys Ser Phe Tyr Lys
530 535 540
Asn Asn Thr Lys Val Ser Tyr Gly Phe Leu Ser Pro Pro Gln Leu Asn
545 550 555 560
Lys Asn Ser Ser Gly Ile Tyr Ser Glu Ala Leu Leu Thr Thr Asn Ile
565 570 575
Val Pro Met Tyr Gln Ser Phe Gln Val Ile Trp Arg Tyr Phe His Asp
580 585 590
Thr Leu Leu Arg Lys Tyr Ala Glu Glu Arg Asn Gly Val Asn Val Val
595 600 605
Ser Gly Pro Val Phe Asp Phe Asp Tyr Asp Gly Arg Cys Asp Ser Leu
610 615 620
Glu Asn Leu Arg Gln Lys Arg Arg Val Ile Arg Asn Gln Glu Ile Leu
625 630 635 640
Ile Pro Thr His Phe Phe Ile Val Leu Thr Ser Cys Lys Asp Thr Ser
645 650 655
Gln Thr Pro Leu His Cys Glu Asn Leu Asp Thr Leu Ala Phe Ile Leu
660 665 670
Pro His Arg Thr Asp Asn Ser Glu Ser Cys Val His Gly Lys His Asp
675 680 685
Ser Ser Trp Val Glu Glu Leu Leu Met Leu His Arg Ala Arg Ile Thr
690 695 700
Asp Val Glu His Ile Thr Gly Leu Ser Phe Tyr Gln Gln Arg Lys Glu
705 710 715 720
Pro Val Ser Asp Ile Leu Lys Leu Lys Thr His Leu Pro Thr Phe Ser
725 730 735
Gln Glu Asp Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
740 745 750
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
755 760 765
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
770 775 780
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
785 790 795 800
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
805 810 815
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
820 825 830
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
835 840 845
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
850 855 860
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
865 870 875 880
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
885 890 895
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
900 905 910
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
915 920 925
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
930 935 940
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
945 950 955 960
Ser Leu Ser Pro Gly Lys
965
<210> 13
<211> 15
<212> PRT
<213> 智人
<400> 13
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 14
<211> 10
<212> PRT
<213> 智人
<400> 14
Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10
<210> 15
<211> 14
<212> PRT
<213> 智人
<400> 15
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10
<210> 16
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
肽
<400> 16
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 17
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
肽
<400> 17
Pro Ser Cys Ala Lys Glu
1 5
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
肽
<400> 18
Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp
1 5 10
<210> 19
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可以包括1-10个重复的"Gly Gly Gly Gly
Ser"单元,其中一些位置可以不存在
<400> 19
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser
50
Claims (59)
1.一种用于降低血管钙化的方法,所述方法包括将两个或更多个剂量的可溶性外核苷酸焦磷酸酶磷酸二酯酶(NPP1)施用至患有低血浆焦磷酸盐(PPi)或高血清磷酸盐(Pi)的受试者,其中每一个剂量包含足以实现所述受试者中血浆PPi的瞬时增加的量的可溶性NPP1,血浆PPi的瞬时增加的特征在于峰值PPi水平为正常血浆PPi水平的至少约40%,并且在施用剂量之后约48小时内回复至基线PPi水平;并且其中剂量之间的时间段为至少2天。
2.如权利要求1所述的方法,其中血浆PPi的瞬时增加的特征在于PPi水平为正常血浆PPi水平的至少约40%。
3.如权利要求1所述的方法,其中血浆PPi的瞬时增加的特征在于PPi水平在正常血浆PPi水平的约40%和约100%之间。
4.如权利要求2或3所述的方法,其中血浆PPi的瞬时增加被维持至少约4小时。
5.如权利要求2或3所述的方法,其中血浆PPi的瞬时增加被维持至少约6小时、至少约8小时、至少约10小时或至少约12小时。
6.如权利要求1-5中任一项所述的方法,其中所述血管钙化为动脉钙化。
7.如权利要求1-5中任一项所述的方法,其中所述血管钙化为内膜钙化。
8.如权利要求1-7中任一项所述的方法,其中所述受试者具有NPP1缺陷。
9.如权利要求1-8中任一项所述的方法,其中所述受试者具有慢性肾脏疾病(CKD)或终末期肾脏疾病(ESRD)。
10.如权利要求1-8中任一项所述的方法,其中所述受试者具有婴儿期广泛性动脉钙化(GACI)。
11.如权利要求1-8中任一项所述的方法,其中所述受试者具有心血管紊乱。
12.如权利要求1-8中任一项所述的方法,其中所述受试者具有II型糖尿病。
13.如权利要求1-8中任一项所述的方法,其中所述受试者具有动脉粥样硬化。
14.如权利要求1-8中任一项所述的方法,其中所述受试者具有弹性假黄色瘤(PXE)。
15.如权利要求1-14中任一项所述的方法,其中所述受试者中血浆焦磷酸盐(PPi)的预处理水平比正常血浆PPi水平低至少约40%。
16.如权利要求1-15中任一项所述的方法,其中所述受试者为人类。
17.如权利要求1-16中任一项所述的方法,其中每一个剂量包含约1.0mg/kg至约5.0mg/kg NPP1。
18.如权利要求1-16中任一项所述的方法,其中每一个剂量包含约1.0mg/kg至约10.0mg/kg NPP1。
19.如权利要求1-18中任一项所述的方法,其中所述NPP1剂量之间的时间段为至少3天。
20.如权利要求1-18中的权利要求任一项所述的方法,其中所述NPP1剂量之间的时间段为至少1周、2周或1个月。
21.如权利要求1-20中任一项所述的方法,其中所述施用为静脉内的、皮下的或腹膜内的。
22.如权利要求21所述的方法,其中所述施用为静脉内的。
23.如权利要求21所述的方法,其中所述施用为皮下的。
24.如权利要求1-23中任一项所述的方法,其中所述NPP1包括分离的重组人类sNPP1、其片段或融合蛋白。
25.如权利要求24所述的方法,其中所述sNPP1为融合蛋白。
26.如权利要求25所述的方法,其中所述融合蛋白包含免疫球蛋白的Fc区。
27.如权利要求25或26所述的方法,其中所述融合蛋白包含靶向部分。
28.如权利要求27所述的方法,其中所述靶向部分包含至少八个连续的天冬氨酸或谷氨酸残基。
29.如前述权利要求中任一项所述的方法,其中所述sNPP1为SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12。
30.如前述权利要求中任一项所述的方法,其中所述受试者具有升高的无机磷酸盐,并且PPi与Pi的比率比正常的高或低至少10%。
31.可溶性外核苷酸焦磷酸酶磷酸二酯酶(NPP1)用于制备用于降低血管钙化的药物的用途,其中所述药物以两个或更多个剂量进行施用并且每一个剂量包含足以实现所述受试者中血浆PPi的瞬时增加的量的可溶性NPP1,血浆PPi的瞬时增加的特征在于峰值PPi水平为正常血浆PPi水平的至少约40%,并且在施用剂量之后约48小时内回复至基线PPi水平;并且其中剂量之间的时间段为至少2天。
32.可溶性外核苷酸焦磷酸酶磷酸二酯酶(NPP1)用于降低血管钙化的用途,其中所述NPP1以两个或更多个剂量被施用并且每一个剂量包含足以实现所述受试者中血浆PPi的瞬时增加的量的可溶性NPP1,血浆PPi的瞬时增加的特征在于峰值PPi水平为正常血浆PPi水平的至少约40%,并且在施用剂量之后约48小时内回复至基线PPi水平;并且其中剂量之间的时间段为至少2天。
33.一种治疗具有NPP1缺陷或NPP1相关疾病的受试者的方法,所述方法包括将有效量的包含分离的重组人类sNPP1、其片段或融合蛋白的药物组合物施用至所述受试者。
34.如权利要求33所述的方法,其中所述NPP1缺陷或NPP1相关疾病为选自由以下组成的组的疾病:特发性婴儿型动脉钙化(IIAC)、胰岛素耐受、低磷酸血症佝偻病、脊柱后纵韧带骨化、慢性肾脏疾病中的血管钙化(VCCKD)、心肌缺血、关节钙化、血管样条纹症和弹性假黄色瘤(PXE)。
35.如权利要求34所述的方法,其中所述NPP1缺陷或NPP1相关疾病为动脉钙化、胰岛素耐受、低磷酸血症佝偻病、心肌缺血、关节钙化或脊柱后纵韧带骨化。
36.如权利要求34所述的方法,其中所述NPP1缺陷或NPP1相关疾病为慢性肾脏疾病中的血管钙化。
37.如权利要求34所述的方法,其中所述NPP1缺陷或NPP1相关疾病为弹性假黄色瘤。
38.如权利要求34所述的方法,其中所述紊乱为特发性婴儿型动脉钙化。
39.如权利要求33所述的方法,其中所述治疗防止动脉中的钙化。
40.如权利要求34所述的方法,其中所述治疗防止主动脉中的钙化。
41.如权利要求33-40中任一项所述的方法,其中所述受试者为人类患者。
42.如权利要求33-41中任一项所述的方法,其中所述药物组合物以约0.10mg/kg至约50mg/kg的量施用。
43.如权利要求42所述的方法,其中所述量为约0.5mg/kg。
44.如权利要求42所述的方法,其中所述量为约1mg/kg。
45.如权利要求42所述的方法,其中所述量为约5.0mg/kg。
46.如权利要求42所述的方法,其中所述量为约6.0mg/kg。
47.如权利要求42所述的方法,其中所述量为约10mg/kg。
48.如权利要求42所述的方法,其中所述量为约15mg/kg。
49.如权利要求42所述的方法,其中所述量为约20mg/kg。
50.如权利要求33-49中任一项所述的方法,其中所述施用为约每周一次。
51.如权利要求33-49中任一项所述的方法,其中所述施用为约两周一次。
52.如权利要求33-49中任一项所述的方法,其中所述施用为约每月一次。
53.如权利要求33-49中任一项所述的方法,其中所述施用为静脉内的、皮下的、鞘内的或腹膜内的。
54.如权利要求33-49中任一项所述的方法,其中所述施用为静脉内的。
55.如权利要求33-49中任一项所述的方法,其中所述施用为皮下的。
56.如权利要求33-49中任一项所述的方法,其中所述施用足以使所述受试者的PPi的血液水平正常化。
57.如权利要求权利要求33-49中任一项的方法,其中所述施用足以防止所述受试者中受影响组织的钙化。
58.分离的重组人类sNPP1、其片段或融合蛋白用于制备用于治疗NPP1缺陷或NPP1相关疾病的药物的用途。
59.分离的重组人类sNPP1、其片段或融合蛋白用于治疗NPP1缺陷或NPP1相关疾病的用途。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462094943P | 2014-12-19 | 2014-12-19 | |
US62/094,943 | 2014-12-19 | ||
US201562249781P | 2015-11-02 | 2015-11-02 | |
US62/249,781 | 2015-11-02 | ||
PCT/US2015/066646 WO2016100803A2 (en) | 2014-12-19 | 2015-12-18 | Methods of treating tissue calcification |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107109381A true CN107109381A (zh) | 2017-08-29 |
Family
ID=56127864
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580069537.6A Pending CN107109381A (zh) | 2014-12-19 | 2015-12-18 | 治疗组织钙化的方法 |
Country Status (15)
Country | Link |
---|---|
US (2) | USRE49529E1 (zh) |
EP (3) | EP4438118A2 (zh) |
JP (3) | JP2018500315A (zh) |
KR (1) | KR20170095367A (zh) |
CN (1) | CN107109381A (zh) |
AU (1) | AU2015364411A1 (zh) |
BR (1) | BR112017012928A2 (zh) |
CA (1) | CA2971414A1 (zh) |
CO (1) | CO2017006032A2 (zh) |
ES (2) | ES2981606T3 (zh) |
HK (1) | HK1245662A1 (zh) |
MX (3) | MX2017007946A (zh) |
PL (1) | PL3967755T3 (zh) |
RU (1) | RU2770698C2 (zh) |
WO (1) | WO2016100803A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112930397A (zh) * | 2018-08-31 | 2021-06-08 | 耶鲁大学 | Enpp1多肽及其使用方法 |
CN113631033A (zh) * | 2019-01-18 | 2021-11-09 | 依诺兹梅制药公司 | 与enpp1或enpp3缺乏有关的疾病的治疗 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2956163A4 (en) * | 2013-02-13 | 2017-03-22 | Yale University | Compositions and methods for treating pathological calcification and ossification |
ES2981606T3 (es) | 2014-12-19 | 2024-10-09 | Inozyme Pharma Inc | NPP1 soluble para su uso en un método para el tratamiento del pseudoxantoma elástico |
CA3176123A1 (en) * | 2015-05-19 | 2016-11-24 | Yale University | Compositions for treating pathological calcification conditions, and methods using same |
WO2017218786A1 (en) | 2016-06-16 | 2017-12-21 | Alexion Pharmaceuticals, Inc. | Methods of treating myointimal proliferation |
CA3032467A1 (en) | 2016-08-05 | 2018-02-08 | Yale University | Compositions and methods for stroke prevention in pediatric sickle cell anemia patients |
WO2019067502A1 (en) * | 2017-09-27 | 2019-04-04 | Alexion Pharmaceuticals, Inc. | METHODS FOR IMPROVING CARDIOVASCULAR FUNCTION AND TREATING CARDIOVASCULAR DISEASE USING RECOMBINANT ECTO-NUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE |
JP2021523139A (ja) * | 2018-05-08 | 2021-09-02 | イエール ユニバーシティ | 腎石症の進行を遅らせるための組成物および方法 |
JP2023529892A (ja) * | 2020-06-09 | 2023-07-12 | イノザイム ファーマ インク. | 可溶性enpp1又はenpp3タンパク質及びその使用 |
KR20230123932A (ko) * | 2020-11-19 | 2023-08-24 | 이노자임 파마, 인코포레이티드 | Enpp1 결핍증 및 abcc6 결핍증의 치료 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012125182A1 (en) * | 2011-03-11 | 2012-09-20 | Synageva Biopharma Corp | Npp1 fusion proteins |
WO2014126965A2 (en) * | 2013-02-13 | 2014-08-21 | Yale University | Compositions and methods for treating pathological calcification and ossification |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4751180A (en) | 1985-03-28 | 1988-06-14 | Chiron Corporation | Expression using fused genes providing for protein product |
US4935233A (en) | 1985-12-02 | 1990-06-19 | G. D. Searle And Company | Covalently linked polypeptide cell modulators |
US6267964B1 (en) | 1989-08-01 | 2001-07-31 | Affibody Technology Sweden Ab | Stabilized protein or peptide conjugates able to bond albumin having extended biological half-lives |
SE509359C2 (sv) | 1989-08-01 | 1999-01-18 | Cemu Bioteknik Ab | Användning av stabiliserade protein- eller peptidkonjugat för framställning av ett läkemedel |
CA2308765C (en) | 1997-11-07 | 2010-10-12 | Transplantation Technologies Inc. | The use of an ox-2 protein or nucleic acid in immunomodulation |
US6272859B1 (en) | 1998-10-02 | 2001-08-14 | Caterpillar Inc. | Device for controlling a variable geometry turbocharger |
PT1240337E (pt) | 1999-12-24 | 2007-01-31 | Genentech Inc | Métodos e composições para prolongar as meias-vidas de eliminação de compostos bioactivos |
ATE447622T1 (de) | 2000-02-23 | 2009-11-15 | Pxe Internat Inc | Methoden und zusammensetzungen zur diagnose und behandlung von pseudoxanthoma elasticum und ähnlichen zuständen |
EP1377306A1 (en) | 2001-03-09 | 2004-01-07 | Dyax Corp. | Serum albumin binding moieties |
US7858297B2 (en) | 2001-12-18 | 2010-12-28 | Centre National De La Recherche Scientifique Cnrs | Chemokine-binding protein and methods of use |
AU2003213246A1 (en) | 2002-02-21 | 2003-09-09 | University Of Virginia Patent Foundation | Bone targeting peptides |
EP1572936A2 (en) | 2002-03-05 | 2005-09-14 | Eli Lilly And Company | Heterologous g-csf fusion proteins |
EP1576172A2 (en) | 2002-06-21 | 2005-09-21 | Dyax Corporation | Serum protein-associated target-specific ligands and identification method therefor |
SI1729795T1 (sl) | 2004-02-09 | 2016-04-29 | Human Genome Sciences, Inc. | Albuminski fuzijski proteini |
US20050287284A1 (en) | 2004-06-28 | 2005-12-29 | Shukla Triveni P | Processed meats comprising dietary fiber gel |
US20090142347A1 (en) * | 2004-09-29 | 2009-06-04 | The Burnham Institute For Medical Research | Tissue-Nonspecific Alkaline Phosphatase (TNAP): a Therapeutic Target for Arterial Calcification |
CN101646689A (zh) | 2006-09-08 | 2010-02-10 | 埃博灵克斯股份有限公司 | 具有长半衰期的血清清蛋白结合蛋白 |
WO2011113027A2 (en) | 2010-03-12 | 2011-09-15 | Synageva Biopharma Corp | Npp1 fusion proteins |
ES2981606T3 (es) * | 2014-12-19 | 2024-10-09 | Inozyme Pharma Inc | NPP1 soluble para su uso en un método para el tratamiento del pseudoxantoma elástico |
CA3176123A1 (en) | 2015-05-19 | 2016-11-24 | Yale University | Compositions for treating pathological calcification conditions, and methods using same |
EP4079322A1 (en) | 2015-11-20 | 2022-10-26 | Yale University | Compositions for treating ectopic calcification disorders, and methods using same |
-
2015
- 2015-12-18 ES ES21192925T patent/ES2981606T3/es active Active
- 2015-12-18 AU AU2015364411A patent/AU2015364411A1/en not_active Abandoned
- 2015-12-18 PL PL21192925.2T patent/PL3967755T3/pl unknown
- 2015-12-18 US US17/111,156 patent/USRE49529E1/en active Active
- 2015-12-18 KR KR1020177019819A patent/KR20170095367A/ko not_active Application Discontinuation
- 2015-12-18 EP EP24165223.9A patent/EP4438118A2/en active Pending
- 2015-12-18 EP EP15871159.8A patent/EP3234116B1/en active Active
- 2015-12-18 US US15/536,880 patent/US10493135B2/en not_active Ceased
- 2015-12-18 JP JP2017531728A patent/JP2018500315A/ja active Pending
- 2015-12-18 RU RU2017119466A patent/RU2770698C2/ru not_active Application Discontinuation
- 2015-12-18 MX MX2017007946A patent/MX2017007946A/es unknown
- 2015-12-18 EP EP21192925.2A patent/EP3967755B1/en active Active
- 2015-12-18 CA CA2971414A patent/CA2971414A1/en active Pending
- 2015-12-18 BR BR112017012928A patent/BR112017012928A2/pt not_active Application Discontinuation
- 2015-12-18 WO PCT/US2015/066646 patent/WO2016100803A2/en active Application Filing
- 2015-12-18 CN CN201580069537.6A patent/CN107109381A/zh active Pending
- 2015-12-18 ES ES15871159T patent/ES2899895T3/es active Active
-
2017
- 2017-06-15 MX MX2022011281A patent/MX2022011281A/es unknown
- 2017-06-15 MX MX2023006083A patent/MX2023006083A/es unknown
- 2017-06-16 CO CONC2017/0006032A patent/CO2017006032A2/es unknown
-
2018
- 2018-04-25 HK HK18105396.9A patent/HK1245662A1/zh unknown
-
2021
- 2021-09-13 JP JP2021148519A patent/JP2022003048A/ja active Pending
-
2023
- 2023-10-20 JP JP2023181332A patent/JP2024010052A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012125182A1 (en) * | 2011-03-11 | 2012-09-20 | Synageva Biopharma Corp | Npp1 fusion proteins |
WO2014126965A2 (en) * | 2013-02-13 | 2014-08-21 | Yale University | Compositions and methods for treating pathological calcification and ossification |
Non-Patent Citations (2)
Title |
---|
REAG R.等: "Inhibitors of vascular calcification as potential therapeutic targets", 《JOURNAL OF NEPHROLOGY》 * |
STEFAN C.等: "NPP-type ectophosphodiesterases:unity in diversity", 《TREDNS IN BIOCHEMICAL SCIENCES》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112930397A (zh) * | 2018-08-31 | 2021-06-08 | 耶鲁大学 | Enpp1多肽及其使用方法 |
CN113631033A (zh) * | 2019-01-18 | 2021-11-09 | 依诺兹梅制药公司 | 与enpp1或enpp3缺乏有关的疾病的治疗 |
Also Published As
Publication number | Publication date |
---|---|
EP3967755A1 (en) | 2022-03-16 |
ES2899895T3 (es) | 2022-03-15 |
US10493135B2 (en) | 2019-12-03 |
EP4438118A2 (en) | 2024-10-02 |
EP3234116A4 (en) | 2018-08-01 |
MX2017007946A (es) | 2017-09-15 |
CA2971414A1 (en) | 2016-06-23 |
ES2981606T3 (es) | 2024-10-09 |
US20180318400A1 (en) | 2018-11-08 |
JP2022003048A (ja) | 2022-01-11 |
RU2017119466A3 (zh) | 2019-12-20 |
RU2017119466A (ru) | 2019-01-21 |
MX2022011281A (es) | 2022-10-18 |
RU2770698C2 (ru) | 2022-04-21 |
EP3234116A2 (en) | 2017-10-25 |
HK1245662A1 (zh) | 2018-08-31 |
JP2024010052A (ja) | 2024-01-23 |
CO2017006032A2 (es) | 2017-10-20 |
EP3967755B1 (en) | 2024-03-27 |
WO2016100803A2 (en) | 2016-06-23 |
BR112017012928A2 (pt) | 2018-05-15 |
KR20170095367A (ko) | 2017-08-22 |
PL3967755T3 (pl) | 2024-08-19 |
MX2023006083A (es) | 2023-06-19 |
AU2015364411A1 (en) | 2017-06-08 |
EP3234116B1 (en) | 2021-09-08 |
WO2016100803A3 (en) | 2016-08-04 |
JP2018500315A (ja) | 2018-01-11 |
USRE49529E1 (en) | 2023-05-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107109381A (zh) | 治疗组织钙化的方法 | |
CN102131515B (zh) | 激活素‑actrii的拮抗剂及在提高红细胞水平中的用途 | |
CN101687015B (zh) | 活化素-actrii拮抗剂及在提高红细胞水平中的用途 | |
CN103920139B (zh) | 活化素‑actriia拮抗剂及在治疗或预防乳腺癌中的用途 | |
CN102655872B (zh) | Gdf捕获物和促红细胞生成素受体激活剂联合应用以增加红细胞水平 | |
AU2014209178B2 (en) | Follistatin in treating Duchenne muscular dystrophy | |
CN107206255A (zh) | 利用actrii配体陷阱治疗心血管疾病 | |
KR20110039265A (ko) | 액티빈-actriia 길항물질을 투약하는 방법 및 치료된 환자의 모니터링 | |
CN108341863A (zh) | 内皮糖蛋白多肽及其用途 | |
CN105924516A (zh) | 变体激活素受体多肽及其用途 | |
MX2015006644A (es) | Proteinas de fusion de enzima lisosomal terapeutica objetivo y usos de las mismas. | |
CN103648518A (zh) | 局部缺血的组合治疗 | |
KR102249454B1 (ko) | 골격 성장 지연 질환의 예방 또는 치료에 사용하기 위한 용해성 섬유아세포 성장 인자 수용체 3(fgr3) 폴리펩티드 | |
EP3060235B1 (en) | Endoglin peptides to treat fibrotic diseases | |
CN108367048A (zh) | 用于组织修复的双特异性治疗性蛋白质 | |
CN101300269A (zh) | 机械生长因子肽及其用途 | |
CA2926173A1 (en) | Insulin-like growth factor mimetics for use in therapy | |
CN116917482A (zh) | 嵌合蛋白和治疗中枢神经系统疾病的方法 | |
WO2012019192A2 (en) | Cell-permeable molecules as growth factor receptor antagonists | |
Agrawal | Design of hFGF1 Variant (s) with Increased Stability and Enhanced Bioactivity | |
JP2024521575A (ja) | Actriiタンパク質およびその使用 | |
WO2024163893A2 (en) | Methods of treatment using igf-1 chimeric proteins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170829 |
|
WD01 | Invention patent application deemed withdrawn after publication |