CN109641036A - 包含白蛋白的融合蛋白和其类似物的组合物、其制备和使用方法 - Google Patents
包含白蛋白的融合蛋白和其类似物的组合物、其制备和使用方法 Download PDFInfo
- Publication number
- CN109641036A CN109641036A CN201780052241.2A CN201780052241A CN109641036A CN 109641036 A CN109641036 A CN 109641036A CN 201780052241 A CN201780052241 A CN 201780052241A CN 109641036 A CN109641036 A CN 109641036A
- Authority
- CN
- China
- Prior art keywords
- ala
- glu
- lys
- leu
- val
- 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
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 158
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 158
- 102000009027 Albumins Human genes 0.000 title claims abstract description 41
- 108010088751 Albumins Proteins 0.000 title claims abstract description 41
- 239000000203 mixture Substances 0.000 title description 11
- 238000002360 preparation method Methods 0.000 title description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 26
- GGYTXJNZMFRSLX-DFTNLTQTSA-N somatostatin-28 Chemical compound N([C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CSSC1)C(O)=O)[C@@H](C)O)[C@@H](C)O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CO GGYTXJNZMFRSLX-DFTNLTQTSA-N 0.000 claims abstract description 26
- 150000001413 amino acids Chemical class 0.000 claims abstract description 14
- VVEJUSYNERNRME-XGFVQVCISA-N (4r,7s,10r,13s,16r,19s,22r,25s,28r,31s)-13,28-bis(4-aminobutyl)-25-(2-amino-2-oxoethyl)-31-[[2-[[(2s)-2-aminopropanoyl]amino]acetyl]amino]-19,22-dibenzyl-10-[(1r)-1-hydroxyethyl]-7-(hydroxymethyl)-16-(1h-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30-nonaoxo- Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@H](C(=O)N[C@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N1)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 VVEJUSYNERNRME-XGFVQVCISA-N 0.000 claims abstract 3
- 101500024338 Homo sapiens Somatostatin-14 Proteins 0.000 claims abstract 3
- 102400000820 Somatostatin-14 Human genes 0.000 claims abstract 3
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical group C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 88
- 229960000553 somatostatin Drugs 0.000 claims description 69
- 108010056088 Somatostatin Proteins 0.000 claims description 67
- 102000005157 Somatostatin Human genes 0.000 claims description 66
- 229920001184 polypeptide Polymers 0.000 claims description 63
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 63
- 125000006850 spacer group Chemical group 0.000 claims description 39
- 239000002773 nucleotide Substances 0.000 claims description 30
- 125000003729 nucleotide group Chemical group 0.000 claims description 30
- 102100027211 Albumin Human genes 0.000 claims description 14
- 239000013612 plasmid Substances 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- 230000001580 bacterial effect Effects 0.000 claims description 7
- 230000002124 endocrine Effects 0.000 claims description 7
- 102100023802 Somatostatin receptor type 2 Human genes 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 5
- 102000007562 Serum Albumin Human genes 0.000 claims description 5
- 108010071390 Serum Albumin Proteins 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 108090000586 somatostatin receptor 2 Proteins 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 102100029329 Somatostatin receptor type 1 Human genes 0.000 claims description 2
- 101710192647 Somatostatin receptor type 3 Proteins 0.000 claims description 2
- 102100023803 Somatostatin receptor type 3 Human genes 0.000 claims description 2
- 101710192645 Somatostatin receptor type 4 Proteins 0.000 claims description 2
- 102100023801 Somatostatin receptor type 4 Human genes 0.000 claims description 2
- 102100023806 Somatostatin receptor type 5 Human genes 0.000 claims description 2
- 108090000680 somatostatin receptor 5 Proteins 0.000 claims description 2
- 108010082379 somatostatin receptor type 1 Proteins 0.000 claims description 2
- 102000018997 Growth Hormone Human genes 0.000 abstract description 14
- 108010051696 Growth Hormone Proteins 0.000 abstract description 14
- 239000000122 growth hormone Substances 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 238000001727 in vivo Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 5
- 210000002966 serum Anatomy 0.000 abstract description 5
- 230000008859 change Effects 0.000 abstract description 2
- 239000005556 hormone Substances 0.000 abstract 9
- 229940088597 hormone Drugs 0.000 abstract 9
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 230000003252 repetitive effect Effects 0.000 abstract 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 48
- 108090000623 proteins and genes Proteins 0.000 description 42
- 108010004073 cysteinylcysteine Proteins 0.000 description 41
- 108010005233 alanylglutamic acid Proteins 0.000 description 39
- 102000004169 proteins and genes Human genes 0.000 description 38
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 38
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 35
- 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 35
- 235000018102 proteins Nutrition 0.000 description 34
- CFVQPNSCQMKDPB-CIUDSAMLSA-N Lys-Cys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N CFVQPNSCQMKDPB-CIUDSAMLSA-N 0.000 description 32
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 30
- 108010092854 aspartyllysine Proteins 0.000 description 30
- 241000700159 Rattus Species 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 29
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 27
- 108010054155 lysyllysine Proteins 0.000 description 26
- 108010074082 phenylalanyl-alanyl-lysine Proteins 0.000 description 26
- WXERCAHAIKMTKX-ZLUOBGJFSA-N Ala-Asp-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O WXERCAHAIKMTKX-ZLUOBGJFSA-N 0.000 description 25
- KWTVLKBOQATPHJ-SRVKXCTJSA-N Leu-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N KWTVLKBOQATPHJ-SRVKXCTJSA-N 0.000 description 25
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 25
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 23
- 108091006905 Human Serum Albumin Proteins 0.000 description 22
- 102000008100 Human Serum Albumin Human genes 0.000 description 22
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 22
- 101800004701 Somatostatin-28 Proteins 0.000 description 21
- 108010034529 leucyl-lysine Proteins 0.000 description 21
- 102100029563 Somatostatin Human genes 0.000 description 20
- 108010092114 histidylphenylalanine Proteins 0.000 description 19
- ULECEJGNDHWSKD-QEJZJMRPSA-N Phe-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 ULECEJGNDHWSKD-QEJZJMRPSA-N 0.000 description 18
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 18
- 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 18
- 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 17
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 17
- 108020004414 DNA Proteins 0.000 description 17
- 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 17
- 108010065920 Insulin Lispro Proteins 0.000 description 17
- 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 17
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 17
- CYZBFPYMSJGBRL-DRZSPHRISA-N Phe-Ala-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CYZBFPYMSJGBRL-DRZSPHRISA-N 0.000 description 17
- 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 17
- 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 17
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 17
- LWTTURISBKEVAC-CIUDSAMLSA-N Cys-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)N LWTTURISBKEVAC-CIUDSAMLSA-N 0.000 description 16
- HHQCBFGKQDMWSP-GUBZILKMSA-N Gln-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N HHQCBFGKQDMWSP-GUBZILKMSA-N 0.000 description 16
- MXPBQDFWIMBACQ-ACZMJKKPSA-N Glu-Cys-Cys Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O MXPBQDFWIMBACQ-ACZMJKKPSA-N 0.000 description 16
- 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 16
- 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 16
- 241000880493 Leptailurus serval Species 0.000 description 16
- PNPYKQFJGRFYJE-GUBZILKMSA-N Lys-Ala-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNPYKQFJGRFYJE-GUBZILKMSA-N 0.000 description 16
- WGLAORUKDGRINI-WDCWCFNPSA-N Lys-Glu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGLAORUKDGRINI-WDCWCFNPSA-N 0.000 description 16
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 16
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 16
- 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 16
- 108010015792 glycyllysine Proteins 0.000 description 16
- 108010080244 somatostatin(3-6) Proteins 0.000 description 16
- WDIYWDJLXOCGRW-ACZMJKKPSA-N Ala-Asp-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WDIYWDJLXOCGRW-ACZMJKKPSA-N 0.000 description 15
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 15
- HYKFOHGZGLOCAY-ZLUOBGJFSA-N Cys-Cys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O HYKFOHGZGLOCAY-ZLUOBGJFSA-N 0.000 description 15
- CQGBSALYGOXQPE-HTUGSXCWSA-N Glu-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O CQGBSALYGOXQPE-HTUGSXCWSA-N 0.000 description 15
- VQUCKIAECLVLAD-SVSWQMSJSA-N Ile-Cys-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N VQUCKIAECLVLAD-SVSWQMSJSA-N 0.000 description 15
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 15
- JIHDFWWRYHSAQB-GUBZILKMSA-N Leu-Ser-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JIHDFWWRYHSAQB-GUBZILKMSA-N 0.000 description 15
- 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 15
- GVMXJJAJLIEASL-ZJDVBMNYSA-N Thr-Pro-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O GVMXJJAJLIEASL-ZJDVBMNYSA-N 0.000 description 15
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 15
- ZXAGTABZUOMUDO-GVXVVHGQSA-N Val-Glu-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N ZXAGTABZUOMUDO-GVXVVHGQSA-N 0.000 description 15
- 108010017391 lysylvaline Proteins 0.000 description 15
- PIPTUBPKYFRLCP-NHCYSSNCSA-N Ala-Ala-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PIPTUBPKYFRLCP-NHCYSSNCSA-N 0.000 description 14
- OVVUNXXROOFSIM-SDDRHHMPSA-N Arg-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O OVVUNXXROOFSIM-SDDRHHMPSA-N 0.000 description 14
- PRBLYKYHAJEABA-SRVKXCTJSA-N Gln-Arg-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O PRBLYKYHAJEABA-SRVKXCTJSA-N 0.000 description 14
- MLCPTRRNICEKIS-FXQIFTODSA-N Glu-Asn-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MLCPTRRNICEKIS-FXQIFTODSA-N 0.000 description 14
- ZXQPJYWZSFGWJB-AVGNSLFASA-N Glu-Cys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N ZXQPJYWZSFGWJB-AVGNSLFASA-N 0.000 description 14
- YPHPEHMXOYTEQG-LAEOZQHASA-N Glu-Val-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O YPHPEHMXOYTEQG-LAEOZQHASA-N 0.000 description 14
- LZEUDRYSAZAJIO-AUTRQRHGSA-N Glu-Val-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LZEUDRYSAZAJIO-AUTRQRHGSA-N 0.000 description 14
- CRNNMTHBMRFQNG-GUBZILKMSA-N Lys-Glu-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N CRNNMTHBMRFQNG-GUBZILKMSA-N 0.000 description 14
- HYSVGEAWTGPMOA-IHRRRGAJSA-N Lys-Pro-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O HYSVGEAWTGPMOA-IHRRRGAJSA-N 0.000 description 14
- MPFGIYLYWUCSJG-AVGNSLFASA-N Phe-Glu-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MPFGIYLYWUCSJG-AVGNSLFASA-N 0.000 description 14
- SRTCFKGBYBZRHA-ACZMJKKPSA-N Ser-Ala-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SRTCFKGBYBZRHA-ACZMJKKPSA-N 0.000 description 14
- 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 14
- PRNGXSILMXSWQQ-OEAJRASXSA-N Thr-Leu-Phe 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=CC=C1)C(O)=O PRNGXSILMXSWQQ-OEAJRASXSA-N 0.000 description 14
- GIOBXJSONRQHKQ-RYUDHWBXSA-N Tyr-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O GIOBXJSONRQHKQ-RYUDHWBXSA-N 0.000 description 14
- CVUDMNSZAIZFAE-TUAOUCFPSA-N Val-Arg-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N CVUDMNSZAIZFAE-TUAOUCFPSA-N 0.000 description 14
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 14
- 108010040856 glutamyl-cysteinyl-alanine Proteins 0.000 description 14
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 14
- YSMPVONNIWLJML-FXQIFTODSA-N Ala-Asp-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(O)=O YSMPVONNIWLJML-FXQIFTODSA-N 0.000 description 13
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 13
- NXDXECQFKHXHAM-HJGDQZAQSA-N Arg-Glu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NXDXECQFKHXHAM-HJGDQZAQSA-N 0.000 description 13
- ZELQAFZSJOBEQS-ACZMJKKPSA-N Asp-Asn-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZELQAFZSJOBEQS-ACZMJKKPSA-N 0.000 description 13
- LYSHSHHDBVKJRN-JBDRJPRFSA-N Cys-Ile-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N LYSHSHHDBVKJRN-JBDRJPRFSA-N 0.000 description 13
- UIKLEGZPIOXFHJ-DLOVCJGASA-N Cys-Phe-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O UIKLEGZPIOXFHJ-DLOVCJGASA-N 0.000 description 13
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 13
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 13
- 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 13
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 13
- PNTWNAXGBOZMBO-MNXVOIDGSA-N Ile-Lys-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PNTWNAXGBOZMBO-MNXVOIDGSA-N 0.000 description 13
- IRNSXVOWSXSULE-DCAQKATOSA-N Lys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN IRNSXVOWSXSULE-DCAQKATOSA-N 0.000 description 13
- DUTMKEAPLLUGNO-JYJNAYRXSA-N Lys-Glu-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DUTMKEAPLLUGNO-JYJNAYRXSA-N 0.000 description 13
- TUSOIZOVPJCMFC-FXQIFTODSA-N Met-Asp-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O TUSOIZOVPJCMFC-FXQIFTODSA-N 0.000 description 13
- VCYJKOLZYPYGJV-AVGNSLFASA-N Pro-Arg-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VCYJKOLZYPYGJV-AVGNSLFASA-N 0.000 description 13
- 108010076504 Protein Sorting Signals Proteins 0.000 description 13
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 13
- IUXGJEIKJBYKOO-SRVKXCTJSA-N Ser-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N IUXGJEIKJBYKOO-SRVKXCTJSA-N 0.000 description 13
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 13
- NSGZILIDHCIZAM-KKUMJFAQSA-N Tyr-Leu-Ser Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NSGZILIDHCIZAM-KKUMJFAQSA-N 0.000 description 13
- CWVHKVVKAQIJKY-ACRUOGEOSA-N Tyr-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CC=C(C=C2)O)N CWVHKVVKAQIJKY-ACRUOGEOSA-N 0.000 description 13
- OBKOPLHSRDATFO-XHSDSOJGSA-N Tyr-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OBKOPLHSRDATFO-XHSDSOJGSA-N 0.000 description 13
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 13
- 108010041407 alanylaspartic acid Proteins 0.000 description 13
- 108010087924 alanylproline Proteins 0.000 description 13
- 108010027371 asparaginyl-leucyl-prolyl-arginine Proteins 0.000 description 13
- 230000027455 binding Effects 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- BHQQRVARKXWXPP-ACZMJKKPSA-N Asn-Asp-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N BHQQRVARKXWXPP-ACZMJKKPSA-N 0.000 description 12
- VWJFQGXPYOPXJH-ZLUOBGJFSA-N Asn-Cys-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)C(=O)N VWJFQGXPYOPXJH-ZLUOBGJFSA-N 0.000 description 12
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 12
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 12
- ORRJQLIATJDMQM-HJGDQZAQSA-N Asp-Leu-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O ORRJQLIATJDMQM-HJGDQZAQSA-N 0.000 description 12
- DRCOAZZDQRCGGP-GHCJXIJMSA-N Asp-Ser-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DRCOAZZDQRCGGP-GHCJXIJMSA-N 0.000 description 12
- MUZAUPFGPMMZSS-GUBZILKMSA-N Cys-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N MUZAUPFGPMMZSS-GUBZILKMSA-N 0.000 description 12
- 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 12
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 12
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 12
- 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 12
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 12
- MHHUEAIBJZWDBH-YUMQZZPRSA-N Gly-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN MHHUEAIBJZWDBH-YUMQZZPRSA-N 0.000 description 12
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 12
- PUFNQIPSRXVLQJ-IHRRRGAJSA-N His-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N PUFNQIPSRXVLQJ-IHRRRGAJSA-N 0.000 description 12
- BOFAFKVZQUMTID-AVGNSLFASA-N Leu-Gln-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N BOFAFKVZQUMTID-AVGNSLFASA-N 0.000 description 12
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 12
- ZAWOJFFMBANLGE-CIUDSAMLSA-N Lys-Cys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N ZAWOJFFMBANLGE-CIUDSAMLSA-N 0.000 description 12
- HWMZUBUEOYAQSC-DCAQKATOSA-N Lys-Gln-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O HWMZUBUEOYAQSC-DCAQKATOSA-N 0.000 description 12
- DRCILAJNUJKAHC-SRVKXCTJSA-N Lys-Glu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DRCILAJNUJKAHC-SRVKXCTJSA-N 0.000 description 12
- MSSJJDVQTFTLIF-KBPBESRZSA-N Lys-Phe-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(O)=O MSSJJDVQTFTLIF-KBPBESRZSA-N 0.000 description 12
- VHGIWFGJIHTASW-FXQIFTODSA-N Met-Ala-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O VHGIWFGJIHTASW-FXQIFTODSA-N 0.000 description 12
- KEGBFULVYKYJRD-LFSVMHDDSA-N Thr-Ala-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KEGBFULVYKYJRD-LFSVMHDDSA-N 0.000 description 12
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 12
- 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 12
- QTPQHINADBYBNA-DCAQKATOSA-N Val-Ser-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN QTPQHINADBYBNA-DCAQKATOSA-N 0.000 description 12
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 12
- 108010048818 seryl-histidine Proteins 0.000 description 12
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 11
- LUVODTFFSXVOAG-ACZMJKKPSA-N Asn-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N LUVODTFFSXVOAG-ACZMJKKPSA-N 0.000 description 11
- 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 11
- FTNRWCPWDWRPAV-BZSNNMDCSA-N Asn-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FTNRWCPWDWRPAV-BZSNNMDCSA-N 0.000 description 11
- OVPHVTCDVYYTHN-AVGNSLFASA-N Asp-Glu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OVPHVTCDVYYTHN-AVGNSLFASA-N 0.000 description 11
- QFMCHXSGIZPBKG-ZLUOBGJFSA-N Cys-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N QFMCHXSGIZPBKG-ZLUOBGJFSA-N 0.000 description 11
- CHRCKSPMGYDLIA-SRVKXCTJSA-N Cys-Phe-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O CHRCKSPMGYDLIA-SRVKXCTJSA-N 0.000 description 11
- JLZCAZJGWNRXCI-XKBZYTNZSA-N Cys-Thr-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O JLZCAZJGWNRXCI-XKBZYTNZSA-N 0.000 description 11
- MTCXQQINVAFZKW-MNXVOIDGSA-N Gln-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MTCXQQINVAFZKW-MNXVOIDGSA-N 0.000 description 11
- OEROYDLRVAYIMQ-YUMQZZPRSA-N His-Gly-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O OEROYDLRVAYIMQ-YUMQZZPRSA-N 0.000 description 11
- 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 11
- FOEHRHOBWFQSNW-KATARQTJSA-N Leu-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)N)O FOEHRHOBWFQSNW-KATARQTJSA-N 0.000 description 11
- KGCLIYGPQXUNLO-IUCAKERBSA-N Leu-Gly-Glu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O KGCLIYGPQXUNLO-IUCAKERBSA-N 0.000 description 11
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 11
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 11
- HEWWNLVEWBJBKA-WDCWCFNPSA-N Lys-Gln-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCCN HEWWNLVEWBJBKA-WDCWCFNPSA-N 0.000 description 11
- 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 11
- VQILILSLEFDECU-GUBZILKMSA-N Met-Pro-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O VQILILSLEFDECU-GUBZILKMSA-N 0.000 description 11
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 11
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 11
- HPQHHRLWSAMMKG-KATARQTJSA-N Thr-Lys-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N)O HPQHHRLWSAMMKG-KATARQTJSA-N 0.000 description 11
- IOETTZIEIBVWBZ-GUBZILKMSA-N Val-Met-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)O)N IOETTZIEIBVWBZ-GUBZILKMSA-N 0.000 description 11
- AJNUKMZFHXUBMK-GUBZILKMSA-N Val-Ser-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N AJNUKMZFHXUBMK-GUBZILKMSA-N 0.000 description 11
- 108010008355 arginyl-glutamine Proteins 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 108010003700 lysyl aspartic acid Proteins 0.000 description 11
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 10
- LCBSSOCDWUTQQV-SDDRHHMPSA-N Arg-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LCBSSOCDWUTQQV-SDDRHHMPSA-N 0.000 description 10
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 10
- LEFKSBYHUGUWLP-ACZMJKKPSA-N Asn-Ala-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LEFKSBYHUGUWLP-ACZMJKKPSA-N 0.000 description 10
- CAXXTYYGFYTBPV-IUCAKERBSA-N Gln-Leu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CAXXTYYGFYTBPV-IUCAKERBSA-N 0.000 description 10
- 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 10
- AIRUUHAOKGVJAD-JYJNAYRXSA-N Leu-Phe-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIRUUHAOKGVJAD-JYJNAYRXSA-N 0.000 description 10
- AKVBOOKXVAMKSS-GUBZILKMSA-N Leu-Ser-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O AKVBOOKXVAMKSS-GUBZILKMSA-N 0.000 description 10
- TXTZMVNJIRZABH-ULQDDVLXSA-N Lys-Val-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 TXTZMVNJIRZABH-ULQDDVLXSA-N 0.000 description 10
- VTVVYQOXJCZVEB-WDCWCFNPSA-N Thr-Leu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VTVVYQOXJCZVEB-WDCWCFNPSA-N 0.000 description 10
- VLOYGOZDPGYWFO-LAEOZQHASA-N Val-Asp-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VLOYGOZDPGYWFO-LAEOZQHASA-N 0.000 description 10
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 10
- 108010043680 somatostatin(7-10) Proteins 0.000 description 10
- OZNSCVPYWZRQPY-CIUDSAMLSA-N Arg-Asp-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OZNSCVPYWZRQPY-CIUDSAMLSA-N 0.000 description 9
- IVPNEDNYYYFAGI-GARJFASQSA-N Asp-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N IVPNEDNYYYFAGI-GARJFASQSA-N 0.000 description 9
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 9
- PMSMKNYRZCKVMC-DRZSPHRISA-N Glu-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCC(=O)O)N PMSMKNYRZCKVMC-DRZSPHRISA-N 0.000 description 9
- KZTLOHBDLMIFSH-XVYDVKMFSA-N His-Ala-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O KZTLOHBDLMIFSH-XVYDVKMFSA-N 0.000 description 9
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 9
- GRADYHMSAUIKPS-DCAQKATOSA-N Lys-Glu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRADYHMSAUIKPS-DCAQKATOSA-N 0.000 description 9
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 9
- PMKIMKUGCSVFSV-CQDKDKBSSA-N Phe-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N PMKIMKUGCSVFSV-CQDKDKBSSA-N 0.000 description 9
- 108010036999 aspartyl-alanyl-histidyl-lysine Proteins 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 8
- KXHAPEPORGOXDT-UWJYBYFXSA-N Cys-Tyr-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O KXHAPEPORGOXDT-UWJYBYFXSA-N 0.000 description 8
- PAOHIZNRJNIXQY-XQXXSGGOSA-N Gln-Thr-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O PAOHIZNRJNIXQY-XQXXSGGOSA-N 0.000 description 8
- LGQZOQRDEUIZJY-YUMQZZPRSA-N Gly-Cys-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CS)NC(=O)CN)C(O)=O LGQZOQRDEUIZJY-YUMQZZPRSA-N 0.000 description 8
- 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 8
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 8
- 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 8
- 229920002873 Polyethylenimine Polymers 0.000 description 8
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 8
- KOVXHANYYYMBRF-IRIUXVKKSA-N Tyr-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O KOVXHANYYYMBRF-IRIUXVKKSA-N 0.000 description 8
- 108010038633 aspartylglutamate Proteins 0.000 description 8
- XWJDVNOOYSANGI-ATOGVRKGSA-N dihydrosomatostatin Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)NC(=O)CNC(=O)[C@@H](N)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O)C1=CC=CC=C1 XWJDVNOOYSANGI-ATOGVRKGSA-N 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 108010085325 histidylproline Proteins 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 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 7
- HYIDEIQUCBKIPL-CQDKDKBSSA-N Ala-Phe-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N HYIDEIQUCBKIPL-CQDKDKBSSA-N 0.000 description 7
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 7
- XDGBFDYXZCMYEX-NUMRIWBASA-N Asp-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)O XDGBFDYXZCMYEX-NUMRIWBASA-N 0.000 description 7
- 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 7
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 7
- KUTPGXNAAOQSPD-LPEHRKFASA-N Glu-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O KUTPGXNAAOQSPD-LPEHRKFASA-N 0.000 description 7
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 7
- YTKOTXRIWQHSAZ-GUBZILKMSA-N His-Glu-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N YTKOTXRIWQHSAZ-GUBZILKMSA-N 0.000 description 7
- 101000632994 Homo sapiens Somatostatin Proteins 0.000 description 7
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 7
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 7
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 7
- LKDXINHHSWFFJC-SRVKXCTJSA-N Lys-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N LKDXINHHSWFFJC-SRVKXCTJSA-N 0.000 description 7
- ZGVYWHODYWRPLK-GUBZILKMSA-N Met-Pro-Cys Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(O)=O ZGVYWHODYWRPLK-GUBZILKMSA-N 0.000 description 7
- 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 7
- ZLGQEBCCANLYRA-RYUDHWBXSA-N Phe-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O ZLGQEBCCANLYRA-RYUDHWBXSA-N 0.000 description 7
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 7
- 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 7
- AMBLXEMWFARNNQ-DCAQKATOSA-N Pro-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H]1CCCN1 AMBLXEMWFARNNQ-DCAQKATOSA-N 0.000 description 7
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 7
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 7
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 7
- REJRKTOJTCPDPO-IRIUXVKKSA-N Thr-Tyr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O REJRKTOJTCPDPO-IRIUXVKKSA-N 0.000 description 7
- PHKQVWWHRYUCJL-HJOGWXRNSA-N Tyr-Phe-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PHKQVWWHRYUCJL-HJOGWXRNSA-N 0.000 description 7
- DDRBQONWVBDQOY-GUBZILKMSA-N Val-Ala-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O DDRBQONWVBDQOY-GUBZILKMSA-N 0.000 description 7
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 7
- 108010011164 acein 1 Proteins 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 108010069495 cysteinyltyrosine Proteins 0.000 description 7
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 7
- 108010070643 prolylglutamic acid Proteins 0.000 description 7
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 7
- 239000013598 vector Substances 0.000 description 7
- XYTNPQNAZREREP-XQXXSGGOSA-N Ala-Glu-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XYTNPQNAZREREP-XQXXSGGOSA-N 0.000 description 6
- LDLSENBXQNDTPB-DCAQKATOSA-N Ala-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LDLSENBXQNDTPB-DCAQKATOSA-N 0.000 description 6
- 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 6
- UPKMBGAAEZGHOC-RWMBFGLXSA-N Arg-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O UPKMBGAAEZGHOC-RWMBFGLXSA-N 0.000 description 6
- DZLQXIFVQFTFJY-BYPYZUCNSA-N Cys-Gly-Gly Chemical compound SC[C@H](N)C(=O)NCC(=O)NCC(O)=O DZLQXIFVQFTFJY-BYPYZUCNSA-N 0.000 description 6
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 6
- WZOGEMJIZBNFBK-CIUDSAMLSA-N His-Asp-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O WZOGEMJIZBNFBK-CIUDSAMLSA-N 0.000 description 6
- BQYZXYCEKYJKAM-VGDYDELISA-N His-Cys-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BQYZXYCEKYJKAM-VGDYDELISA-N 0.000 description 6
- GVNNAHIRSDRIII-AJNGGQMLSA-N Ile-Lys-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N GVNNAHIRSDRIII-AJNGGQMLSA-N 0.000 description 6
- HASRFYOMVPJRPU-SRVKXCTJSA-N Leu-Arg-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O HASRFYOMVPJRPU-SRVKXCTJSA-N 0.000 description 6
- WMTOVWLLDGQGCV-GUBZILKMSA-N Leu-Glu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N WMTOVWLLDGQGCV-GUBZILKMSA-N 0.000 description 6
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 6
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 6
- BWECSLVQIWEMSC-IHRRRGAJSA-N Lys-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCCN)N BWECSLVQIWEMSC-IHRRRGAJSA-N 0.000 description 6
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 6
- YUPRIZTWANWWHK-DZKIICNBSA-N Phe-Val-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N YUPRIZTWANWWHK-DZKIICNBSA-N 0.000 description 6
- ODPIUQVTULPQEP-CIUDSAMLSA-N Pro-Gln-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@@H]1CCCN1 ODPIUQVTULPQEP-CIUDSAMLSA-N 0.000 description 6
- PULPZRAHVFBVTO-DCAQKATOSA-N Pro-Glu-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PULPZRAHVFBVTO-DCAQKATOSA-N 0.000 description 6
- FCRMLGJMPXCAHD-FXQIFTODSA-N Ser-Arg-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O FCRMLGJMPXCAHD-FXQIFTODSA-N 0.000 description 6
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 6
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 6
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 6
- 108010078114 alanyl-tryptophyl-alanine Proteins 0.000 description 6
- 108010034445 albutensin A Proteins 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- DKJPOZOEBONHFS-ZLUOBGJFSA-N Ala-Ala-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O DKJPOZOEBONHFS-ZLUOBGJFSA-N 0.000 description 5
- NJPMYXWVWQWCSR-ACZMJKKPSA-N Ala-Glu-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NJPMYXWVWQWCSR-ACZMJKKPSA-N 0.000 description 5
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 5
- ZPXCNXMJEZKRLU-LSJOCFKGSA-N Ala-His-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CN=CN1 ZPXCNXMJEZKRLU-LSJOCFKGSA-N 0.000 description 5
- SAHQGRZIQVEJPF-JXUBOQSCSA-N Ala-Thr-Lys Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN SAHQGRZIQVEJPF-JXUBOQSCSA-N 0.000 description 5
- KZXPVYVSHUJCEO-ULQDDVLXSA-N Arg-Phe-Lys Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=CC=C1 KZXPVYVSHUJCEO-ULQDDVLXSA-N 0.000 description 5
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 5
- HJRBIWRXULGMOA-ACZMJKKPSA-N Asn-Gln-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJRBIWRXULGMOA-ACZMJKKPSA-N 0.000 description 5
- QOVWVLLHMMCFFY-ZLUOBGJFSA-N Asp-Asp-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QOVWVLLHMMCFFY-ZLUOBGJFSA-N 0.000 description 5
- VFUXXFVCYZPOQG-WDSKDSINSA-N Asp-Glu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VFUXXFVCYZPOQG-WDSKDSINSA-N 0.000 description 5
- DCJNIJAWIRPPBB-CIUDSAMLSA-N Cys-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N DCJNIJAWIRPPBB-CIUDSAMLSA-N 0.000 description 5
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 5
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 5
- YJIUYQKQBBQYHZ-ACZMJKKPSA-N Gln-Ala-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O YJIUYQKQBBQYHZ-ACZMJKKPSA-N 0.000 description 5
- RCCDHXSRMWCOOY-GUBZILKMSA-N Glu-Arg-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCCDHXSRMWCOOY-GUBZILKMSA-N 0.000 description 5
- OHWJUIXZHVIXJJ-GUBZILKMSA-N Glu-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N OHWJUIXZHVIXJJ-GUBZILKMSA-N 0.000 description 5
- ZIYGTCDTJJCDDP-JYJNAYRXSA-N Glu-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZIYGTCDTJJCDDP-JYJNAYRXSA-N 0.000 description 5
- QXUPRMQJDWJDFR-NRPADANISA-N Glu-Val-Ser Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXUPRMQJDWJDFR-NRPADANISA-N 0.000 description 5
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 5
- 101000829127 Homo sapiens Somatostatin receptor type 2 Proteins 0.000 description 5
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 5
- 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 5
- HVJVUYQWFYMGJS-GVXVVHGQSA-N Leu-Glu-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVJVUYQWFYMGJS-GVXVVHGQSA-N 0.000 description 5
- HNDWYLYAYNBWMP-AJNGGQMLSA-N Leu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N HNDWYLYAYNBWMP-AJNGGQMLSA-N 0.000 description 5
- UBZGNBKMIJHOHL-BZSNNMDCSA-N Leu-Leu-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 UBZGNBKMIJHOHL-BZSNNMDCSA-N 0.000 description 5
- 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 5
- VKCPHIOZDWUFSW-ONGXEEELSA-N Lys-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN VKCPHIOZDWUFSW-ONGXEEELSA-N 0.000 description 5
- CEGVMWAVGBRVFS-XGEHTFHBSA-N Met-Cys-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CEGVMWAVGBRVFS-XGEHTFHBSA-N 0.000 description 5
- CDQCFGOQNYOICK-IHRRRGAJSA-N Phe-Glu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CDQCFGOQNYOICK-IHRRRGAJSA-N 0.000 description 5
- APKRGYLBSCWJJP-FXQIFTODSA-N Pro-Ala-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O APKRGYLBSCWJJP-FXQIFTODSA-N 0.000 description 5
- SUENWIFTSTWUKD-AVGNSLFASA-N Pro-Leu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SUENWIFTSTWUKD-AVGNSLFASA-N 0.000 description 5
- OFGUOWQVEGTVNU-DCAQKATOSA-N Pro-Lys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OFGUOWQVEGTVNU-DCAQKATOSA-N 0.000 description 5
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 5
- 108050001286 Somatostatin Receptor Proteins 0.000 description 5
- 102000011096 Somatostatin receptor Human genes 0.000 description 5
- ZWZOCUWOXSDYFZ-CQDKDKBSSA-N Tyr-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 ZWZOCUWOXSDYFZ-CQDKDKBSSA-N 0.000 description 5
- REJBPZVUHYNMEN-LSJOCFKGSA-N Val-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N REJBPZVUHYNMEN-LSJOCFKGSA-N 0.000 description 5
- ZMDCGGKHRKNWKD-LAEOZQHASA-N Val-Asn-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZMDCGGKHRKNWKD-LAEOZQHASA-N 0.000 description 5
- 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 5
- 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 5
- DLRZGNXCXUGIDG-KKHAAJSZSA-N Val-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O DLRZGNXCXUGIDG-KKHAAJSZSA-N 0.000 description 5
- 108010047495 alanylglycine Proteins 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 108010077245 asparaginyl-proline Proteins 0.000 description 5
- 108010016616 cysteinylglycine Proteins 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 108010038320 lysylphenylalanine Proteins 0.000 description 5
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- RCGFMNKLEKXILD-XYCLDAKMSA-N (2s,3r)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-amino-3-phenylpropanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]hexanoyl]amino]-3-hydroxybutanoic acid Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](O)C)C(O)=O)C1=CC=CC=C1 RCGFMNKLEKXILD-XYCLDAKMSA-N 0.000 description 4
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 4
- WQVYAWIMAWTGMW-ZLUOBGJFSA-N Ala-Asp-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N WQVYAWIMAWTGMW-ZLUOBGJFSA-N 0.000 description 4
- LJFNNUBZSZCZFN-WHFBIAKZSA-N Ala-Gly-Cys Chemical compound N[C@@H](C)C(=O)NCC(=O)N[C@@H](CS)C(=O)O LJFNNUBZSZCZFN-WHFBIAKZSA-N 0.000 description 4
- WEZNQZHACPSMEF-QEJZJMRPSA-N Ala-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 WEZNQZHACPSMEF-QEJZJMRPSA-N 0.000 description 4
- ZVWXMTTZJKBJCI-BHDSKKPTSA-N Ala-Trp-Ala Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 ZVWXMTTZJKBJCI-BHDSKKPTSA-N 0.000 description 4
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 4
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 4
- GMRGSBAMMMVDGG-GUBZILKMSA-N Asn-Arg-Arg Chemical compound C(C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N GMRGSBAMMMVDGG-GUBZILKMSA-N 0.000 description 4
- MECFLTFREHAZLH-ACZMJKKPSA-N Asn-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N MECFLTFREHAZLH-ACZMJKKPSA-N 0.000 description 4
- LTXGDRFJRZSZAV-CIUDSAMLSA-N Asp-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N LTXGDRFJRZSZAV-CIUDSAMLSA-N 0.000 description 4
- DGKCOYGQLNWNCJ-ACZMJKKPSA-N Asp-Glu-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O DGKCOYGQLNWNCJ-ACZMJKKPSA-N 0.000 description 4
- GKWFMNNNYZHJHV-SRVKXCTJSA-N Asp-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O GKWFMNNNYZHJHV-SRVKXCTJSA-N 0.000 description 4
- GRNOCLDFUNCIDW-ACZMJKKPSA-N Cys-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N GRNOCLDFUNCIDW-ACZMJKKPSA-N 0.000 description 4
- PRXCTTWKGJAPMT-ZLUOBGJFSA-N Cys-Ala-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O PRXCTTWKGJAPMT-ZLUOBGJFSA-N 0.000 description 4
- KABHAOSDMIYXTR-GUBZILKMSA-N Cys-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N KABHAOSDMIYXTR-GUBZILKMSA-N 0.000 description 4
- VOBMMKMWSIVIOA-SRVKXCTJSA-N Cys-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N VOBMMKMWSIVIOA-SRVKXCTJSA-N 0.000 description 4
- MINZLORERLNSPP-ACZMJKKPSA-N Gln-Asn-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N MINZLORERLNSPP-ACZMJKKPSA-N 0.000 description 4
- NNXIQPMZGZUFJJ-AVGNSLFASA-N Gln-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N NNXIQPMZGZUFJJ-AVGNSLFASA-N 0.000 description 4
- SBYVDRJAXWSXQL-AVGNSLFASA-N Glu-Asn-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SBYVDRJAXWSXQL-AVGNSLFASA-N 0.000 description 4
- PHONAZGUEGIOEM-GLLZPBPUSA-N Glu-Glu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PHONAZGUEGIOEM-GLLZPBPUSA-N 0.000 description 4
- VSRCAOIHMGCIJK-SRVKXCTJSA-N Glu-Leu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VSRCAOIHMGCIJK-SRVKXCTJSA-N 0.000 description 4
- WNRZUESNGGDCJX-JYJNAYRXSA-N Glu-Leu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WNRZUESNGGDCJX-JYJNAYRXSA-N 0.000 description 4
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 4
- 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 4
- 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 4
- CKRJBQJIGOEKMC-SRVKXCTJSA-N His-Lys-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O CKRJBQJIGOEKMC-SRVKXCTJSA-N 0.000 description 4
- PYNPBMCLAKTHJL-SRVKXCTJSA-N His-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O PYNPBMCLAKTHJL-SRVKXCTJSA-N 0.000 description 4
- CCUSLCQWVMWTIS-IXOXFDKPSA-N His-Thr-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O CCUSLCQWVMWTIS-IXOXFDKPSA-N 0.000 description 4
- LDRALPZEVHVXEK-KBIXCLLPSA-N Ile-Cys-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N LDRALPZEVHVXEK-KBIXCLLPSA-N 0.000 description 4
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 4
- 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 4
- FDBTVENULFNTAL-XQQFMLRXSA-N Leu-Val-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N FDBTVENULFNTAL-XQQFMLRXSA-N 0.000 description 4
- WTZUSCUIVPVCRH-SRVKXCTJSA-N Lys-Gln-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N WTZUSCUIVPVCRH-SRVKXCTJSA-N 0.000 description 4
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 4
- JMNRXRPBHFGXQX-GUBZILKMSA-N Lys-Ser-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JMNRXRPBHFGXQX-GUBZILKMSA-N 0.000 description 4
- TVOOGUNBIWAURO-KATARQTJSA-N Lys-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N)O TVOOGUNBIWAURO-KATARQTJSA-N 0.000 description 4
- 108010016076 Octreotide Proteins 0.000 description 4
- AJOKKVTWEMXZHC-DRZSPHRISA-N Phe-Ala-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 AJOKKVTWEMXZHC-DRZSPHRISA-N 0.000 description 4
- OQTDZEJJWWAGJT-KKUMJFAQSA-N Phe-Lys-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O OQTDZEJJWWAGJT-KKUMJFAQSA-N 0.000 description 4
- AFNJAQVMTIQTCB-DLOVCJGASA-N Phe-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 AFNJAQVMTIQTCB-DLOVCJGASA-N 0.000 description 4
- DEDANIDYQAPTFI-IHRRRGAJSA-N Pro-Asp-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O DEDANIDYQAPTFI-IHRRRGAJSA-N 0.000 description 4
- ZBAGOWGNNAXMOY-IHRRRGAJSA-N Pro-Cys-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZBAGOWGNNAXMOY-IHRRRGAJSA-N 0.000 description 4
- LHALYDBUDCWMDY-CIUDSAMLSA-N Pro-Glu-Ala Chemical compound C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O LHALYDBUDCWMDY-CIUDSAMLSA-N 0.000 description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 4
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 4
- KNZQGAUEYZJUSQ-ZLUOBGJFSA-N Ser-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)N KNZQGAUEYZJUSQ-ZLUOBGJFSA-N 0.000 description 4
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 4
- JLPMFVAIQHCBDC-CIUDSAMLSA-N Ser-Lys-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N JLPMFVAIQHCBDC-CIUDSAMLSA-N 0.000 description 4
- VOHWDZNIESHTFW-XKBZYTNZSA-N Thr-Glu-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O VOHWDZNIESHTFW-XKBZYTNZSA-N 0.000 description 4
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 4
- KVEWWQRTAVMOFT-KJEVXHAQSA-N Thr-Tyr-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O KVEWWQRTAVMOFT-KJEVXHAQSA-N 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 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 4
- ZRSZTKTVPNSUNA-IHRRRGAJSA-N Val-Lys-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(O)=O ZRSZTKTVPNSUNA-IHRRRGAJSA-N 0.000 description 4
- 108010060035 arginylproline Proteins 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 108010049041 glutamylalanine Proteins 0.000 description 4
- 108010073093 leucyl-glycyl-glycyl-glycine Proteins 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229960002700 octreotide Drugs 0.000 description 4
- 108010051242 phenylalanylserine Proteins 0.000 description 4
- 108010004914 prolylarginine Proteins 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- 108010073969 valyllysine Proteins 0.000 description 4
- IFMZMDAHXSSNLT-QAETUUGQSA-N (2s)-2-[[(2s)-4-amino-2-[[(2s)-6-amino-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]hexanoyl]amino]-4-oxobutanoyl]amino]-3-phenylpropanoic acid Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IFMZMDAHXSSNLT-QAETUUGQSA-N 0.000 description 3
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 3
- OTEWWRBKGONZBW-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]-4-methylpentanoyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NC(CC(C)C)C(=O)NCC(=O)NCC(O)=O OTEWWRBKGONZBW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 3
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 3
- 108010011667 Ala-Phe-Ala Proteins 0.000 description 3
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 3
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 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
- YRBGRUOSJROZEI-NHCYSSNCSA-N Asp-His-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(O)=O YRBGRUOSJROZEI-NHCYSSNCSA-N 0.000 description 3
- LBFYTUPYYZENIR-GHCJXIJMSA-N Asp-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N LBFYTUPYYZENIR-GHCJXIJMSA-N 0.000 description 3
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 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
- QTIZKMMLNUMHHU-DCAQKATOSA-N Asp-Pro-His Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O QTIZKMMLNUMHHU-DCAQKATOSA-N 0.000 description 3
- OQMGSMNZVHYDTQ-ZKWXMUAHSA-N Asp-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N OQMGSMNZVHYDTQ-ZKWXMUAHSA-N 0.000 description 3
- GXIUDSXIUSTSLO-QXEWZRGKSA-N Asp-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N GXIUDSXIUSTSLO-QXEWZRGKSA-N 0.000 description 3
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 3
- ISWAQPWFWKGCAL-ACZMJKKPSA-N Cys-Cys-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISWAQPWFWKGCAL-ACZMJKKPSA-N 0.000 description 3
- SBDVXRYCOIEYNV-YUMQZZPRSA-N Cys-His-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CS)N SBDVXRYCOIEYNV-YUMQZZPRSA-N 0.000 description 3
- 238000012286 ELISA Assay Methods 0.000 description 3
- ZFADFBPRMSBPOT-KKUMJFAQSA-N Gln-Arg-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O ZFADFBPRMSBPOT-KKUMJFAQSA-N 0.000 description 3
- RRBLZNIIMHSHQF-FXQIFTODSA-N Gln-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N RRBLZNIIMHSHQF-FXQIFTODSA-N 0.000 description 3
- JKDBRTNMYXYLHO-JYJNAYRXSA-N Gln-Tyr-Leu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 JKDBRTNMYXYLHO-JYJNAYRXSA-N 0.000 description 3
- YKLNMGJYMNPBCP-ACZMJKKPSA-N Glu-Asn-Asp Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YKLNMGJYMNPBCP-ACZMJKKPSA-N 0.000 description 3
- KIMXNQXJJWWVIN-AVGNSLFASA-N Glu-Cys-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N)O KIMXNQXJJWWVIN-AVGNSLFASA-N 0.000 description 3
- QQLBPVKLJBAXBS-FXQIFTODSA-N Glu-Glu-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QQLBPVKLJBAXBS-FXQIFTODSA-N 0.000 description 3
- ZQYZDDXTNQXUJH-CIUDSAMLSA-N Glu-Met-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)O)N ZQYZDDXTNQXUJH-CIUDSAMLSA-N 0.000 description 3
- UMHRCVCZUPBBQW-GARJFASQSA-N Glu-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N UMHRCVCZUPBBQW-GARJFASQSA-N 0.000 description 3
- UERORLSAFUHDGU-AVGNSLFASA-N Glu-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)O)N UERORLSAFUHDGU-AVGNSLFASA-N 0.000 description 3
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 3
- QGDOOCIPHSSADO-STQMWFEESA-N Gly-Met-Phe Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGDOOCIPHSSADO-STQMWFEESA-N 0.000 description 3
- FDQYIRHBVVUTJF-ZETCQYMHSA-N His-Gly-Gly Chemical compound [O-]C(=O)CNC(=O)CNC(=O)[C@@H]([NH3+])CC1=CN=CN1 FDQYIRHBVVUTJF-ZETCQYMHSA-N 0.000 description 3
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 3
- QEYUCKCWTMIERU-SRVKXCTJSA-N His-Lys-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N QEYUCKCWTMIERU-SRVKXCTJSA-N 0.000 description 3
- DBSLVQBXKVKDKJ-BJDJZHNGSA-N Leu-Ile-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O DBSLVQBXKVKDKJ-BJDJZHNGSA-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
- ZRHDPZAAWLXXIR-SRVKXCTJSA-N Leu-Lys-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O ZRHDPZAAWLXXIR-SRVKXCTJSA-N 0.000 description 3
- DCGXHWINSHEPIR-SRVKXCTJSA-N Leu-Lys-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N DCGXHWINSHEPIR-SRVKXCTJSA-N 0.000 description 3
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 3
- VJGQRELPQWNURN-JYJNAYRXSA-N Leu-Tyr-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O VJGQRELPQWNURN-JYJNAYRXSA-N 0.000 description 3
- 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 3
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 3
- PINHPJWGVBKQII-SRVKXCTJSA-N Lys-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N PINHPJWGVBKQII-SRVKXCTJSA-N 0.000 description 3
- 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 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- QCHNRQQVLJYDSI-DLOVCJGASA-N Phe-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 QCHNRQQVLJYDSI-DLOVCJGASA-N 0.000 description 3
- DDYIRGBOZVKRFR-AVGNSLFASA-N Phe-Asp-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DDYIRGBOZVKRFR-AVGNSLFASA-N 0.000 description 3
- UMKYAYXCMYYNHI-AVGNSLFASA-N Phe-Gln-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N UMKYAYXCMYYNHI-AVGNSLFASA-N 0.000 description 3
- JEBWZLWTRPZQRX-QWRGUYRKSA-N Phe-Gly-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O JEBWZLWTRPZQRX-QWRGUYRKSA-N 0.000 description 3
- RSPUIENXSJYZQO-JYJNAYRXSA-N Phe-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RSPUIENXSJYZQO-JYJNAYRXSA-N 0.000 description 3
- LRBSWBVUCLLRLU-BZSNNMDCSA-N Phe-Leu-Lys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(O)=O LRBSWBVUCLLRLU-BZSNNMDCSA-N 0.000 description 3
- 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 3
- 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 3
- 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 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
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- RNFKSBPHLTZHLU-WHFBIAKZSA-N Ser-Cys-Gly Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N)O RNFKSBPHLTZHLU-WHFBIAKZSA-N 0.000 description 3
- 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 3
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 3
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 3
- XIFAHCUNWWKUDE-DCAQKATOSA-N Val-Cys-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N XIFAHCUNWWKUDE-DCAQKATOSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 108010060199 cysteinylproline Proteins 0.000 description 3
- 239000013024 dilution buffer Substances 0.000 description 3
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 3
- 108010054666 glycyl-leucyl-glycyl-glycine Proteins 0.000 description 3
- 102000045305 human SST Human genes 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 108010021336 lanreotide Proteins 0.000 description 3
- 229960002437 lanreotide Drugs 0.000 description 3
- 108010009298 lysylglutamic acid Proteins 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000010355 oscillation Effects 0.000 description 3
- 108010012581 phenylalanylglutamate Proteins 0.000 description 3
- 108020001580 protein domains Proteins 0.000 description 3
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 2
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- IHMCQESUJVZTKW-UBHSHLNASA-N Ala-Phe-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 IHMCQESUJVZTKW-UBHSHLNASA-N 0.000 description 2
- JCAISGGAOQXEHJ-ZPFDUUQYSA-N Arg-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N JCAISGGAOQXEHJ-ZPFDUUQYSA-N 0.000 description 2
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 2
- OERMIMJQPQUIPK-FXQIFTODSA-N Asp-Arg-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O OERMIMJQPQUIPK-FXQIFTODSA-N 0.000 description 2
- SVFOIXMRMLROHO-SRVKXCTJSA-N Asp-Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SVFOIXMRMLROHO-SRVKXCTJSA-N 0.000 description 2
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 2
- GPPIDDWYKJPRES-YDHLFZDLSA-N Asp-Phe-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O GPPIDDWYKJPRES-YDHLFZDLSA-N 0.000 description 2
- NWAHPBGBDIFUFD-KKUMJFAQSA-N Asp-Tyr-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O NWAHPBGBDIFUFD-KKUMJFAQSA-N 0.000 description 2
- UFOBYROTHHYVGW-CIUDSAMLSA-N Cys-Cys-His Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CNC=N1)C(O)=O UFOBYROTHHYVGW-CIUDSAMLSA-N 0.000 description 2
- KZZYVYWSXMFYEC-DCAQKATOSA-N Cys-Val-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KZZYVYWSXMFYEC-DCAQKATOSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 2
- CYHBMLHCQXXCCT-AVGNSLFASA-N Glu-Asp-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CYHBMLHCQXXCCT-AVGNSLFASA-N 0.000 description 2
- BCYGDJXHAGZNPQ-DCAQKATOSA-N Glu-Lys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O BCYGDJXHAGZNPQ-DCAQKATOSA-N 0.000 description 2
- 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 2
- VHPVBPCCWVDGJL-IRIUXVKKSA-N Glu-Thr-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VHPVBPCCWVDGJL-IRIUXVKKSA-N 0.000 description 2
- 102000005720 Glutathione transferase Human genes 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- CUYLIWAAAYJKJH-RYUDHWBXSA-N Gly-Glu-Tyr Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CUYLIWAAAYJKJH-RYUDHWBXSA-N 0.000 description 2
- PDAWDNVHMUKWJR-ZETCQYMHSA-N Gly-Gly-His Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 PDAWDNVHMUKWJR-ZETCQYMHSA-N 0.000 description 2
- JCOSMKPAOYDKRO-AVGNSLFASA-N His-Glu-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N JCOSMKPAOYDKRO-AVGNSLFASA-N 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 102100020992 Interferon lambda-3 Human genes 0.000 description 2
- 101710099621 Interferon lambda-3 Proteins 0.000 description 2
- 241000235058 Komagataella pastoris Species 0.000 description 2
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- RFUBXQQFJFGJFV-GUBZILKMSA-N Leu-Asn-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RFUBXQQFJFGJFV-GUBZILKMSA-N 0.000 description 2
- QPXBPQUGXHURGP-UWVGGRQHSA-N Leu-Gly-Met Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)O)N QPXBPQUGXHURGP-UWVGGRQHSA-N 0.000 description 2
- 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 2
- YRWCPXOFBKTCFY-NUTKFTJISA-N Lys-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N YRWCPXOFBKTCFY-NUTKFTJISA-N 0.000 description 2
- CKSXSQUVEYCDIW-AVGNSLFASA-N Lys-Arg-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)N CKSXSQUVEYCDIW-AVGNSLFASA-N 0.000 description 2
- GKFNXYMAMKJSKD-NHCYSSNCSA-N Lys-Asp-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O GKFNXYMAMKJSKD-NHCYSSNCSA-N 0.000 description 2
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 2
- PIXVFCBYEGPZPA-JYJNAYRXSA-N Lys-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N PIXVFCBYEGPZPA-JYJNAYRXSA-N 0.000 description 2
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 2
- LRALLISKBZNSKN-BQBZGAKWSA-N Met-Gly-Ser Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LRALLISKBZNSKN-BQBZGAKWSA-N 0.000 description 2
- DNAXXTQSTKOHFO-QEJZJMRPSA-N Phe-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 DNAXXTQSTKOHFO-QEJZJMRPSA-N 0.000 description 2
- FKKHDBFNOLCYQM-FXQIFTODSA-N Pro-Cys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O FKKHDBFNOLCYQM-FXQIFTODSA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- AJCRQOHDLCBHFA-SRVKXCTJSA-N Pro-His-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O AJCRQOHDLCBHFA-SRVKXCTJSA-N 0.000 description 2
- FDMCIBSQRKFSTJ-RHYQMDGZSA-N Pro-Thr-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O FDMCIBSQRKFSTJ-RHYQMDGZSA-N 0.000 description 2
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 2
- 101150084577 SST2 gene Proteins 0.000 description 2
- CNIIKZQXBBQHCX-FXQIFTODSA-N Ser-Asp-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O CNIIKZQXBBQHCX-FXQIFTODSA-N 0.000 description 2
- QKQDTEYDEIJPNK-GUBZILKMSA-N Ser-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CO QKQDTEYDEIJPNK-GUBZILKMSA-N 0.000 description 2
- 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 2
- ZSDXEKUKQAKZFE-XAVMHZPKSA-N Ser-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N)O ZSDXEKUKQAKZFE-XAVMHZPKSA-N 0.000 description 2
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 2
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 2
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 2
- SCSVNSNWUTYSFO-WDCWCFNPSA-N Thr-Lys-Glu Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O SCSVNSNWUTYSFO-WDCWCFNPSA-N 0.000 description 2
- YGCDFAJJCRVQKU-RCWTZXSCSA-N Thr-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O YGCDFAJJCRVQKU-RCWTZXSCSA-N 0.000 description 2
- 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 2
- OLYXUGBVBGSZDN-ACRUOGEOSA-N Tyr-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=C(O)C=C1 OLYXUGBVBGSZDN-ACRUOGEOSA-N 0.000 description 2
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 2
- OJOMXGVLFKYDKP-QXEWZRGKSA-N Val-Met-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OJOMXGVLFKYDKP-QXEWZRGKSA-N 0.000 description 2
- BGXVHVMJZCSOCA-AVGNSLFASA-N Val-Pro-Lys Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N BGXVHVMJZCSOCA-AVGNSLFASA-N 0.000 description 2
- 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 2
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 2
- 108010070944 alanylhistidine Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 230000001593 cAMP accumulation Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 108010009297 diglycyl-histidine Proteins 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 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 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 108010068488 methionylphenylalanine Proteins 0.000 description 2
- MXHCPCSDRGLRER-UHFFFAOYSA-N pentaglycine Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O MXHCPCSDRGLRER-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 102000004052 somatostatin receptor 2 Human genes 0.000 description 2
- 108010049553 somatostatin receptor sst2A Proteins 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 1
- IGXNPQWXIRIGBF-KEOOTSPTSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoic acid Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 IGXNPQWXIRIGBF-KEOOTSPTSA-N 0.000 description 1
- NPJIOCBFOAHEDO-AVWFULIKSA-N (3s,6s,9s,12r,15s,18s)-9-(4-aminobutyl)-3-benzyl-15-[(4-hydroxyphenyl)methyl]-12-(1h-indol-3-ylmethyl)-1,18-dimethyl-6-propan-2-yl-1,4,7,10,13,16-hexazacyclooctadecane-2,5,8,11,14,17-hexone Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N(C)[C@@H](C)C(=O)N1)=O)C(C)C)C1=CC=C(O)C=C1 NPJIOCBFOAHEDO-AVWFULIKSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- MUSGYEMSJUFFHT-UWABRSFTSA-N 2-[(4R,7S,10S,13S,19S,22S,25S,28S,31S,34R)-34-[[(2S,3S)-2-[[(2R)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-4-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]-methylcarbamoyl]-25-(3-amino-3-oxopropyl)-7-(3-carbamimidamidopropyl)-10-(1H-imidazol-5-ylmethyl)-19-(1H-indol-3-ylmethyl)-13,17-dimethyl-28-[(1-methylindol-3-yl)methyl]-6,9,12,15,18,21,24,27,30,33-decaoxo-31-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29,32-decazacyclopentatriacont-22-yl]acetic acid Chemical group CC[C@H](C)[C@H](NC(=O)[C@H](N)Cc1ccc(O)cc1)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H](C)NC(=O)CN(C)C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc2cn(C)c3ccccc23)NC(=O)[C@@H](NC1=O)C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)C(N)=O MUSGYEMSJUFFHT-UWABRSFTSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical class OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- 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
- XJFPXLWGZWAWRQ-UHFFFAOYSA-N 2-[[2-[[2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O XJFPXLWGZWAWRQ-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- 108010091324 3C proteases Proteins 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 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 1
- GWFSQQNGMPGBEF-GHCJXIJMSA-N Ala-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N GWFSQQNGMPGBEF-GHCJXIJMSA-N 0.000 description 1
- LSLIRHLIUDVNBN-CIUDSAMLSA-N Ala-Asp-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LSLIRHLIUDVNBN-CIUDSAMLSA-N 0.000 description 1
- CXZFXHGJJPVUJE-CIUDSAMLSA-N Ala-Cys-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)O)N CXZFXHGJJPVUJE-CIUDSAMLSA-N 0.000 description 1
- 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 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- QUIGLPSHIFPEOV-CIUDSAMLSA-N Ala-Lys-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O QUIGLPSHIFPEOV-CIUDSAMLSA-N 0.000 description 1
- 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 1
- XUCHENWTTBFODJ-FXQIFTODSA-N Ala-Met-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O XUCHENWTTBFODJ-FXQIFTODSA-N 0.000 description 1
- CYBJZLQSUJEMAS-LFSVMHDDSA-N Ala-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C)N)O CYBJZLQSUJEMAS-LFSVMHDDSA-N 0.000 description 1
- XKHLBBQNPSOGPI-GUBZILKMSA-N Ala-Val-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)N XKHLBBQNPSOGPI-GUBZILKMSA-N 0.000 description 1
- UZGFHWIJWPUPOH-IHRRRGAJSA-N Arg-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UZGFHWIJWPUPOH-IHRRRGAJSA-N 0.000 description 1
- YVTHEZNOKSAWRW-DCAQKATOSA-N Arg-Lys-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O YVTHEZNOKSAWRW-DCAQKATOSA-N 0.000 description 1
- FOQFHANLUJDQEE-GUBZILKMSA-N Arg-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CS)C(=O)O FOQFHANLUJDQEE-GUBZILKMSA-N 0.000 description 1
- XSPKAHFVDKRGRL-DCAQKATOSA-N Arg-Pro-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XSPKAHFVDKRGRL-DCAQKATOSA-N 0.000 description 1
- SLHOOKXYTYAJGQ-XVYDVKMFSA-N Asp-Ala-His Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 SLHOOKXYTYAJGQ-XVYDVKMFSA-N 0.000 description 1
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 1
- LIVXPXUVXFRWNY-CIUDSAMLSA-N Asp-Lys-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O LIVXPXUVXFRWNY-CIUDSAMLSA-N 0.000 description 1
- VSMYBNPOHYAXSD-GUBZILKMSA-N Asp-Lys-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O VSMYBNPOHYAXSD-GUBZILKMSA-N 0.000 description 1
- SFJUYBCDQBAYAJ-YDHLFZDLSA-N Asp-Val-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SFJUYBCDQBAYAJ-YDHLFZDLSA-N 0.000 description 1
- 108010077805 Bacterial Proteins Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- HIPHJNWPLMUBQQ-ACZMJKKPSA-N Cys-Cys-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O HIPHJNWPLMUBQQ-ACZMJKKPSA-N 0.000 description 1
- NXTYATMDWQYLGJ-BQBZGAKWSA-N Cys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CS NXTYATMDWQYLGJ-BQBZGAKWSA-N 0.000 description 1
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 1
- RESAHOSBQHMOKH-KKUMJFAQSA-N Cys-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CS)N RESAHOSBQHMOKH-KKUMJFAQSA-N 0.000 description 1
- SAEVTQWAYDPXMU-KATARQTJSA-N Cys-Thr-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O SAEVTQWAYDPXMU-KATARQTJSA-N 0.000 description 1
- FCXJJTRGVAZDER-FXQIFTODSA-N Cys-Val-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O FCXJJTRGVAZDER-FXQIFTODSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 108010013369 Enteropeptidase Proteins 0.000 description 1
- 102100029727 Enteropeptidase Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 108010058643 Fungal Proteins Proteins 0.000 description 1
- 102400000921 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- RTOOAKXIJADOLL-GUBZILKMSA-N Glu-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](CCC(=O)O)N RTOOAKXIJADOLL-GUBZILKMSA-N 0.000 description 1
- OAGVHWYIBZMWLA-YFKPBYRVSA-N Glu-Gly-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(O)=O OAGVHWYIBZMWLA-YFKPBYRVSA-N 0.000 description 1
- KRGZZKWSBGPLKL-IUCAKERBSA-N Glu-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N KRGZZKWSBGPLKL-IUCAKERBSA-N 0.000 description 1
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 1
- HVKAAUOFFTUSAA-XDTLVQLUSA-N Glu-Tyr-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O HVKAAUOFFTUSAA-XDTLVQLUSA-N 0.000 description 1
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- NTOWAXLMQFKJPT-YUMQZZPRSA-N Gly-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN NTOWAXLMQFKJPT-YUMQZZPRSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 1
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- CJGDTAHEMXLRMB-ULQDDVLXSA-N His-Arg-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CJGDTAHEMXLRMB-ULQDDVLXSA-N 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 241001506991 Komagataella phaffii GS115 Species 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- ILJREDZFPHTUIE-GUBZILKMSA-N Leu-Asp-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ILJREDZFPHTUIE-GUBZILKMSA-N 0.000 description 1
- HQUXQAMSWFIRET-AVGNSLFASA-N Leu-Glu-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN HQUXQAMSWFIRET-AVGNSLFASA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-N 0.000 description 1
- MJWVXZABPOKJJF-ACRUOGEOSA-N Leu-Phe-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MJWVXZABPOKJJF-ACRUOGEOSA-N 0.000 description 1
- VTJUNIYRYIAIHF-IUCAKERBSA-N Leu-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O VTJUNIYRYIAIHF-IUCAKERBSA-N 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- NPBGTPKLVJEOBE-IUCAKERBSA-N Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=N NPBGTPKLVJEOBE-IUCAKERBSA-N 0.000 description 1
- YFGWNAROEYWGNL-GUBZILKMSA-N Lys-Gln-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YFGWNAROEYWGNL-GUBZILKMSA-N 0.000 description 1
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 1
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 1
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- BJEYSVHMGIJORT-NHCYSSNCSA-N Phe-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 BJEYSVHMGIJORT-NHCYSSNCSA-N 0.000 description 1
- 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 1
- JKJSIYKSGIDHPM-WBAXXEDZSA-N Phe-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1)C(O)=O JKJSIYKSGIDHPM-WBAXXEDZSA-N 0.000 description 1
- XNQMZHLAYFWSGJ-HTUGSXCWSA-N Phe-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XNQMZHLAYFWSGJ-HTUGSXCWSA-N 0.000 description 1
- 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 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- MWMKFWJYRRGXOR-ZLUOBGJFSA-N Ser-Ala-Asn Chemical compound N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)CC(N)=O)C)CO MWMKFWJYRRGXOR-ZLUOBGJFSA-N 0.000 description 1
- BTKUIVBNGBFTTP-WHFBIAKZSA-N Ser-Ala-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(O)=O BTKUIVBNGBFTTP-WHFBIAKZSA-N 0.000 description 1
- DKKGAAJTDKHWOD-BIIVOSGPSA-N Ser-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)C(=O)O DKKGAAJTDKHWOD-BIIVOSGPSA-N 0.000 description 1
- YRBGKVIWMNEVCZ-WDSKDSINSA-N Ser-Glu-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YRBGKVIWMNEVCZ-WDSKDSINSA-N 0.000 description 1
- 101800001707 Spacer peptide Proteins 0.000 description 1
- 108010076818 TEV protease Proteins 0.000 description 1
- LOHBIDZYHQQTDM-IXOXFDKPSA-N Thr-Cys-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LOHBIDZYHQQTDM-IXOXFDKPSA-N 0.000 description 1
- GYUUYCIXELGTJS-MEYUZBJRSA-N Thr-Phe-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O GYUUYCIXELGTJS-MEYUZBJRSA-N 0.000 description 1
- WKQNLTQSCYXKQK-VFAJRCTISA-N Trp-Lys-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WKQNLTQSCYXKQK-VFAJRCTISA-N 0.000 description 1
- JAGGEZACYAAMIL-CQDKDKBSSA-N Tyr-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JAGGEZACYAAMIL-CQDKDKBSSA-N 0.000 description 1
- CVIXTAITYJQMPE-LAEOZQHASA-N Val-Glu-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CVIXTAITYJQMPE-LAEOZQHASA-N 0.000 description 1
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 1
- MLADEWAIYAPAAU-IHRRRGAJSA-N Val-Lys-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N MLADEWAIYAPAAU-IHRRRGAJSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 1
- 108010010430 asparagine-proline-alanine Proteins 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000012787 harvest procedure Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 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 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 108700024167 iodine-Tyr- somatostatin Proteins 0.000 description 1
- 108010027338 isoleucylcysteine Proteins 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000004025 pancreas hormone Substances 0.000 description 1
- 108700017947 pasireotide Proteins 0.000 description 1
- 229960005415 pasireotide Drugs 0.000 description 1
- VMZMNAABQBOLAK-DBILLSOUSA-N pasireotide Chemical compound C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 VMZMNAABQBOLAK-DBILLSOUSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 108010052231 seglitide Proteins 0.000 description 1
- 229950002758 seglitide Drugs 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 229940075620 somatostatin analogue Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012536 storage buffer Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124598 therapeutic candidate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Plant Pathology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Immunology (AREA)
Abstract
本发明涉及人生长抑素(例如，SST‑14或SST‑28)和人血清白蛋白的融合蛋白，包括与人生长抑素至少85％同源的区域和与人血清白蛋白至少85％同源的区域或具有人血清白蛋白的部分氨基酸序列的区域，其中接头肽序列可存在于生长抑素和生长抑素部分或生长抑素和白蛋白部分之间。还公开了构建体，其中生长抑素部分包含生长抑素序列的多个串联重复序列。在选定的实施方式中，生长抑素和白蛋白部分的取向可以变化，并且这些序列可以影响所公开的融合蛋白的结合和功效。还公开了制备和使用前述构建体的方法。与游离生长抑素相比，生长抑素‑白蛋白融合蛋白在体外在大鼠血浆中温育时表现出增强的稳定性，并且在体内表现出延长的血浆半衰期。
Description
相关申请的交叉引用
本申请要求于2016年8月26日提交的美国专利申请15/249,346的优先权，其内容通过引用并入本文。
美国专利申请15/249,346是PCT/US2016/019950的部分继续申请，其要求于2015年2月26日提交的美国临时专利申请系列号US 62/121,487的优先权的权益，其各自的内容通过引用并入本文。
美国专利申请15/249,346也要求了于2016年2月26日提交的台湾专利申请No.105106088的优先权，其也要求了于2015年2月26日提交的美国临时专利申请No.62/121,487的优先权的权益，其各自的内容通过引用并入本文。
技术领域
本发明涉及融合蛋白，包括生长抑素，或其类似物或衍生物，接头或间隔物(spacer)以及白蛋白，或其类似物或变体。
本发明还涉及重组融合蛋白，包含通过间隔物序列和其类似物间隔开的人血清白蛋白部分和生长抑素部分。
背景技术
生长抑素(“SST”)是各种内分泌和非内分泌组织的分泌产物，且广泛分布于全身。生长抑素抑制垂体、胰腺和胃肠激素分泌的释放，以及细胞因子的产生，肠道能动性和吸收，血管收缩性和细胞增殖。最近的研究发现，SST可用于治疗癌症，抑制肿瘤生长，抑制内分泌肿瘤的增殖，以及许多其他实体肿瘤，诸如乳腺癌、结肠直肠癌、肝癌、肺癌、内分泌癌、神经内分泌癌、胰腺癌和前列腺癌。生长抑素分子具有两种生物活性形式：生长抑素-14(SST-14)，环十四肽和生长抑素-28(SST-28)，SST-14的N末端伸长形式。SST-14是长度为14个残基的环肽，在3位和14位的半胱氨酸之间包含二硫键。SST-28是相同前体的N末端延伸形式(28个残基)，该前体会被蛋白水解切割以产生SST-14。尽管两者具有相似的活性，但它们各自的效力和组织学特点各不相同。例如，SST-14显示出对胰高血糖素和胃泌素的抑制作用更明显，而SST-28显示出对生长激素和胰岛素作用的抑制作用更明显。两种形式的生长抑素通过细胞内途径和靶细胞上的受体发挥其各自的生物学功能。已经识别出5种生长抑素受体亚型(SSTR1-5)，SSTR2的两种剪接变异体：SSTR2A和SSTR2B，具有不同的羧基末端。
生长抑素在治疗某些分泌过多的内分泌紊乱中的有益作用及其对肿瘤的抗增殖作用已得到公认。然而，由于酶促降解和内吞作用，体内生长抑素的半衰期仅为2-3分钟，限制了生长抑素的临床应用。在过去的十年中，已经开发了许多稳定的生长抑素类似物。例如，奥曲肽(octreotide)和兰瑞肽(lanreotide)用于治疗生长激素(GH)-分泌腺瘤和类癌。然而，由于对SSTR的结合亲和力改变，仍然存在治疗限制。结果，本领域仍然需要实现高体内半衰期，同时保持对SSTR的理想的结合亲和力的生长抑制素构建体。
白蛋白是血浆中最丰富的蛋白质，在肝脏中作为67kDa的单体蛋白质产生，并且负责血浆的80％的胶体渗透压。与HSA融合的人粒细胞集落刺激因子(G-CSF)、人生长激素(GH)、人胰岛素、人干扰素-a-2b(INF-2b)和白细胞介素-28B(IL-28B)被有效地用于构建长效治疗候选药物。然而，HSA融合蛋白与母体分子之间在生物学和分子机制方面的比较研究的报道较少。
中国专利申请CN102391376A和CN102675467A(均通过引用并入本文)公开了生长抑素-白蛋白融合蛋白。然而，仍然需要进一步开发生长抑素-白蛋白融合蛋白。
发明内容
本发明提供了生长抑素-白蛋白融合蛋白和其类似物，以及生产和使用其的方法。根据本发明制备的构建体包括白蛋白(或其类似物)部分、生长抑素部分(SST-14、SST-28)和将两部分间隔开的间隔物，诸如间隔物肽或接头肽。
根据本发明的融合蛋白本文也描述为多肽。在某些实施方式中，根据本发明的多肽可任选地包括一种或多种非天然存在的氨基酸或氨基酸残基。
生长抑素-白蛋白融合蛋白和其类似物广泛地包括人SST肽部分、接头或间隔物和人白蛋白部分。SST肽部分可包括其类似物和衍生物，其主动/积极抑制人生长激素的活性。任选地，SST肽部分从天然或合成来源获得。白蛋白部分是例如人白蛋白和/或其活性片段或亚结构域。选择接头和间隔物以增强生长抑素-白蛋白融合蛋白的稳定性。更特别地，生长抑素-白蛋白融合蛋白和其类似物具有以下结构。
本发明提供的融合蛋白包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素，它的类似物或衍生物；
L是间隔物或接头；以及
ALB是白蛋白，它的类似物或变体。
优选地，本发明的融合蛋白是分离并纯化的。
任选地，本发明融合蛋白的ALB组分是哺乳动物血清白蛋白。在一种实施方式中，哺乳动物血清白蛋白是SEQ ID NO:25，或具有与其至少85％序列同一性的序列。
在其他具体实施方式中，本发明的融合蛋白选自由以下组成的组：
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；
以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
x1、x2、x3、x4、y1、y2或y3独立为零或选自1-10的整数，或更特别地选自1-5的整数，或选自1-4的整数，前提是在编码白蛋白-生长抑素融合蛋白的核苷酸序列中存在至少一个L。
在替代实施方式中，本发明的融合蛋白包括或是天然存在的或是合成制备的SST。
在又一实施方式中，本发明的融合蛋白的SST包括编码分别由SEQ ID NO：17或18表示的SST-14或SST-28的序列，或者与这些序列的任一具有至少85％同一性的序列的一个或多个串联重复序列。
SST部分任选为SST-14或SST-28。
在又一实施方式中，融合蛋白包括L，其为柔性或α螺旋结构的多肽接头或间隔物。
在又一实施方式中，融合蛋白包括L，其是具有2-100个氨基酸的多肽。根据本发明的又一实施方式的接头或间隔物涵盖在一个末端与生长抑素共价连接并在另一末端与白蛋白共价连接的肽。
术语“接头”或“间隔物(间隔序列)”在本文中可互换使用，是指用于分隔单个蛋白质中的多个结构域的短氨基酸序列。蛋白质中两个或更多个离散结构域之间不存在接头可导致蛋白质结构域的功能性降低或不正确，例如，由于空间位阻，对受体/配体的结合亲和力或催化活性降低。使用人工接头连接嵌合蛋白中的蛋白质结构域可以增加结构域之间的空间。优选地，接头或间隔物的选择独立于生长抑素和白蛋白。
接头L或是柔性的或是α螺旋结构的多肽接头或间隔物。在某些实施方式中，L包含GGGGS、A(EAAAK)4A、(AP)n(其中n是选自10-34的整数)、(G)8、(G)5中至少一种或其任何组合。
本文所述的白蛋白-生长抑素融合构建体还可包括信号肽序列(“SP”)。信号肽被理解为是指存在于多肽的N-末端的短氨基酸序列，其引导新合成蛋白质的细胞定位。例如，信号肽可使蛋白质定位于给定的细胞内区域(例如，细胞核)，插入膜(例如，细胞膜或内质网)或从细胞中分泌。除了引导定位，还可以将信号肽掺入重组蛋白中以改善稳定性，改变表达水平，并且有助于重组蛋白的正确折叠。前体蛋白的信号肽序列通常通过宿主细胞中的信号肽酶移除以产生成熟蛋白。
本文所述的白蛋白-生长抑素融合蛋白构建体还可包括亲和或纯化标签，作为多肽序列的一部分以促进纯化。这种标签用作亲和层析方法的一部分，例如高效液相色谱(HPLC)，以从粗生物来源提纯蛋白质样品。合适的纯化标签包括但不限于：聚组氨酸(例如，His-6或H6)、谷胱甘肽-S-转移酶(GST)、麦芽糖结合蛋白(MBP)、几丁质结合蛋白(CBP)、FLAG-标签(FLAG八肽)。当需要从融合蛋白中移除亲和标签时，可以在接头区域引入特异性酶切位点。通常用于移除亲和标签的酶包括，但不限于：因子Xa、肠激酶、凝血酶、TEV蛋白酶和鼻病毒3C蛋白酶。
在又一实施方式中，本发明提供了编码多肽的核苷酸序列，该多肽包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素或它的类似物或衍生物；
L是间隔物或接头；以及
ALB是白蛋白或它的类似物或变体。
在具体实施方式中，本发明核苷酸编码选自由以下组成的组的多肽：
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
x1、x2、x3、x4、y1、y2或y3各自独立为零或选自1-10的整数，或更特别地选自1-5或选自1-4的整数，前提是在多肽中存在至少一个L。
在又一实施方式中，核苷酸序列编码融合蛋白，其中SST包括编码分别由SEQ IDNO：17或18表示的SST-14或SST-28的序列，或者与这些序列的任一具有至少85％同一性的序列的一个或多个串联重复序列。
进一步预期本发明包括表达载体，例如质粒构建体，包含该表达载体的宿主细胞，其能够表达本发明的白蛋白-生长抑素融合蛋白。宿主细胞可以是合适的细菌宿主细胞、合适的哺乳动物宿主细胞、合适的植物宿主细胞或合适的昆虫宿主细胞。
本发明还提供了通过给药有效量的包含本发明融合蛋白的药物组合物来治疗哺乳动物(诸如人受试者)内分泌释放的疾病或疾患的方法，其中内分泌释放的疾病或疾患是对给药生长抑素有反应的病症。
例如，疾病或疾患是选自由以下组成的组的癌症：乳腺癌、结肠直肠癌、肝癌、内分泌癌、神经内分泌癌、胰腺癌、前列腺癌、脑癌和肺癌。在某些实施方式中，癌症表达生长抑素受体1、2、3、4或5型。
还应该理解，为了方便起见，在本申请通篇使用的诸如“一(a)”、“一个(an)”和“该(the)”的单数形式，除非上下文另有说明或另有明确的陈述，否则单数形式旨在包括复数。此外，应该理解的是，本文提及的每篇期刊文章、专利、专利申请、出版物等均通过引用整体并入本文并用于所有目的。
应该将所有数值范围理解为包括数值范围内的每个及每一个数值点，并且应该被解释为单独地例举每个及每一个数值点。涉及相同组分或性质的所有范围的端点都是包含性的，并且旨在可独立组合。
如本文所用，术语“约”意指在报告的数值的10％内，优选在报告的数值的5％内。
短语“基本上由......组成”意指该组合物或方法可包括另外的成分和/或步骤，但仅在另外的成分和/或步骤不能实质上改变所要求保护的组合物或方法的基本或新颖特点时。
本申请的SST和白蛋白融合蛋白提供优于天然SST的优点：(a)更高的体内稳定性，(b)对SST受体更高的结合亲和力，(c)更高的蛋白质表达产率和(d)更好的药代动力学/药效动力学学行为。
在下文详细描述本发明之前，应理解本发明不限于本文所述的具体方法、方案和试剂，因为它们可以变化的。还应理解，本文使用的术语仅用于描述具体实施方式的目的，并不意图限制本发明的范围，本发明的范围仅受所附权利要求的限制。除非另有限定，否则本文所用的所有技术和科学术语具有与本领域普通技术人员通常理解相同的含义。
附图说明
图1示出了SST在大鼠中的药代动力学曲线：
其中
菱形标记的曲线表示来自大鼠#6的数据；
三角(▲)标记的曲线表示来自大鼠#7的数据；
方块(■)标记的曲线表示来自大鼠#8的数据；
“Y”轴是Ln(Ct/C0)，表示在时间“t”时测量的SST血浆浓度(Ct)除以初始测量的SST的血浆浓度(C0)的自然对数；以及
“X”轴是以小时为单位的血浆采样时间('t")。
注意，在某些时间点，SST血浆浓度的检测低于定量限。
图2示出了SST融合蛋白在大鼠中的双相药代动力学曲线(黑色虚线区分了α相(0-0.5小时)和β相(0.75-4小时)：
其中，
菱形标记的曲线表示来自大鼠#1的数据；
三角(▲)标记的曲线表示来自大鼠#2的数据；
星型(*)标记的曲线表示来自大鼠#3的数据；
方块(■)标记的曲线表示来自大鼠#4的数据；
“x”(×)标记的曲线表示来自大鼠#5的数据；
“Y”轴是Ln(Ct/C0)，表示在时间“t”时测量的SST融合蛋白的血浆浓度(Ct)除以初始测量的SST融合蛋白的血浆浓度(C0)的自然对数；以及
“X”轴是以小时为单位的血浆采样时间('t")。
具体实施方式
本发明涵盖生长抑素-白蛋白融合蛋白和其类似物，以及生产和使用其的方法。根据本发明制备的构建体包括白蛋白(或其类似物)部分、生长抑素部分(例如SST-14、SST-28)和将两部分分隔的间隔物。
本发明某些实施方式的生长抑素-白蛋白融合蛋白包括白蛋白(包括人血清白蛋白)的变体和/或生长抑素的衍生物。根据本发明的另一实施方式的间隔物涵盖在一个末端与生长抑素共价连接并在另一末端与白蛋白共价连接的肽。本发明的其他实施方式中的间隔物包括具有2-100个氨基酸的肽序列。
在一种实施方式中，本发明提供的融合蛋白包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素或它的类似物或衍生物；
L是间隔物或接头；
ALB是白蛋白或它的类似物或变体。
在某些实施方式中，本发明的融合蛋白选自式I-X，如下。
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
每个x1、x2、x3、x4、y1、y2或y3独立为零或选自1-10的整数，
前提是在融合蛋白中存在至少一个L。
在又一实施方式中，本发明提供了编码白蛋白-生长抑素融合蛋白的核苷酸序列，该白蛋白-生长抑素融合蛋白包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素或它的类似物或衍生物；
L是间隔物或接头；
ALB是白蛋白或它的类似物或变体。
在某些实施方式中，选择本发明的核苷酸序列以编码以下白蛋白-生长抑素融合蛋白，
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
每个x1、x2、x3、x4、y1、y2或y3独立为零或选自1-10，1-5或1-4的整数，前提是在编码白蛋白-生长抑素融合蛋白的核苷酸序列中存在至少一个L。
本发明的另一实施方式提供了编码白蛋白-生长抑素融合蛋白的核苷酸序列，其中间隔物序列由编码SEQ ID NO：31或-GGGGS-表示的氨基酸序列的序列组成。
本发明的其他某些实施方式提供了编码白蛋白-生长抑素融合蛋白的核苷酸序列，其中第二区域(b)编码与SEQ ID NO：19、白蛋白或其片段具有至少85％序列同一性的多肽。
本发明的一种实施方式提供了编码白蛋白-生长抑素融合蛋白的核苷酸序列，其中第一区域(a)编码与SEQ ID NOS：17或18、SST-14、SST-28或其片段具有至少85％序列同一性的多肽。
本发明还提供了编码白蛋白-生长抑素融合蛋白的核苷酸序列，包括：
(a)第一区域，其包括含有编码人生长抑素肽的序列的一个或多个相邻重复序列的核苷酸序列；
(b)第二区域，其包括编码人血清白蛋白的核苷酸序列或其片段；
(c)间隔物区域，其包括编码长度为2-100个残基的多肽的核苷酸序列；
其中间隔物区域存在于第一区域与第二区域之间，或者位于第一区域与另一第一区域之间；
其中编码人生长抑素肽的序列的一个或多个相邻重复序列编码如SEQ ID NO：17和18分别表示的SST-14或SST-28，或与这两个序列的任一个具有至少85％同一性的序列；或者
其中间隔物序列由编码SEQ ID NO:31或GGGGS或SEQ ID NO:30A(EAAAK)4A表示的氨基酸序列的序列组成；或者
其中区域(a)由分别由SEQ ID NO：23或24表示的SST-14或SST-28，或者与这两个序列的任一具有至少85％同一性的序列的一个或多个相邻重复序列组成。
另外，本发明提供了白蛋白-生长抑素融合蛋白的多肽序列，包括：
(a)第一区域，其包括生长抑素肽(其可以是人生长抑素肽)的多肽序列；
(b)第二区域，其包括血清白蛋白(其可以是人血清白蛋白)的多肽序列或其片段；
(c)间隔物区域，其包括长度为2-100个残基的多肽。
间隔物区域(c)可以存在于区域(a)和区域(b)之间或在区域(a)和区域(a)之间。另外，区域(a)可包括编码分别由SEQ ID NO：17或18表示的SST-14或SST-28的序列或者与这些序列的任一具有至少85％同一性的序列的一个或多个串联重复序列。
本发明的另一实施方式提供了表达具有上述任一融合蛋白或多肽序列的白蛋白-生长抑素融合蛋白的质粒构建体。
本发明的又一实施方式包括用上述质粒构建体转化的细菌细胞。
本发明的另一实施方式包括具有上述多肽序列的分离和纯化的白蛋白-生长抑素融合蛋白(例如，白蛋白-生长抑素融合蛋白的多肽序列或表达这种蛋白的质粒构建体)。
对于融合蛋白，例如SEQ ID NO:1-5、7-10和13-16，应该注意，这些蛋白被编码为具有22残基信号肽(SEQ ID NO：20)的前蛋白。
生长抑素-白蛋白融合蛋白
本发明涵盖多肽构建体，其中生长抑素部分由与内源性人SST-14或SST-28的核苷酸序列(分别为SEQ ID No：23和24)具有至少85％序列同一性的核苷酸编码。
本发明还涵盖多肽构建体，其中人血清白蛋白部分由与内源人血清白蛋白的核苷酸序列(SEQ ID NO：25)具有至少85％序列同一性的核苷酸编码。本发明还涵盖多肽构建体，其中人血清白蛋白部分是内源人血清白蛋白蛋白的片段，例如，其由由SEQ ID NO：25的子序列组成的核苷酸编码。例如，人血清白蛋白片段任选地包括三个人血清白蛋白球状结构域中的一个或多个，每个结构域包含两个亚域，命名为亚结构域IA、IB、IIA、IIB、IIIA和IIIB(Dockal,1999,The Journal Of Biological Chemistry,274(41):29303–29310)。
本发明还涵盖多肽构建体，其中生长抑素部分具有与内源性SST-14或SST-28的多肽序列(分别为SEQ ID No：17和18)具有至少85％序列同一性，优选至少90％序列同一性的多肽序列。
本发明还涵盖多肽构建体，其中人血清白蛋白部分具有与成熟人血清白蛋白的多肽序列(SEQ ID NO：19)具有至少85％序列同一性的多肽序列。
本发明还涵盖融合蛋白，该融合蛋白包括信号肽、纯化标签(His-6)、第一接头、人血清白蛋白部分、第二接头和生长抑素部分。在一种实施方式中，融合蛋白是由SEQ ID NO:9表示的多肽或具有与其85％序列同一性的序列。
本发明还涵盖融合蛋白，该融合蛋白包括生长抑素部分、第一接头、人血清白蛋白部分、第二接头、生长抑素部分和纯化标签(His-6)。在一种实施方式中，融合蛋白是由SEQID NO:10表示的多肽或具有与其85％序列同一性的序列。
本发明还涵盖编码融合蛋白的核苷酸序列(SEQ ID NO:11)，该融合蛋白包括通过肽间隔物分隔的N-末端人血清白蛋白部分和C-末端生长抑素部分。本发明还涵盖编码白蛋白-生长抑素融合构建体的核苷酸序列，其与SEQ ID NO:11具有85％的序列同一性。
本发明还涵盖编码融合蛋白的核苷酸序列(SEQ ID NO:12)，该融合蛋白包括通过肽间隔物分隔的N-末端生长抑素部分和C-末端人血清白蛋白部分。本发明还涵盖编码白蛋白-生长抑素融合构建体的核苷酸序列，其与SEQ ID NO:12具有85％的序列同一性。
本发明还涵盖多肽构建体，其中生长抑素部分包括串联排布的SST-14或SST-28序列的两个或更多个拷贝，即分别为“(SST-14)2”或“(SST-14)3”或“(SST-28)2”或“(SST-28)3”。任选地，接头序列包括在两个或更多个串联生长抑素部分之间，和/或信号肽序列包括在融合蛋白的N-末端。
本发明还涵盖多肽构建体，其中生长抑素部分包括SST-14序列的两个或更多个拷贝，排布成使得SST14的至少一个拷贝分别连接至白蛋白的两侧。任选地，接头序列包括在两个或更多个串联生长抑素部分之间和生长抑素和白蛋白之间，和/或信号肽序列包括在融合蛋白的N-末端。例如，多肽构建体可以包括信号肽、通过间隔物间隔的两个SST-14部分、第二间隔物和所述HSA部分。任选地，构建体省略了N-末端信号肽。
本发明还涵盖多肽构建体，其中生长抑素部分包括串联排布的SST-28序列的两个或三个拷贝，即分别为“(SST-28)2”或“(SST-28)3”。任选地，接头序列包括在两个或更多个串联生长抑素部分之间。
本发明还涵盖多肽构建体，其包括前述段落中所述的任何白蛋白-生长抑素融合蛋白，其中相比于内源性SST-14或SST-28肽，白蛋白-生长抑素融合蛋白具有更长的体内半衰期。
本发明还涵盖多肽构建体，其包括前述段落中所述的任何白蛋白-生长抑素融合蛋白，其中相比于内源性SST-14或SST-28，白蛋白-生长抑素融合蛋白对生长抑素受体具有近似相等或更高的结合亲和力。
本发明还涵盖白蛋白-生长抑素融合蛋白，包括由SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:2表示的N-末端白蛋白部分，内部SST部分和由SEQ ID NO:7何SEQ ID NO:8表示的C-末端白蛋白部分。任选地，N-末端还可包括信号肽。任选地，一个或多个白蛋白和SST结构域可各自通过独立选择的接头序列间隔开，如SEQ ID NO:1所示。
在一些实施方式中，SST部分可包括一对或多个串联SST序列，例如(SST-14)2或(SST-28)3，在两个或更多个串联SST重复序列之间具有或不具有居间间隔序列。任选地，一个或多个纯化标签序列可包括在序列中的两个部分之间或在N或C末端，以有助于纯化融合蛋白。替代实施方式包括通过间隔物间隔的一对SST-14部分，如SEQ ID NO:4所示。另一实施方式可省略纯化标签(例如，His6)，如SEQ ID NO:5表示的多肽所示。
生长抑素
本发明使用的生长抑素可以是任一生长抑素，它的类似物或衍生物。它可以是人生长抑素、任何其他分离的或天然存在的生长抑素。SST部分可以是类似物，例如奥曲肽、兰瑞肽、帕瑞肽(pasireotide)、司格列肽(seglitide)或伐普肽(vapreotide)。
本发明还涵盖多肽构建体，其中生长抑素部分包括生长抑素类似物。优选地，这种类似物适合于在重组宿主细胞中作为融合蛋白的一部分表达。应当理解，可以使用合适的生长抑素类似物序列代替本文公开的任何实例中包括的SST-14或SST-28序列。
本发明还涵盖多肽构建体，其中生长抑素部分包括生长抑素多肽序列(例如分别为SST-14或SST-28，SEQ ID NOS：17和18)的两个或更多个串联重复序列。每个重复的生长抑素多肽序列可以是与SST-14或SST-28具有至少85％序列同一性的多肽序列。独立地选择这些重复的变体序列，即，在一些实施方式中，重复序列是相同的，而在其他实施方式中，它们是独有的。
白蛋白
本发明使用的白蛋白可以是任一白蛋白、它的类似物或衍生物。白蛋白可以是人血清白蛋白，或任何其他分离的或天然存在的白蛋白。
本发明还涵盖多肽构建体，其中人血清白蛋白部分包括具有替代排列或数目的二硫键的多肽序列变体，这是由于相比于天然形式存在额外的或较少的半胱氨酸残基(SEQID NO:25)。
间隔物或接头
如之前所述，间隔物或接头可用于本发明。间隔物或接头可独立于生长抑素或白蛋白。
本发明还涵盖多肽构建体，其中可替代地称为接头的肽间隔物，由长度为约2至约100个氨基酸残基的多肽序列组成。本发明还涵盖多肽构建体，其中肽间隔物为长度为约2至约50个氨基酸残基，优选长度为约2至约30个氨基酸残基，或更优选长度为从约3至约20个氨基酸残基。
本发明还涵盖多肽构建体，其中肽间隔物(或称为接头)具有多肽序列“GGGGS”(SEQ ID NO:31)。富含Gly、Ser或Thr的多肽提供了特定的优点，包括但不限于：(i)多肽骨架的旋转自由度，使得相邻结构域可自由移动；(ii)溶解度增加；(iii)对蛋白水解的抗性。此外，许多天然接头表现出α-螺旋结构。α-螺旋结构比富含Gly的接头更刚性和稳定。具有序列A(EAAAK)4A(SEQ ID NO:30)的经验性刚性接头可用于分离功能结构域。除了将蛋白质结构域连接在一起的作用之外，人工接头可以为融合蛋白的产生提供其他优势，诸如生物活性改善、蛋白质表达增加和实现期望的药代动力学曲线。
生长抑素-白蛋白融合蛋白的制备
本发明的实施方式提供了制备生长抑素-白蛋白融合蛋白的方法。在一种实施方式中，通过表达包含编码基因的载体并将载体引入合适的宿主细胞中来制备本发明的生长抑素-白蛋白融合蛋白。例如，融合蛋白通过在宿主(诸如酵母)中表达合适的载体来获得。在一种实施方式中，巴斯德毕赤酵母(Pichia pastoris)GS115可以用做合适的表达宿主，且载体为pPIC9K。特别地，哺乳动物细胞系诸如CHO或HEK293可用作表达宿主。
本发明还涵盖能够表达白蛋白生长抑素融合蛋白的质粒构建体，包括编码如任一前述段落所述的生长抑素白蛋白融合蛋白的核苷酸序列。例如，合适的质粒构建体包括，但不限于SEQ ID NO：26所示的pcDNA3.1载体，其中编码本文公开的任何白蛋白-生长抑素融合蛋白的DNA序列连接到该载体的多克隆位点。可以基于表达宿主选择本领域已知的其他合适的蛋白质表达载体(例如，具有哺乳动物启动子系统的表达载体适合在人细胞系中表达，而选择酵母或细菌表达质粒，如果需要在这些生物体中的任一种中表达。
本发明还包括细菌或酵母蛋白表达系统，包括转化了质粒构建体的细菌或酵母细胞，所述质粒构建体包括编码生长抑素白蛋白融合蛋白的核苷酸序列，如前述段落中任一段所述。合适的细菌菌株包括，例如，大肠杆菌(Escherichiacoli)。合适的酵母菌株包括，例如，巴斯德毕赤酵母(Pichia pastoris)。示例性质粒构建体包括SEQ ID NO：27所示的pPIC9K(Invitrogen)，其中编码本文公开的任何白蛋白-生长抑素融合蛋白的核苷酸序列掺入到该载体的多克隆位点。
本发明还涵盖分离的和纯化的融合生长抑素融合蛋白，其具有上述段落中任一段所述的多肽序列。
当SST是生长抑素类似物时，可以使用本领域已知的替代方法来制备缀合物。
生长抑素-白蛋白融合蛋白的应用
本发明的融合蛋白可用于治疗本领域已知采用生长抑素的病症。因此，本发明还涵盖通过给药如前述段落中任一段所述的分离的和纯化的白蛋白-生长抑素融合蛋白来治疗人受试者中的癌症的方法，其中癌症是已知对生长抑素治疗有反应的任何癌症，例如，选自乳腺癌、结肠直肠癌、肝癌、肺癌、内分泌癌、神经内分泌癌、胰腺癌和前列腺癌。
本发明还涵盖通过给药包含本发明融合蛋白的组合物治疗人受试者的癌症的方法，诸如前述段落中任一段所述的分离的和纯化的白蛋白-生长抑素融合蛋白。该组合物还可包含合适的载体。
设计了具有各种接头序列的11个SST14-白蛋白融合蛋白构建体。将这些构建体中的八个制成质粒内的融合基因，并通过HEK 293瞬时表达以100mL规模产生。从培养基中收集蛋白质，通过基于白蛋白的亲和纯化纯化，并透析至储存缓冲液。评估这些融合蛋白对SSTR2受体的结合亲和力，以及抑制SSTR2过表达CHO-K1细胞系中cAMP的产生的基于细胞的活性。这些研究的结果表明，接头的长度和类型显著影响SSTR2受体结合亲和力，体外基于细胞的功能活性和融合蛋白产量。
与相应的未融合的游离SST分子相比，本发明的SST-白蛋白融合蛋白在体外和/或体内在溶液或药物组合物中显示出明显更长的血清半衰期和/或改善的药代动力学曲线。在体外大鼠血浆中比较游离SST和SST融合蛋白的稳定性。当在新鲜制备的大鼠血浆中于37℃温育时，游离SST和SST融合蛋白展现的降解半衰期分别为33分钟和5.5小时(表4)。
还生成了体内药代动力学曲线以证明相对于游离SST，SST融合蛋白的改善的稳定性。静脉内给药SST的大鼠显示计算的T1/2为3.5分钟。另一方面，静脉内给药SST融合蛋白的大鼠展现出双相药代动力学曲线，其中α相T1/2为1.01小时且β相T1/2为6.14小时。SST融合蛋白的计算的半衰期明显长于大鼠中游离SST的计算的T1/2(3.5分钟)以及报道的大鼠中游离SST的血浆T1/2(＜1分钟；参考文献#1)(表4)。
参考文献#1：Yogesh C.Patel和Thomas Wheatley。In Vivo and in VitroPlasma Disappearance and Metabolism of Somatostatin-28and Somatostatin-14inthe Rat.Endocrinology.Vol.112,No.1(1992),pages 220-225。
实施例
本发明选择的实施方式将在下文中参考以下实验例和比较例进一步详述。这些实施例仅用于说明目的，并非旨在限制本发明的范围。
实施例1：在哺乳动物系统中的表达
实施例1-1.重组基因合成
制备对应于表5中列出的融合蛋白的八种构建体。首先，从头合成编码每种融合蛋白的基因序列，然后将其插入pcDNA3.1载体。
实施例1-2.产生质粒
使用Maxi-prep或Mega-prep产生DNA，每种DNA约20mg。
实施例1-3。转染和蛋白质生产
(A)悬浮细胞法
将FreeStyleTM 293-F细胞以0.55-0.6×106个细胞/mL接种在烧瓶中。约24小时后，将细胞以1.1-1.2×106个细胞/mL接种在摇瓶中。以500μgDNA/80mLFreeStyle培养基制备DNA。以每80mLFreeStyle培养基1.8mL PEI，制备聚乙烯亚胺(PEI)。将DNA在FreeStyle培养基中混合，并将有效量的PEI加入到DNA溶液中，并将混合物在室温下涡旋温育约15分钟以形成DNA-PEI复合物。将80mL温育的DNA-PEI复合物加入细胞培养物中。约3小时后，加入TC Yeastolate进料(BD)使最终浓度为4克/升培养物。约7-8天后，通过离心收获培养基。
(B)贴壁细胞法
转染前约24小时，将HEK293细胞接种到烧瓶至50-90％汇合度，并加入完全培养基。约24小时后，洗涤细胞，然后加入基础培养基。
通过将DNA添加到无血清培养基中来制备DNA和PEI溶液。将PEI溶液加入到DNA溶液中并在室温下温育15分钟以形成DNA-PEI复合物。
将PEI/DNA混合物加入细胞中，并将混合物在37℃下温育约4-6小时。除去培养基，加入具有谷氨酰胺和血清的新鲜培养基，然后在37℃下培养4天。
约4天后收获培养基，通过离心收集上清液。用具有L-谷氨酰胺的新鲜培养基补充沉淀物，再培养3天以重复收获过程。
实施例1-4：蛋白质浓缩、Ni-NTA纯化和缓冲液更换
收集的培养基通过TFF系统(Millipore)浓缩至一定体积，其取决于纯化方法(或连续色谱或人工分批纯化)。
浓缩的蛋白质用新鲜的Ni-NTA树脂在约4℃下在结合缓冲液中温育，并使用色谱或分批系统用洗涤缓冲液洗涤。用洗脱缓冲液洗脱蛋白质，收集级分并浓缩以回收纯化的蛋白质。可以使用尺寸排阻色谱纯化进一步纯化蛋白质。
最终洗脱物的缓冲液可以通过透析交换到所需的缓冲液中。
实施例2：几种SST-白蛋白融合蛋白的产率
SST-HSA融合蛋白均以可溶形式高产率的表达。接头的长度或性质可以影响融合蛋白的蛋白质产率和溶解度。结果表明，随着融合蛋白构建体变得更长且更为复杂，生产产率略微降低。然而，所有的构建体都展现出规模化生产的产率。
实施例3：几种SST-白蛋白融合蛋白的结合亲和力
该测定法测量[125I]生长抑素与人生长抑素sst2受体的结合。用编码人生长抑素sst2受体的质粒稳定转染的CHO-K1细胞用于使用标准技术在改良的HEPES pH 7.4缓冲液中制备膜。将0.1mg等分试样的膜与0.03nM[125I]生长抑素和测试融合蛋白在25℃下一起温育240分钟。在1μM生长抑素的存在下估计非特异性结合。过滤膜并洗涤3次，计数过滤器以确定[125I]生长抑素的特异性结合。
125I-Tyr-生长抑素与融合蛋白的竞争性结合研究显示出以下结果。抑制效率根据融合蛋白的构建而变化。具有两个α-螺旋接头(A(EAAAK)4A)的融合蛋白构建体(SEQ IDNO：1)显示出对生长抑素及其受体相互作用的100％抑制。SEQ ID NO:1构建体在人血清白蛋白的N和C末端都具有两个生长抑素部分。在通过相同的α-螺旋接头连接的人血清白蛋白的C末端侧具有一个生长抑素的较小构建体(SEQ ID NO：2)显示96％的抑制。具有更柔性的GGGGS接头的相同构建体显示出82-85％的较低抑制，这取决于长度。GGGGS接头的长度也影响抑制。具有5个氨基酸GGGGS接头的构建体(SEQ ID NO：9和SEQ ID NO：8)显示57-59％的抑制，而具有15个氨基酸的构建体(SEQ ID NO：15)或30个氨基酸GGGGS接头的构建体(SEQID NO：16)显示超过80％的抑制，表明长于5个氨基酸GGGGS对SST功能更有利。与柔性GGGGS接头相比，更刚性的A(EAAAK)4A(α-螺旋)接头在结合方面更有效。多重SST可以增加用于SST受体结合的配体的有效浓度。组氨酸纯化标签的位置可能不会影响结合。改变融合蛋白中白蛋白的取向或位置可以进一步提高蛋白质结合的效率。
实施例4.几种SST-白蛋白融合蛋白对表达SSTR2的细胞中cAMP积累的抑制
使用在CHO-K1细胞中表达的人重组生长抑素sst2a受体。将测试化合物和/或媒介物与细胞(2×105个细胞/mL)在温育缓冲液中于37℃温育20分钟。相对于10nM奥曲肽响应，测试化合物诱导的cAMP降低百分之50(50％)或更多显示了sst2a受体激动剂活性。
在表达2型SST受体的CHO-K1细胞中观察到cAMP积累的抑制。EC50的值为260nM。具有较长接头的构建体(SEQ ID NO：1、15和2)展现出较低的EC50值，其与结合测定数据一致。当比较白蛋白-(GGGGS)3-SST14和白蛋白-(GGGGS)3-SST14的EC50值时，α-螺旋接头似乎在抑制cAMP产生方面更有效。
实施例5.大鼠血浆中游离SST和SST融合蛋白稳定性的测定
使用ELISA证实了SST融合蛋白在大鼠血浆中改善的稳定性。测试结果显示，与游离SST相比，SST融合蛋白(SEQ ID NO：1)展现出5.5小时的降解半衰期，其在37℃下大鼠血浆中温育时显示出小于33分钟的半衰期(表4)。
实施例5-1：样品的制备
将500pg/mL游离SST或750ng/mL SST融合蛋白(SEQ ID NO：1)在合并的大鼠血浆中温育1分钟、2分钟、5分钟、20分钟、60分钟、80分钟、100分钟、120分钟、150分钟和180分钟。将每个时间点的血液样品一式三份温育。将所有血液样品以5500rpm离心10分钟以获得用于分析的血浆样品。合并的大鼠血浆用作背景测量的空白。所有样品一式两份分析。
用合并的大鼠血浆将具有SST融合蛋白的所有血浆样品稀释15倍。例如，向具有SST融合蛋白的10μL血浆样品中加入140μL合并的大鼠血浆。
实施例5-2：游离SST和SST融合蛋白标准品的制备
(1).游离SST标准品的制备
通过以下步骤制备标准曲线。通过用稀释缓冲液连续稀释游离SST原液(1mg/mL)以产生5、2.5、1.25、0.625、0.313、0.156、0.078和0.039ng/mL溶液，来制备一式两份的标准点。
(2).SST融合蛋白标准品的制备
通过以下步骤制备标准曲线。通过用稀释缓冲液连续稀释SST融合蛋白原液(2.42mg/mL)以产生225、112.5、56.2、28.1、14.1、7.03、3.51和1.76ng/mL溶液，来制备一式两份的标准点。
实施例5-3：ELISA测定步骤
1)所有试剂盒组分在分析前都保持在室温(20-25℃)。
2)向试剂盒中加入50μL/孔标准品、样品或阳性对照溶液。然后，向除了空白孔，其它各孔中加入25μL/孔的一级抗体。最后，向除了空白孔的其它各孔中加入25μL/孔的生物素化的肽。将免疫板在室温下温育2小时，同时以300-400rpm振荡。将孔清空并用300μL洗涤溶液洗涤三次。在最后一次洗涤之后，通过在吸收性薄纸上轻敲条带来清空孔。
3)弃去孔的内容物，用300μL的1×EIA测定缓冲液洗涤各孔，弃去缓冲液，倒置并吸干平板。重复4次。
4)在各孔中加入100μL的SA-HRP溶液。将免疫板在室温下温育1小时，以300-400rpm振荡。
5)如上文步骤3中所述，用1×EIA测定缓冲液洗涤并印迹干燥免疫板4次。
6)在各孔中加入100μL的TMB底物溶液。覆盖免疫板以防止光线照射。将免疫板在室温下温育1小时，以300-400rpm振荡。
7)向各孔中加入100μL 2N HCl以停止反应。孔中的颜色应从蓝变为黄。如果颜色显得并不均匀，轻敲板以确保彻底混合。在20分钟内进行下一步骤。
8)将免疫板装入酶标仪。在450nm处读取吸光度O.D.。
实施例6.大鼠中游离SST和SST融合蛋白体内药代动力学曲线的确定
SST和SST融合蛋白(SEQ ID NO：1)分别以0.02和27.1mg/kg剂量通过尾静脉注射分别给药三只和五只雄性Sprague Dawley大鼠，以分别确定SST和SST融合蛋白的药代动力学曲线和参数(表8和表9)。在注射前将动物禁食过夜并自由饮水，之后未观察到负面临床症状。在给药SST的每只大鼠中，SST展现出快速的药代动力学曲线(图1)，并且计算的T1/2为3.5分钟(表4)。在给药SST融合蛋白的每只大鼠中，SST融合蛋白展现出双相药代动力学曲线(图2)，其中平均α相T1/2(0-0.5小时)和β相T1/2(0.75-4小时)分别计算为1.01小时和6.14小时(表4)。大鼠中SST融合蛋白的计算的半衰期明显长于游离SST的计算的血浆T1/2(3.5分钟)以及报道的游离SST的血浆T1/2(＜1分钟；参考文献#1)(表4)。这组结果表明SST融合蛋白显著改善了SST体内的稳定性并延长了SST体内的半衰期。
实施例6-1：样品的制备
在指定的时间点手动约束大鼠，通过颈静脉将约300μL血液样品收集到EDTA-K2管中，随后在4℃和1500g下离心10分钟以获得血浆样品。
实施例6-2：SST和SST融合蛋白标准品的制备
(1).游离SST标准品的制备
通过以下步骤制备标准曲线。通过用稀释缓冲液连续稀释游离SST原液(1mg/mL)以产生5、2.5、1.25、0.625、0.313、0.156、0.078和0.039ng/mL溶液，来制备一式两份的标准点。
(2).SST融合蛋白标准品的制备
通过以下步骤制备标准曲线。通过用合并的大鼠血浆连续稀释SST融合蛋白(2.42mg/mL)以产生225、112.5、56.2、28.1、14.1、7.03、3.51和1.76ng/mL溶液，来制备一式两份的标准点。
实施例6-3：ELISA测定步骤
如实施例5-3所述进行ELISA测定。
序列表
<110> 安能泰制药有限公司（NAL PHARMACEUTICAL GROUP LIMITED）
莫业钧（MO, Y.Joseph）
<120> 包含白蛋白的融合蛋白和其类似物的组合物、及其制备和使用方法
<130> PN19004211P
<150> US 15/249,346
<151> 2016-08-26
<150> PCT/US2016/019950
<151> 2016-02-26
<150> TW 105106088
<151> 2016-02-26
<150> US 62/121,487
<151> 2015-02-26
<160> 48
<170> PatentIn version 3.5
<210> 1
<211> 657
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 1
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Ala Glu
1 5 10 15
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
35 40 45
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
50 55 60
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
65 70 75 80
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
85 90 95
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
100 105 110
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
115 120 125
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
130 135 140
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
145 150 155 160
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
165 170 175
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
180 185 190
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
195 200 205
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
210 215 220
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
225 230 235 240
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
245 250 255
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
260 265 270
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
275 280 285
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
290 295 300
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
305 310 315 320
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
325 330 335
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
340 345 350
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
355 360 365
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
370 375 380
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
385 390 395 400
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
405 410 415
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
420 425 430
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
435 440 445
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
450 455 460
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
465 470 475 480
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
485 490 495
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
500 505 510
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
515 520 525
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
530 535 540
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
545 550 555 560
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
565 570 575
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
580 585 590
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
595 600 605
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Ala Glu Ala
610 615 620
Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala
625 630 635 640
Ala Lys Ala Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser
645 650 655
Cys
<210> 2
<211> 621
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 2
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Ala Glu Ala Ala Ala Lys Glu
580 585 590
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Ala Ala
595 600 605
Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys
610 615 620
<210> 3
<211> 1203
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 3
His His His His His His Gly Gly Ser Asp Ala His Lys Ser Glu Val
1 5 10 15
Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val
20 25 30
Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His
35 40 45
Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala
50 55 60
Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly
65 70 75 80
Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met
85 90 95
Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu
100 105 110
Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu
115 120 125
Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
130 135 140
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala
145 150 155 160
Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu
165 170 175
Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp
180 185 190
Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys
195 200 205
Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala
210 215 220
Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val
225 230 235 240
Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His
245 250 255
Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr
260 265 270
Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys
275 280 285
Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn
290 295 300
Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu
305 310 315 320
Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu
325 330 335
Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val
340 345 350
Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys
355 360 365
Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp
370 375 380
Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn
385 390 395 400
Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu
405 410 415
Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu
420 425 430
Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys
435 440 445
His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val
450 455 460
Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp
465 470 475 480
Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys
485 490 495
Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn
500 505 510
Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys
515 520 525
Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His
530 535 540
Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe
545 550 555 560
Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys
565 570 575
Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu
580 585 590
Gly Leu Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys
595 600 605
Thr Phe Thr Ser Cys Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu
610 615 620
Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu
625 630 635 640
Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp
645 650 655
His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val
660 665 670
Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe
675 680 685
Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu
690 695 700
Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
705 710 715 720
Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro
725 730 735
Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe
740 745 750
Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
755 760 765
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr
770 775 780
Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu
785 790 795 800
Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
805 810 815
Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
820 825 830
Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu
835 840 845
Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
850 855 860
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys
865 870 875 880
Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys
885 890 895
Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu
900 905 910
Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
915 920 925
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
930 935 940
Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser
945 950 955 960
Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu
965 970 975
Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe
980 985 990
Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
995 1000 1005
Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn
1010 1015 1020
Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
1025 1030 1035
Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser
1040 1045 1050
Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu
1055 1060 1065
Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu
1070 1075 1080
Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
1085 1090 1095
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu
1100 1105 1110
Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His
1115 1120 1125
Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
1130 1135 1140
Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
1145 1150 1155
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val
1160 1165 1170
Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
1175 1180 1185
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
1190 1195 1200
<210> 4
<211> 1222
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 4
His His His His His His Gly Gly Ser Asp Ala His Lys Ser Glu Val
1 5 10 15
Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val
20 25 30
Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His
35 40 45
Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala
50 55 60
Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly
65 70 75 80
Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met
85 90 95
Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu
100 105 110
Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu
115 120 125
Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
130 135 140
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala
145 150 155 160
Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu
165 170 175
Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp
180 185 190
Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys
195 200 205
Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala
210 215 220
Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val
225 230 235 240
Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His
245 250 255
Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr
260 265 270
Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys
275 280 285
Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn
290 295 300
Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu
305 310 315 320
Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu
325 330 335
Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val
340 345 350
Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys
355 360 365
Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp
370 375 380
Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn
385 390 395 400
Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu
405 410 415
Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu
420 425 430
Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys
435 440 445
His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val
450 455 460
Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp
465 470 475 480
Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys
485 490 495
Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn
500 505 510
Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys
515 520 525
Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His
530 535 540
Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe
545 550 555 560
Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys
565 570 575
Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu
580 585 590
Gly Leu Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys
595 600 605
Thr Phe Thr Ser Cys Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe
610 615 620
Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly Gly Gly Ser Asp Ala His
625 630 635 640
Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe
645 650 655
Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro
660 665 670
Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys
675 680 685
Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His
690 695 700
Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr
705 710 715 720
Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn
725 730 735
Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu
740 745 750
Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu
755 760 765
Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro
770 775 780
Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala
785 790 795 800
Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu
805 810 815
Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys
820 825 830
Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe
835 840 845
Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu
850 855 860
Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr
865 870 875 880
Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp
885 890 895
Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu
900 905 910
Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala
915 920 925
Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala
930 935 940
Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys
945 950 955 960
Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro
965 970 975
Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr
980 985 990
Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala
995 1000 1005
Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn
1010 1015 1020
Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr
1025 1030 1035
Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
1040 1045 1050
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly
1055 1060 1065
Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met
1070 1075 1080
Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys
1085 1090 1095
Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
1100 1105 1110
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu
1115 1120 1125
Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr
1130 1135 1140
Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg
1145 1150 1155
Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
1160 1165 1170
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe
1175 1180 1185
Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr
1190 1195 1200
Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala
1205 1210 1215
Ala Leu Gly Leu
1220
<210> 5
<211> 1213
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 5
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Ala Gly
580 585 590
Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly Gly Gly
595 600 605
Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly
610 615 620
Gly Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
625 630 635 640
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
645 650 655
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
660 665 670
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
675 680 685
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
690 695 700
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
705 710 715 720
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
725 730 735
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
740 745 750
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
755 760 765
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
770 775 780
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
785 790 795 800
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
805 810 815
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
820 825 830
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
835 840 845
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
850 855 860
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
865 870 875 880
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
885 890 895
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
900 905 910
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
915 920 925
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
930 935 940
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
945 950 955 960
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
965 970 975
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
980 985 990
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
995 1000 1005
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe
1010 1015 1020
Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg
1025 1030 1035
Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu
1040 1045 1050
Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
1055 1060 1065
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val
1070 1075 1080
Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser
1085 1090 1095
Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg
1100 1105 1110
Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
1115 1120 1125
Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr
1130 1135 1140
Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val
1145 1150 1155
Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys
1160 1165 1170
Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
1175 1180 1185
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu
1190 1195 1200
Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
1205 1210
<210> 6
<211> 8
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 6
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 7
<211> 614
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 7
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly
1 5 10 15
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ala His
20 25 30
Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe
35 40 45
Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro
50 55 60
Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys
65 70 75 80
Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His
85 90 95
Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr
100 105 110
Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn
115 120 125
Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu
130 135 140
Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu
145 150 155 160
Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro
165 170 175
Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala
180 185 190
Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu
195 200 205
Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys
210 215 220
Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe
225 230 235 240
Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu
245 250 255
Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr
260 265 270
Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp
275 280 285
Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu
290 295 300
Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala
305 310 315 320
Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala
325 330 335
Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys
340 345 350
Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro
355 360 365
Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr
370 375 380
Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala
385 390 395 400
Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu
405 410 415
Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe
420 425 430
Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser
435 440 445
Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser
450 455 460
Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp
465 470 475 480
Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr
485 490 495
Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn
500 505 510
Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro
515 520 525
Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr
530 535 540
Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu
545 550 555 560
Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val
565 570 575
Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp
580 585 590
Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser
595 600 605
Gln Ala Ala Leu Gly Leu
610
<210> 8
<211> 621
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 8
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Ala Glu
1 5 10 15
Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala
20 25 30
Ala Ala Lys Ala Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys
35 40 45
Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala
50 55 60
Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn
65 70 75 80
Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu
85 90 95
Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr
100 105 110
Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala
115 120 125
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp
130 135 140
Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys
145 150 155 160
Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr
165 170 175
Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe
180 185 190
Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala
195 200 205
Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu
210 215 220
Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln
225 230 235 240
Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser
245 250 255
Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr
260 265 270
Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu
275 280 285
Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln
290 295 300
Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu
305 310 315 320
Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala
325 330 335
Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys
340 345 350
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr
355 360 365
Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg
370 375 380
Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala
385 390 395 400
Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu
405 410 415
Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu
420 425 430
Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr
435 440 445
Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg
450 455 460
Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys
465 470 475 480
Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
485 490 495
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys
500 505 510
Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu
515 520 525
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr
530 535 540
Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys
545 550 555 560
Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr
565 570 575
Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu
580 585 590
Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly
595 600 605
Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
610 615 620
<210> 9
<211> 613
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 9
His His His His His His Gly Gly Ser Asp Ala His Lys Ser Glu Val
1 5 10 15
Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val
20 25 30
Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His
35 40 45
Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala
50 55 60
Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly
65 70 75 80
Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met
85 90 95
Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu
100 105 110
Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu
115 120 125
Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
130 135 140
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala
145 150 155 160
Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu
165 170 175
Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp
180 185 190
Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys
195 200 205
Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala
210 215 220
Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val
225 230 235 240
Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His
245 250 255
Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr
260 265 270
Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys
275 280 285
Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn
290 295 300
Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu
305 310 315 320
Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu
325 330 335
Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val
340 345 350
Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys
355 360 365
Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp
370 375 380
Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn
385 390 395 400
Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu
405 410 415
Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu
420 425 430
Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys
435 440 445
His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val
450 455 460
Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp
465 470 475 480
Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys
485 490 495
Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn
500 505 510
Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys
515 520 525
Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His
530 535 540
Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe
545 550 555 560
Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys
565 570 575
Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu
580 585 590
Gly Leu Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys
595 600 605
Thr Phe Thr Ser Cys
610
<210> 10
<211> 613
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 10
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly
1 5 10 15
Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp
20 25 30
Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln
35 40 45
Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu
50 55 60
Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn
65 70 75 80
Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val
85 90 95
Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys
100 105 110
Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn
115 120 125
Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr
130 135 140
Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu
145 150 155 160
Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe
165 170 175
Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp
180 185 190
Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly
195 200 205
Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys
210 215 220
Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln
225 230 235 240
Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp
245 250 255
Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys
260 265 270
Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp
275 280 285
Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu
290 295 300
Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp
305 310 315 320
Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys
325 330 335
Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu
340 345 350
Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu
355 360 365
Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp
370 375 380
Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val
385 390 395 400
Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln
405 410 415
Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys
420 425 430
Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn
435 440 445
Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg
450 455 460
Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys
465 470 475 480
Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys
485 490 495
Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val
500 505 510
Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe
515 520 525
His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
530 535 540
Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys
545 550 555 560
Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys
565 570 575
Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys
580 585 590
Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Ser His
595 600 605
His His His His His
610
<210> 11
<211> 604
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 11
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Ala Gly
580 585 590
Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys
595 600
<210> 12
<211> 604
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 12
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly
1 5 10 15
Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp
20 25 30
Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln
35 40 45
Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu
50 55 60
Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn
65 70 75 80
Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val
85 90 95
Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys
100 105 110
Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn
115 120 125
Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr
130 135 140
Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu
145 150 155 160
Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe
165 170 175
Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp
180 185 190
Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly
195 200 205
Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys
210 215 220
Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln
225 230 235 240
Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp
245 250 255
Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys
260 265 270
Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp
275 280 285
Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu
290 295 300
Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp
305 310 315 320
Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys
325 330 335
Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu
340 345 350
Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu
355 360 365
Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp
370 375 380
Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val
385 390 395 400
Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln
405 410 415
Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys
420 425 430
Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn
435 440 445
Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg
450 455 460
Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys
465 470 475 480
Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys
485 490 495
Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val
500 505 510
Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe
515 520 525
His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys
530 535 540
Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys
545 550 555 560
Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys
565 570 575
Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys
580 585 590
Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
595 600
<210> 13
<211> 623
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 13
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly
1 5 10 15
Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser
20 25 30
Cys Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu Val Ala His Arg
35 40 45
Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala
50 55 60
Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu
65 70 75 80
Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
85 90 95
Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
100 105 110
Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys
115 120 125
Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
130 135 140
Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val
145 150 155 160
Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr
165 170 175
Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
180 185 190
Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln
195 200 205
Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg
210 215 220
Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser
225 230 235 240
Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
245 250 255
Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu
260 265 270
Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu
275 280 285
Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu
290 295 300
Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro
305 310 315 320
Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met
325 330 335
Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp
340 345 350
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe
355 360 365
Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu
370 375 380
Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala
385 390 395 400
Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys
405 410 415
Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu
420 425 430
Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg
435 440 445
Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val
450 455 460
Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu
465 470 475 480
Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn
485 490 495
Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr
500 505 510
Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala
515 520 525
Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr
530 535 540
Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln
545 550 555 560
Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys
565 570 575
Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe
580 585 590
Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu
595 600 605
Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu
610 615 620
<210> 14
<211> 661
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 14
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys Gly Gly
1 5 10 15
Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser
20 25 30
Cys Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr
35 40 45
Phe Thr Ser Cys Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe
50 55 60
Trp Lys Thr Phe Thr Ser Cys Gly Gly Gly Gly Ser Asp Ala His Lys
65 70 75 80
Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys
85 90 95
Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe
100 105 110
Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr
115 120 125
Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr
130 135 140
Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr
145 150 155 160
Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu
165 170 175
Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val
180 185 190
Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu
195 200 205
Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr
210 215 220
Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala
225 230 235 240
Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro
245 250 255
Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln
260 265 270
Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys
275 280 285
Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe
290 295 300
Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu
305 310 315 320
Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu
325 330 335
Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys
340 345 350
Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu
355 360 365
Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp
370 375 380
Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
385 390 395 400
Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
405 410 415
Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr
420 425 430
Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys
435 440 445
Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile
450 455 460
Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln
465 470 475 480
Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr
485 490 495
Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys
500 505 510
Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr
515 520 525
Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro
530 535 540
Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg
545 550 555 560
Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys
565 570 575
Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu
580 585 590
Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu
595 600 605
Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met
610 615 620
Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys
625 630 635 640
Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
645 650 655
Ala Ala Leu Gly Leu
660
<210> 15
<211> 614
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 15
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp
595 600 605
Lys Thr Phe Thr Ser Cys
610
<210> 16
<211> 629
<212> PRT
<213> 人工的
<220>
<223> 融合蛋白, 成熟蛋白
<400> 16
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
595 600 605
Gly Ser Gly Gly Gly Gly Ser Ala Gly Cys Lys Asn Phe Phe Trp Lys
610 615 620
Thr Phe Thr Ser Cys
625
<210> 17
<211> 14
<212> PRT
<213> 智人
<400> 17
Ala Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys
1 5 10
<210> 18
<211> 28
<212> PRT
<213> 智人
<400> 18
Ser Ala Asn Ser Asn Pro Ala Met Ala Pro Arg Glu Arg Lys Ala Gly
1 5 10 15
Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys
20 25
<210> 19
<211> 585
<212> PRT
<213> 智人
<400> 19
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 20
<211> 22
<212> PRT
<213> 人工的
<220>
<223> 用于融合蛋白的信号肽
<400> 20
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys
20
<210> 21
<211> 20
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 21
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro
20
<210> 22
<211> 40
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 22
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
1 5 10 15
Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
20 25 30
Ala Pro Ala Pro Ala Pro Ala Pro
35 40
<210> 23
<211> 42
<212> DNA
<213> 智人
<400> 23
gctggctgca agaatttctt ctggaagact ttcacatcct gt 42
<210> 24
<211> 84
<212> DNA
<213> 智人
<400> 24
tctgctaact caaacccggc tatggcaccc cgagaacgca aagctggctg caagaatttc 60
ttctggaaga ctttcacatc ctgt 84
<210> 25
<211> 1755
<212> DNA
<213> 智人
<400> 25
gatgcacaca agagtgaggt tgctcatcgg tttaaagatt tgggagaaga aaatttcaaa 60
gccttggtgt tgattgcctt tgctcagtat cttcagcagt gtccatttga agatcatgta 120
aaattagtga atgaagtaac tgaatttgca aaaacatgtg ttgctgatga gtcagctgaa 180
aattgtgaca aatcacttca tacccttttt ggagacaaat tatgcacagt tgcaactctt 240
cgtgaaacct atggtgaaat ggctgactgc tgtgcaaaac aagaacctga gagaaatgaa 300
tgcttcttgc aacacaaaga tgacaaccca aacctccccc gattggtgag accagaggtt 360
gatgtgatgt gcactgcttt tcatgacaat gaagagacat ttttgaaaaa atacttatat 420
gaaattgcca gaagacatcc ttacttttat gccccggaac tccttttctt tgctaaaagg 480
tataaagctg cttttacaga atgttgccaa gctgctgata aagctgcctg cctgttgcca 540
aagctcgatg aacttcggga tgaagggaag gcttcgtctg ccaaacagag actcaagtgt 600
gccagtctcc aaaaatttgg agaaagagct ttcaaagcat gggcagtagc tcgcctgagc 660
cagagatttc ccaaagctga gtttgcagaa gtttccaagt tagtgacaga tcttaccaaa 720
gtccacacgg aatgctgcca tggagatctg cttgaatgtg ctgatgacag ggcggacctt 780
gccaagtata tctgtgaaaa tcaagattcg atctccagta aactgaagga atgctgtgaa 840
aaacctctgt tggaaaaatc ccactgcatt gccgaagtgg aaaatgatga gatgcctgct 900
gacttgcctt cattagctgc tgattttgtt gaaagtaagg atgtttgcaa aaactatgct 960
gaggcaaagg atgtcttcct gggcatgttt ttgtatgaat atgcaagaag gcatcctgat 1020
tactctgtcg tgctgctgct gagacttgcc aagacatatg aaaccactct agagaagtgc 1080
tgtgccgctg cagatcctca tgaatgctat gccaaagtgt tcgatgaatt taaacctctt 1140
gtggaagagc ctcagaattt aatcaaacaa aattgtgagc tttttgagca gcttggagag 1200
tacaaattcc agaatgcgct attagttcgt tacaccaaga aagtacccca agtgtcaact 1260
ccaactcttg tagaggtctc aagaaaccta ggaaaagtgg gcagcaaatg ttgtaaacat 1320
cctgaagcaa aaagaatgcc ctgtgcagaa gactatctat ccgtggtcct gaaccagtta 1380
tgtgtgttgc atgagaaaac gccagtaagt gacagagtca ccaaatgctg cacagaatcc 1440
ttggtgaaca ggcgaccatg cttttcagct ctggaagtcg atgaaacata cgttcccaaa 1500
gagtttaatg ctgaaacatt caccttccat gcagatatat gcacactttc tgagaaggag 1560
agacaaatca agaaacaaac tgcacttgtt gagctcgtga aacacaagcc caaggcaaca 1620
aaagagcaac tgaaagctgt tatggatgat ttcgcagctt ttgtagagaa gtgctgcaag 1680
gctgacgata aggagacctg ctttgccgag gagggtaaaa aacttgttgc tgcaagtcaa 1740
gctgccttag gctta 1755
<210> 26
<211> 5428
<212> DNA
<213> 人工的
<220>
<223> 哺乳动物表达载体
<400> 26
gacggatcgg gagatctccc gatcccctat ggtgcactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180
ttagggttag gcgttttgcg ctgcttcgcg atgtacgggc cagatatacg cgttgacatt 240
gattattgac tagttattaa tagtaatcaa ttacggggtc attagttcat agcccatata 300
tggagttccg cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc 360
cccgcccatt gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc 420
attgacgtca atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt 480
atcatatgcc aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt 540
atgcccagta catgacctta tgggactttc ctacttggca gtacatctac gtattagtca 600
tcgctattac catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg 660
actcacgggg atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc 720
aaaatcaacg ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg 780
gtaggcgtgt acggtgggag gtctatataa gcagagctct ctggctaact agagaaccca 840
ctgcttactg gcttatcgaa attaatacga ctcactatag ggagacccaa gctggctagc 900
gtttaaactt aagcttggta ccgagctcgg atccactagt ccagtgtggt ggaattctgc 960
agatatccag cacagtggcg gccgctcgag tctagagggc ccgtttaaac ccgctgatca 1020
gcctcgactg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 1080
ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 1140
cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 1200
gaggattggg aagacaatag caggcatgct ggggatgcgg tgggctctat ggcttctgag 1260
gcggaaagaa ccagctgggg ctctaggggg tatccccacg cgccctgtag cggcgcatta 1320
agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag cgccctagcg 1380
cccgctcctt tcgctttctt cccttccttt ctcgccacgt tcgccggctt tccccgtcaa 1440
gctctaaatc gggggctccc tttagggttc cgatttagtg ctttacggca cctcgacccc 1500
aaaaaacttg attagggtga tggttcacgt agtgggccat cgccctgata gacggttttt 1560
cgccctttga cgttggagtc cacgttcttt aatagtggac tcttgttcca aactggaaca 1620
acactcaacc ctatctcggt ctattctttt gatttataag ggattttgcc gatttcggcc 1680
tattggttaa aaaatgagct gatttaacaa aaatttaacg cgaattaatt ctgtggaatg 1740
tgtgtcagtt agggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca 1800
tgcatctcaa ttagtcagca accaggtgtg gaaagtcccc aggctcccca gcaggcagaa 1860
gtatgcaaag catgcatctc aattagtcag caaccatagt cccgccccta actccgccca 1920
tcccgcccct aactccgccc agttccgccc attctccgcc ccatggctga ctaatttttt 1980
ttatttatgc agaggccgag gccgcctctg cctctgagct attccagaag tagtgaggag 2040
gcttttttgg aggcctaggc ttttgcaaaa agctcccggg agcttgtata tccattttcg 2100
gatctgatca agagacagga tgaggatcgt ttcgcatgat tgaacaagat ggattgcacg 2160
caggttctcc ggccgcttgg gtggagaggc tattcggcta tgactgggca caacagacaa 2220
tcggctgctc tgatgccgcc gtgttccggc tgtcagcgca ggggcgcccg gttctttttg 2280
tcaagaccga cctgtccggt gccctgaatg aactgcagga cgaggcagcg cggctatcgt 2340
ggctggccac gacgggcgtt ccttgcgcag ctgtgctcga cgttgtcact gaagcgggaa 2400
gggactggct gctattgggc gaagtgccgg ggcaggatct cctgtcatct caccttgctc 2460
ctgccgagaa agtatccatc atggctgatg caatgcggcg gctgcatacg cttgatccgg 2520
ctacctgccc attcgaccac caagcgaaac atcgcatcga gcgagcacgt actcggatgg 2580
aagccggtct tgtcgatcag gatgatctgg acgaagagca tcaggggctc gcgccagccg 2640
aactgttcgc caggctcaag gcgcgcatgc ccgacggcga ggatctcgtc gtgacccatg 2700
gcgatgcctg cttgccgaat atcatggtgg aaaatggccg cttttctgga ttcatcgact 2760
gtggccggct gggtgtggcg gaccgctatc aggacatagc gttggctacc cgtgatattg 2820
ctgaagagct tggcggcgaa tgggctgacc gcttcctcgt gctttacggt atcgccgctc 2880
ccgattcgca gcgcatcgcc ttctatcgcc ttcttgacga gttcttctga gcgggactct 2940
ggggttcgaa atgaccgacc aagcgacgcc caacctgcca tcacgagatt tcgattccac 3000
cgccgccttc tatgaaaggt tgggcttcgg aatcgttttc cgggacgccg gctggatgat 3060
cctccagcgc ggggatctca tgctggagtt cttcgcccac cccaacttgt ttattgcagc 3120
ttataatggt tacaaataaa gcaatagcat cacaaatttc acaaataaag catttttttc 3180
actgcattct agttgtggtt tgtccaaact catcaatgta tcttatcatg tctgtatacc 3240
gtcgacctct agctagagct tggcgtaatc atggtcatag ctgtttcctg tgtgaaattg 3300
ttatccgctc acaattccac acaacatacg agccggaagc ataaagtgta aagcctgggg 3360
tgcctaatga gtgagctaac tcacattaat tgcgttgcgc tcactgcccg ctttccagtc 3420
gggaaacctg tcgtgccagc tgcattaatg aatcggccaa cgcgcgggga gaggcggttt 3480
gcgtattggg cgctcttccg cttcctcgct cactgactcg ctgcgctcgg tcgttcggct 3540
gcggcgagcg gtatcagctc actcaaaggc ggtaatacgg ttatccacag aatcagggga 3600
taacgcagga aagaacatgt gagcaaaagg ccagcaaaag gccaggaacc gtaaaaaggc 3660
cgcgttgctg gcgtttttcc ataggctccg cccccctgac gagcatcaca aaaatcgacg 3720
ctcaagtcag aggtggcgaa acccgacagg actataaaga taccaggcgt ttccccctgg 3780
aagctccctc gtgcgctctc ctgttccgac cctgccgctt accggatacc tgtccgcctt 3840
tctcccttcg ggaagcgtgg cgctttctca tagctcacgc tgtaggtatc tcagttcggt 3900
gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc cccgttcagc ccgaccgctg 3960
cgccttatcc ggtaactatc gtcttgagtc caacccggta agacacgact tatcgccact 4020
ggcagcagcc actggtaaca ggattagcag agcgaggtat gtaggcggtg ctacagagtt 4080
cttgaagtgg tggcctaact acggctacac tagaagaaca gtatttggta tctgcgctct 4140
gctgaagcca gttaccttcg gaaaaagagt tggtagctct tgatccggca aacaaaccac 4200
cgctggtagc ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca 4260
agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta 4320
agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa 4380
atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg 4440
cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg 4500
actccccgtc gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc 4560
aatgataccg cgagacccac gctcaccggc tccagattta tcagcaataa accagccagc 4620
cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa 4680
ttgttgccgg gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc 4740
cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg 4800
ttcccaacga tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc 4860
cttcggtcct ccgatcgttg tcagaagtaa gttggccgca gtgttatcac tcatggttat 4920
ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg 4980
tgagtactca accaagtcat tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc 5040
ggcgtcaata cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg 5100
aaaacgttct tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat 5160
gtaacccact cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg 5220
gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaaatg 5280
ttgaatactc atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct 5340
catgagcgga tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac 5400
atttccccga aaagtgccac ctgacgtc 5428
<210> 27
<211> 9276
<212> DNA
<213> 人工的
<220>
<223> 酵母表达载体
<400> 27
agatctaaca tccaaagacg aaaggttgaa tgaaaccttt ttgccatccg acatccacag 60
gtccattctc acacataagt gccaaacgca acaggagggg atacactagc agcagaccgt 120
tgcaaacgca ggacctccac tcctcttctc ctcaacaccc acttttgcca tcgaaaaacc 180
agcccagtta ttgggcttga ttggagctcg ctcattccaa ttccttctat taggctacta 240
acaccatgac tttattagcc tgtctatcct ggcccccctg gcgaggttca tgtttgttta 300
tttccgaatg caacaagctc cgcattacac ccgaacatca ctccagatga gggctttctg 360
agtgtggggt caaatagttt catgttcccc aaatggccca aaactgacag tttaaacgct 420
gtcttggaac ctaatatgac aaaagcgtga tctcatccaa gatgaactaa gtttggttcg 480
ttgaaatgct aacggccagt tggtcaaaaa gaaacttcca aaagtcgcca taccgtttgt 540
cttgtttggt attgattgac gaatgctcaa aaataatctc attaatgctt agcgcagtct 600
ctctatcgct tctgaacccc ggtgcacctg tgccgaaacg caaatgggga aacacccgct 660
ttttggatga ttatgcattg tctccacatt gtatgcttcc aagattctgg tgggaatact 720
gctgatagcc taacgttcat gatcaaaatt taactgttct aacccctact tgacagcaat 780
atataaacag aaggaagctg ccctgtctta aacctttttt tttatcatca ttattagctt 840
actttcataa ttgcgactgg ttccaattga caagcttttg attttaacga cttttaacga 900
caacttgaga agatcaaaaa acaactaatt attcgaagga tccaaacgat gagatttcct 960
tcaattttta ctgcagtttt attcgcagca tcctccgcat tagctgctcc agtcaacact 1020
acaacagaag atgaaacggc acaaattccg gctgaagctg tcatcggtta ctcagattta 1080
gaaggggatt tcgatgttgc tgttttgcca ttttccaaca gcacaaataa cgggttattg 1140
tttataaata ctactattgc cagcattgct gctaaagaag aaggggtatc tctcgagaaa 1200
agagaggctg aagcttacgt agaattccct agggcggccg cgaattaatt cgccttagac 1260
atgactgttc ctcagttcaa gttgggcact tacgagaaga ccggtcttgc tagattctaa 1320
tcaagaggat gtcagaatgc catttgcctg agagatgcag gcttcatttt tgatactttt 1380
ttatttgtaa cctatatagt ataggatttt ttttgtcatt ttgtttcttc tcgtacgagc 1440
ttgctcctga tcagcctatc tcgcagctga tgaatatctt gtggtagggg tttgggaaaa 1500
tcattcgagt ttgatgtttt tcttggtatt tcccactcct cttcagagta cagaagatta 1560
agtgagaagt tcgtttgtgc aagcttatcg ataagcttta atgcggtagt ttatcacagt 1620
taaattgcta acgcagtcag gcaccgtgta tgaaatctaa caatgcgctc atcgtcatcc 1680
tcggcaccgt caccctggat gctgtaggca taggcttggt tatgccggta ctgccgggcc 1740
tcttgcggga tatcgtccat tccgacagca tcgccagtca ctatggcgtg ctgctagcgc 1800
tatatgcgtt gatgcaattt ctatgcgcac ccgttctcgg agcactgtcc gaccgctttg 1860
gccgccgccc agtcctgctc gcttcgctac ttggagccac tatcgactac gcgatcatgg 1920
cgaccacacc cgtcctgtgg atctatcgaa tctaaatgta agttaaaatc tctaaataat 1980
taaataagtc ccagtttctc catacgaacc ttaacagcat tgcggtgagc atctagacct 2040
tcaacagcag ccagatccat cactgcttgg ccaatatgtt tcagtccctc aggagttacg 2100
tcttgtgaag tgatgaactt ctggaaggtt gcagtgttaa ctccgctgta ttgacgggca 2160
tatccgtacg ttggcaaagt gtggttggta ccggaggagt aatctccaca actctctgga 2220
gagtaggcac caacaaacac agatccagcg tgttgtactt gatcaacata agaagaagca 2280
ttctcgattt gcaggatcaa gtgttcagga gcgtactgat tggacatttc caaagcctgc 2340
tcgtaggttg caaccgatag ggttgtagag tgtgcaatac acttgcgtac aatttcaacc 2400
cttggcaact gcacagcttg gttgtgaaca gcatcttcaa ttctggcaag ctccttgtct 2460
gtcatatcga cagccaacag aatcacctgg gaatcaatac catgttcagc ttgagacaga 2520
aggtctgagg caacgaaatc tggatcagcg tatttatcag caataactag aacttcagaa 2580
ggcccagcag gcatgtcaat actacacagg gctgatgtgt cattttgaac catcatcttg 2640
gcagcagtaa cgaactggtt tcctggacca aatattttgt cacacttagg aacagtttct 2700
gttccgtaag ccatagcagc tactgcctgg gcgcctcctg ctagcacgat acacttagca 2760
ccaaccttgt gggcaacgta gatgacttct ggggtaaggg taccatcctt cttaggtgga 2820
gatgcaaaaa caatttcttt gcaaccagca actttggcag gaacacccag catcagggaa 2880
gtggaaggca gaattgcggt tccaccagga atatagaggc caactttctc aataggtctt 2940
gcaaaacgag agcagactac accagggcaa gtctcaactt gcaacgtctc cgttagttga 3000
gcttcatgga atttcctgac gttatctata gagagatcaa tggctctctt aacgttatct 3060
ggcaattgca taagttcctc tgggaaagga gcttctaaca caggtgtctt caaagcgact 3120
ccatcaaact tggcagttag ttctaaaagg gctttgtcac cattttgacg aacattgtcg 3180
acaattggtt tgactaattc cataatctgt tccgttttct ggataggacg acgaagggca 3240
tcttcaattt cttgtgagga ggccttagaa acgtcaattt tgcacaattc aatacgacct 3300
tcagaaggga cttctttagg tttggattct tctttaggtt gttccttggt gtatcctggc 3360
ttggcatctc ctttccttct agtgaccttt agggacttca tatccaggtt tctctccacc 3420
tcgtccaacg tcacaccgta cttggcacat ctaactaatg caaaataaaa taagtcagca 3480
cattcccagg ctatatcttc cttggattta gcttctgcaa gttcatcagc ttcctcccta 3540
attttagcgt tcaacaaaac ttcgtcgtca aataaccgtt tggtataaga accttctgga 3600
gcattgctct tacgatccca caaggtggct tccatggctc taagaccctt tgattggcca 3660
aaacaggaag tgcgttccaa gtgacagaaa ccaacacctg tttgttcaac cacaaatttc 3720
aagcagtctc catcacaatc caattcgata cccagcaact tttgagttgc tccagatgta 3780
gcacctttat accacaaacc gtgacgacga gattggtaga ctccagtttg tgtccttata 3840
gcctccggaa tagacttttt ggacgagtac accaggccca acgagtaatt agaagagtca 3900
gccaccaaag tagtgaatag accatcgggg cggtcagtag tcaaagacgc caacaaaatt 3960
tcactgacag ggaacttttt gacatcttca gaaagttcgt attcagtagt caattgccga 4020
gcatcaataa tggggattat accagaagca acagtggaag tcacatctac caactttgcg 4080
gtctcagaaa aagcataaac agttctacta ccgccattag tgaaactttt caaatcgccc 4140
agtggagaag aaaaaggcac agcgatacta gcattagcgg gcaaggatgc aactttatca 4200
accagggtcc tatagataac cctagcgcct gggatcatcc tttggacaac tctttctgcc 4260
aaatctaggt ccaaaatcac ttcattgata ccattattgt acaacttgag caagttgtcg 4320
atcagctcct caaattggtc ctctgtaacg gatgactcaa cttgcacatt aacttgaagc 4380
tcagtcgatt gagtgaactt gatcaggttg tgcagctggt cagcagcata gggaaacacg 4440
gcttttccta ccaaactcaa ggaattatca aactctgcaa cacttgcgta tgcaggtagc 4500
aagggaaatg tcatacttga agtcggacag tgagtgtagt cttgagaaat tctgaagccg 4560
tatttttatt atcagtgagt cagtcatcag gagatcctct acgccggacg catcgtggcc 4620
gacctgcagg gggggggggg gcgctgaggt ctgcctcgtg aagaaggtgt tgctgactca 4680
taccaggcct gaatcgcccc atcatccagc cagaaagtga gggagccacg gttgatgaga 4740
gctttgttgt aggtggacca gttggtgatt ttgaactttt gctttgccac ggaacggtct 4800
gcgttgtcgg gaagatgcgt gatctgatcc ttcaactcag caaaagttcg atttattcaa 4860
caaagccgcc gtcccgtcaa gtcagcgtaa tgctctgcca gtgttacaac caattaacca 4920
attctgatta gaaaaactca tcgagcatca aatgaaactg caatttattc atatcaggat 4980
tatcaatacc atatttttga aaaagccgtt tctgtaatga aggagaaaac tcaccgaggc 5040
agttccatag gatggcaaga tcctggtatc ggtctgcgat tccgactcgt ccaacatcaa 5100
tacaacctat taatttcccc tcgtcaaaaa taaggttatc aagtgagaaa tcaccatgag 5160
tgacgactga atccggtgag aatggcaaaa gcttatgcat ttctttccag acttgttcaa 5220
caggccagcc attacgctcg tcatcaaaat cactcgcatc aaccaaaccg ttattcattc 5280
gtgattgcgc ctgagcgaga cgaaatacgc gatcgctgtt aaaaggacaa ttacaaacag 5340
gaatcgaatg caaccggcgc aggaacactg ccagcgcatc aacaatattt tcacctgaat 5400
caggatattc ttctaatacc tggaatgctg ttttcccggg gatcgcagtg gtgagtaacc 5460
atgcatcatc aggagtacgg ataaaatgct tgatggtcgg aagaggcata aattccgtca 5520
gccagtttag tctgaccatc tcatctgtaa catcattggc aacgctacct ttgccatgtt 5580
tcagaaacaa ctctggcgca tcgggcttcc catacaatcg atagattgtc gcacctgatt 5640
gcccgacatt atcgcgagcc catttatacc catataaatc agcatccatg ttggaattta 5700
atcgcggcct cgagcaagac gtttcccgtt gaatatggct cataacaccc cttgtattac 5760
tgtttatgta agcagacagt tttattgttc atgatgatat atttttatct tgtgcaatgt 5820
aacatcagag attttgagac acaacgtggc tttccccccc ccccctgcag gtcggcatca 5880
ccggcgccac aggtgcggtt gctggcgcct atatcgccga catcaccgat ggggaagatc 5940
gggctcgcca cttcgggctc atgagcgctt gtttcggcgt gggtatggtg gcaggccccg 6000
tggccggggg actgttgggc gccatctcct tgcatgcacc attccttgcg gcggcggtgc 6060
tcaacggcct caacctacta ctgggctgct tcctaatgca ggagtcgcat aagggagagc 6120
gtcgagtatc tatgattgga agtatgggaa tggtgatacc cgcattcttc agtgtcttga 6180
ggtctcctat cagattatgc ccaactaaag caaccggagg aggagatttc atggtaaatt 6240
tctctgactt ttggtcatca gtagactcga actgtgagac tatctcggtt atgacagcag 6300
aaatgtcctt cttggagaca gtaaatgaag tcccaccaat aaagaaatcc ttgttatcag 6360
gaacaaactt cttgtttcga actttttcgg tgccttgaac tataaaatgt agagtggata 6420
tgtcgggtag gaatggagcg ggcaaatgct taccttctgg accttcaaga ggtatgtagg 6480
gtttgtagat actgatgcca acttcagtga caacgttgct atttcgttca aaccattccg 6540
aatccagaga aatcaaagtt gtttgtctac tattgatcca agccagtgcg gtcttgaaac 6600
tgacaatagt gtgctcgtgt tttgaggtca tctttgtatg aataaatcta gtctttgatc 6660
taaataatct tgacgagcca aggcgataaa tacccaaatc taaaactctt ttaaaacgtt 6720
aaaaggacaa gtatgtctgc ctgtattaaa ccccaaatca gctcgtagtc tgatcctcat 6780
caacttgagg ggcactatct tgttttagag aaatttgcgg agatgcgata tcgagaaaaa 6840
ggtacgctga ttttaaacgt gaaatttatc tcaagatctc tgcctcgcgc gtttcggtga 6900
tgacggtgaa aacctctgac acatgcagct cccggagacg gtcacagctt gtctgtaagc 6960
ggatgccggg agcagacaag cccgtcaggg cgcgtcagcg ggtgttggcg ggtgtcgggg 7020
cgcagccatg acccagtcac gtagcgatag cggagtgtat actggcttaa ctatgcggca 7080
tcagagcaga ttgtactgag agtgcaccat atgcggtgtg aaataccgca cagatgcgta 7140
aggagaaaat accgcatcag gcgctcttcc gcttcctcgc tcactgactc gctgcgctcg 7200
gtcgttcggc tgcggcgagc ggtatcagct cactcaaagg cggtaatacg gttatccaca 7260
gaatcagggg ataacgcagg aaagaacatg tgagcaaaag gccagcaaaa ggccaggaac 7320
cgtaaaaagg ccgcgttgct ggcgtttttc cataggctcc gcccccctga cgagcatcac 7380
aaaaatcgac gctcaagtca gaggtggcga aacccgacag gactataaag ataccaggcg 7440
tttccccctg gaagctccct cgtgcgctct cctgttccga ccctgccgct taccggatac 7500
ctgtccgcct ttctcccttc gggaagcgtg gcgctttctc aatgctcacg ctgtaggtat 7560
ctcagttcgg tgtaggtcgt tcgctccaag ctgggctgtg tgcacgaacc ccccgttcag 7620
cccgaccgct gcgccttatc cggtaactat cgtcttgagt ccaacccggt aagacacgac 7680
ttatcgccac tggcagcagc cactggtaac aggattagca gagcgaggta tgtaggcggt 7740
gctacagagt tcttgaagtg gtggcctaac tacggctaca ctagaaggac agtatttggt 7800
atctgcgctc tgctgaagcc agttaccttc ggaaaaagag ttggtagctc ttgatccggc 7860
aaacaaacca ccgctggtag cggtggtttt tttgtttgca agcagcagat tacgcgcaga 7920
aaaaaaggat ctcaagaaga tcctttgatc ttttctacgg ggtctgacgc tcagtggaac 7980
gaaaactcac gttaagggat tttggtcatg agattatcaa aaaggatctt cacctagatc 8040
cttttaaatt aaaaatgaag ttttaaatca atctaaagta tatatgagta aacttggtct 8100
gacagttacc aatgcttaat cagtgaggca cctatctcag cgatctgtct atttcgttca 8160
tccatagttg cctgactccc cgtcgtgtag ataactacga tacgggaggg cttaccatct 8220
ggccccagtg ctgcaatgat accgcgagac ccacgctcac cggctccaga tttatcagca 8280
ataaaccagc cagccggaag ggccgagcgc agaagtggtc ctgcaacttt atccgcctcc 8340
atccagtcta ttaattgttg ccgggaagct agagtaagta gttcgccagt taatagtttg 8400
cgcaacgttg ttgccattgc tgcaggcatc gtggtgtcac gctcgtcgtt tggtatggct 8460
tcattcagct ccggttccca acgatcaagg cgagttacat gatcccccat gttgtgcaaa 8520
aaagcggtta gctccttcgg tcctccgatc gttgtcagaa gtaagttggc cgcagtgtta 8580
tcactcatgg ttatggcagc actgcataat tctcttactg tcatgccatc cgtaagatgc 8640
ttttctgtga ctggtgagta ctcaaccaag tcattctgag aatagtgtat gcggcgaccg 8700
agttgctctt gcccggcgtc aacacgggat aataccgcgc cacatagcag aactttaaaa 8760
gtgctcatca ttggaaaacg ttcttcgggg cgaaaactct caaggatctt accgctgttg 8820
agatccagtt cgatgtaacc cactcgtgca cccaactgat cttcagcatc ttttactttc 8880
accagcgttt ctgggtgagc aaaaacagga aggcaaaatg ccgcaaaaaa gggaataagg 8940
gcgacacgga aatgttgaat actcatactc ttcctttttc aatattattg aagcatttat 9000
cagggttatt gtctcatgag cggatacata tttgaatgta tttagaaaaa taaacaaata 9060
ggggttccgc gcacatttcc ccgaaaagtg ccacctgacg tctaagaaac cattattatc 9120
atgacattaa cctataaaaa taggcgtatc acgaggccct ttcgtcttca agaattaatt 9180
ctcatgtttg acagcttatc atcgataagc tgactcatgt tggtattgtg aaatagacgc 9240
agatcgggaa cactgaaaaa taacagttat tattcg 9276
<210> 28
<211> 45
<212> DNA
<213> 人工的
<220>
<223> 柔性、延伸的接头
<400> 28
ggtggaggtg gctcaggtgg aggtggctca ggtggaggtg gctca 45
<210> 29
<211> 66
<212> DNA
<213> 人工的
<220>
<223> α螺旋接头
<400> 29
gctgaagctg cagccaaaga agctgcagcc aaagaggccg cagctaagga agccgcagca 60
aaagct 66
<210> 30
<211> 22
<212> PRT
<213> 人工的
<220>
<223> α螺旋肽接头
<400> 30
Ala Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys Glu Ala Ala Ala Lys
1 5 10 15
Glu Ala Ala Ala Lys Ala
20
<210> 31
<211> 5
<212> PRT
<213> 人工的
<220>
<223> 柔性、延伸的肽接头
<400> 31
Gly Gly Gly Gly Ser
1 5
<210> 32
<211> 16
<212> PRT
<213> 人工的
<220>
<223> 具有凝血酶切割位点的接头
<400> 32
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 33
<211> 6
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 33
Gly Ser Gly Ser Gly Ser
1 5
<210> 34
<211> 15
<212> PRT
<213> 人工的
<220>
<223> 具有凝血酶切割位点的接头
<400> 34
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly
1 5 10 15
<210> 35
<211> 16
<212> PRT
<213> 人工的
<220>
<223> 具有凝血酶切割位点的接头
<400> 35
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 36
<211> 11
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 36
Gly Gly Ser Gly Gly His Met Gly Ser Gly Gly
1 5 10
<210> 37
<211> 11
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 37
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly
1 5 10
<210> 38
<211> 11
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 38
Gly Gly Ser Gly Gly His Met Gly Ser Gly Gly
1 5 10
<210> 39
<211> 5
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 39
Gly Gly Ser Gly Gly
1 5
<210> 40
<211> 16
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 40
Gly Gly Gly Gly Ser Leu Val Pro Arg Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 41
<211> 8
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 41
Gly Gly Ser Gly Gly Gly Gly Gly
1 5
<210> 42
<211> 8
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 42
Gly Ser Gly Ser Gly Ser Gly Ser
1 5
<210> 43
<211> 18
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 43
Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly Gly Gly Ser Glu Gly
1 5 10 15
Gly Gly
<210> 44
<211> 8
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 44
Ala Ala Gly Ala Ala Thr Ala Ala
1 5
<210> 45
<211> 5
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 45
Gly Gly Gly Gly Gly
1 5
<210> 46
<211> 5
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 46
Gly Gly Ser Ser Gly
1 5
<210> 47
<211> 11
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 47
Gly Ser Gly Gly Gly Thr Gly Gly Gly Ser Gly
1 5 10
<210> 48
<211> 26
<212> PRT
<213> 人工的
<220>
<223> 接头
<400> 48
Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly
1 5 10 15
Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
20 25
Claims (21)
1.一种融合蛋白，包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素、它的类似物或衍生物；
L是间隔物或接头；以及
ALB是白蛋白、它的类似物或变体。
2.根据权利要求1所述的融合蛋白，选自由以下组成的组：
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；
以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
x1、x2、x3、x4、y1、y2或y3独立为零或选自1-10的整数，前提是在编码白蛋白-生长抑素融合蛋白的核苷酸序列中存在至少一个L。
3.根据权利要求1所述的融合蛋白，其中所述SST或是天然存在的或是合成制备的。
4.根据权利要求1所述的融合蛋白，其中，所述SST包括编码分别由SEQ ID NO：17或18表示的SST-14或SST-28的序列或者与这些序列的任一具有至少85％同一性的序列的一个或多个串联重复序列。
5.根据权利要求1所述的融合蛋白，其中，所述SST是SST-14或SST-28。
6.根据权利要求1所述的融合蛋白，其中，L或是柔性的或α螺旋结构的多肽接头或间隔物。
7.根据权利要求1所述的融合蛋白，其中，L是具有2-100个氨基酸的多肽。
8.根据权利要求6所述的融合蛋白，其中，所述多肽包含GGGGS、A(EAAAK)4A、(AP)n、(G)8、(G)5中的至少一种或其任何组合，其中n是选自10-34的整数。
9.根据权利要求1所述的融合蛋白，其中，ALB是哺乳动物血清白蛋白。
10.根据权利要求1所述的融合蛋白，其中，所述哺乳动物血清白蛋白是SEQ ID NO:25，或具有与其至少85％序列同一性的序列。
11.根据权利要求2所述的融合蛋白，其中x1、x2、x3、x4各自独立为选自1-5的整数。
12.根据权利要求2所述的融合蛋白，其中y1、y2、y3各自独立为选自1-5的整数。
13.一种编码多肽的核苷酸序列，所述多肽包括：
SST；
L；以及
ALB，
其中，
SST是生长抑素或它的类似物或衍生物；
L是间隔物或接头；以及
ALB是白蛋白或它的类似物或变体。
14.根据权利要求13的核苷酸序列，编码选自由以下组成的组的多肽：
SST-(L)x1-ALB (I)；
ALB-(L)x1-SST (II)；
[SST-(L)x1]y1-ALB (III)；
ALB-[(L)x1-SST]y1 (IV)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2 (V)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB (VI)；
[SST-(L)x1]y1-ALB-[(L)x2-SST]y2-(L)x3-ALB-[(L)x4-SST]y3 (VII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB (VIII)；
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB (IX)；
以及
ALB-(L)x1-[SST-(L)x2]y1-ALB-[(L)x3-SST]y2-(L)x1-ALB-[(L)x4-SST]y3 (X)；
其中，
每个x1、x2、x3、x4、y1、y2或y3独立地为零或选自1-10的整数，
前提是在所述多肽中存在至少一个L。
15.根据权利要求13所述的核苷酸序列，编码多肽序列，其中，所述SST包括编码分别由SEQ ID NO：17或18表示的SST-14或SST-28的序列，或者与SEQ ID NO:17或SEQ ID NO:18具有至少85％同一性的序列的一个或多个串联重复序列。
16.一种表达包括权利要求1所述的融合蛋白的白蛋白-生长抑素融合蛋白的质粒构建体。
17.一种用权利要求16所述的质粒构建体转化的细菌宿主细胞。
18.根据权利要求1所述的融合蛋白，所述融合蛋白是分离的和纯化的。
19.一种通过给药有效量的包括权利要求1所述的融合蛋白的药物组合物来治疗人受试者内分泌释放的疾病或疾患的方法，其中所述内分泌释放的疾病或疾患是对给药生长抑素有反应的病症。
20.根据权利要求19所述的方法，其中所述病症是选自由以下组成的组的癌症：乳腺癌、结肠直肠癌、肝癌、内分泌癌、神经内分泌癌、胰腺癌、前列腺癌、脑癌和肺癌。
21.根据权利要求20所述的方法，其中，所述癌症表达生长抑素受体1、2、3、4或5型。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2016/019950 WO2017146738A1 (en) | 2016-02-26 | 2016-02-26 | Compositions containing fusion protein of albumin and analogs thereof, methods for making and using the same |
| TW105106088A TWI719963B (zh) | 2015-02-26 | 2016-02-26 | 含有白蛋白及其類似物之融合蛋白之組合物、其製備及使用方法 |
| US15/249,346 US20170002057A1 (en) | 2015-02-26 | 2016-08-26 | Compositions containing fusion protein of albumin and analogs thereof, methods for making and using the same |
| US15/249,346 | 2016-08-26 | ||
| PCT/US2017/039477 WO2018038803A1 (en) | 2016-08-26 | 2017-06-27 | Compositions containing fusion protein of albumin and analogs thereof, methods for making and using the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109641036A true CN109641036A (zh) | 2019-04-16 |
Family
ID=59685659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780052241.2A Pending CN109641036A (zh) | 2016-02-26 | 2017-06-27 | 包含白蛋白的融合蛋白和其类似物的组合物、其制备和使用方法 |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR20190039967A (zh) |
| CN (1) | CN109641036A (zh) |
| WO (1) | WO2017146738A1 (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4599229A (en) * | 1985-09-09 | 1986-07-08 | International Minerals & Chemical Corp. | Method of promoting animal growth using antibodies against somatostatin |
| CN102391376A (zh) * | 2011-03-15 | 2012-03-28 | 江苏省原子医学研究所 | 人生长抑素十四肽与人血清白蛋白的融合蛋白及其编码基因和制备方法 |
| CN102675467A (zh) * | 2011-03-15 | 2012-09-19 | 无锡坤洲大得药业有限公司 | 人生长抑素二十八肽与人血清白蛋白的融合蛋白及其编码基因和制备方法 |
| US20130157933A1 (en) * | 2001-12-21 | 2013-06-20 | Craig A. Rosen | Albumin fusion proteins |
-
2016
- 2016-02-26 WO PCT/US2016/019950 patent/WO2017146738A1/en active Application Filing
-
2017
- 2017-06-27 KR KR1020197006100A patent/KR20190039967A/ko not_active Application Discontinuation
- 2017-06-27 CN CN201780052241.2A patent/CN109641036A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4599229A (en) * | 1985-09-09 | 1986-07-08 | International Minerals & Chemical Corp. | Method of promoting animal growth using antibodies against somatostatin |
| US20130157933A1 (en) * | 2001-12-21 | 2013-06-20 | Craig A. Rosen | Albumin fusion proteins |
| CN102391376A (zh) * | 2011-03-15 | 2012-03-28 | 江苏省原子医学研究所 | 人生长抑素十四肽与人血清白蛋白的融合蛋白及其编码基因和制备方法 |
| CN102675467A (zh) * | 2011-03-15 | 2012-09-19 | 无锡坤洲大得药业有限公司 | 人生长抑素二十八肽与人血清白蛋白的融合蛋白及其编码基因和制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| YUEDI DING等: ""The Effect of Albumin Fusion Patterns on the Production and Bioactivity of the Somatostatin-14 Fusion Protein in Pichia pastoris"", 《APPL BIOCHEM BIOTECHNOL》 * |
| YUEDI DING等: ""The effect of albumin fusion structure on the production and bioactivity of the somatostatin-28 fusion protein in Pichia pastoris"", 《J IND MICROBIOL BIOTECHNOL》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017146738A1 (en) | 2017-08-31 |
| KR20190039967A (ko) | 2019-04-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108103098B (zh) | 一种化合物皮肤致敏体外评估细胞模型及其构建方法 | |
| CN110511286B (zh) | 一种rna碱基编辑分子 | |
| CN102649947A (zh) | 一种用于测定glp-1及其功能类似物生物活性的细胞株及其应用 | |
| KR100913984B1 (ko) | 플라비바이러스 감염 예방용 핵산 백신 | |
| KR102475799B1 (ko) | 비-펩티드 결합을 함유하는 하이브리드 면역글로불린 | |
| Ng et al. | The eighth component of human complement: evidence that it is an oligomeric serum protein assembled from products of three different genes | |
| CN113631033A (zh) | 与enpp1或enpp3缺乏有关的疾病的治疗 | |
| CN110699380B (zh) | 一种ev71病毒核酸质粒及其构建方法及应用 | |
| RU2740438C1 (ru) | Активирующий nk-клетки слитый белок, nk-клетки и фармацевтическая композиция, включающая их | |
| CN110714027A (zh) | 一种表达质粒、用于包装二代腺病毒的细胞株及其应用 | |
| CN109641036A (zh) | 包含白蛋白的融合蛋白和其类似物的组合物、其制备和使用方法 | |
| JPH0687895A (ja) | 可溶性、低密度リポ蛋白質レセプター及びその調製方法 | |
| CN107384917B (zh) | mini-gene剪接报告质粒及其构建方法与应用 | |
| JP5450985B2 (ja) | 真核細胞において組換えタンパク質を細胞外に放出させるためのポリヌクレオチド | |
| Tatzel et al. | Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology | |
| CN100503832C (zh) | 关中奶山羊酪蛋白基因启动子表达载体 | |
| CA3195071A1 (en) | Liver specific production of enpp1 or enpp3 | |
| US20030114644A1 (en) | Melanin concentrating hormone receptors | |
| CN110628815B (zh) | 一种基于基因编辑技术的监测miRNA表达的报告基因探针及其构建方法 | |
| CN111733188B (zh) | 促进骨骼肌发育的方法和促进骨骼肌发育的抑制剂及应用 | |
| CN112646838B (zh) | 一种hspa13基因表达载体及其构建方法和应用 | |
| US20030166834A1 (en) | Melanin concentrating hormone receptors | |
| CN114836421A (zh) | 一种翻译增强序列组合 | |
| CN113209136B (zh) | 一种可注射水凝胶和基因工程化细胞的组合物及其治疗骨关节炎的应用 | |
| KR100514979B1 (ko) | 갈렉틴-3 관련 질병을 예방 및 치료하기 위한 약학 조성물 |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190416 |