CN1209437A - 获得具有正确键合的胱氨酸键的胰岛素前体的改进的方法 - Google Patents
获得具有正确键合的胱氨酸键的胰岛素前体的改进的方法 Download PDFInfo
- Publication number
- CN1209437A CN1209437A CN98117909A CN98117909A CN1209437A CN 1209437 A CN1209437 A CN 1209437A CN 98117909 A CN98117909 A CN 98117909A CN 98117909 A CN98117909 A CN 98117909A CN 1209437 A CN1209437 A CN 1209437A
- Authority
- CN
- China
- Prior art keywords
- amino
- insulin
- acid residue
- arg
- residue
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 47
- 239000002243 precursor Substances 0.000 title claims abstract description 36
- 229960003067 cystine Drugs 0.000 title claims abstract description 30
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 101
- 102000004877 Insulin Human genes 0.000 claims abstract description 81
- 108090001061 Insulin Proteins 0.000 claims abstract description 81
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 69
- 229940125396 insulin Drugs 0.000 claims abstract description 50
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229960001305 cysteine hydrochloride Drugs 0.000 claims abstract description 26
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 86
- 125000000539 amino acid group Chemical group 0.000 claims description 69
- 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 claims description 53
- 229950004152 insulin human Drugs 0.000 claims description 45
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 41
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 39
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 37
- 239000007788 liquid Substances 0.000 claims description 35
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 32
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 28
- 108090000623 proteins and genes Proteins 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 25
- 239000004475 Arginine Substances 0.000 claims description 21
- 239000012752 auxiliary agent Substances 0.000 claims description 21
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 150000001413 amino acids Chemical group 0.000 claims description 19
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000010790 dilution Methods 0.000 claims description 14
- 239000012895 dilution Substances 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 229930182817 methionine Natural products 0.000 claims description 13
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 9
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 8
- 239000004473 Threonine Substances 0.000 claims description 8
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 8
- 239000004471 Glycine Substances 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 7
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims description 7
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000013329 compounding Methods 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- 101500021084 Locusta migratoria 5 kDa peptide Proteins 0.000 claims description 3
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 230000003196 chaotropic effect Effects 0.000 abstract 1
- 229960002433 cysteine Drugs 0.000 abstract 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract 1
- 235000018417 cysteine Nutrition 0.000 abstract 1
- 239000004026 insulin derivative Substances 0.000 abstract 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 59
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 43
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 41
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 31
- 108010076181 Proinsulin Proteins 0.000 description 29
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 26
- 125000003275 alpha amino acid group Chemical group 0.000 description 25
- 230000004927 fusion Effects 0.000 description 22
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 19
- 229940024606 amino acid Drugs 0.000 description 19
- 235000001014 amino acid Nutrition 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 17
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 210000003000 inclusion body Anatomy 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000855 fermentation Methods 0.000 description 9
- 230000004151 fermentation Effects 0.000 description 9
- 230000000968 intestinal effect Effects 0.000 description 9
- JYOAXOMPIXKMKK-YUMQZZPRSA-N Leu-Gln Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CCC(N)=O JYOAXOMPIXKMKK-YUMQZZPRSA-N 0.000 description 8
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 102000003670 Carboxypeptidase B Human genes 0.000 description 5
- 108090000087 Carboxypeptidase B Proteins 0.000 description 5
- 239000003463 adsorbent Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000012239 gene modification Methods 0.000 description 5
- 230000005017 genetic modification Effects 0.000 description 5
- 235000013617 genetically modified food Nutrition 0.000 description 5
- JFOWDKWFHZIMTR-RUCXOUQFSA-N (2s)-2-aminopentanedioic acid;(2s)-2,5-diamino-5-oxopentanoic acid Chemical compound OC(=O)[C@@H](N)CCC(N)=O.OC(=O)[C@@H](N)CCC(O)=O JFOWDKWFHZIMTR-RUCXOUQFSA-N 0.000 description 4
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 4
- MPZWMIIOPAPAKE-BQBZGAKWSA-N Glu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=N MPZWMIIOPAPAKE-BQBZGAKWSA-N 0.000 description 4
- MMFKFJORZBJVNF-UWVGGRQHSA-N His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 MMFKFJORZBJVNF-UWVGGRQHSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 108010025306 histidylleucine Proteins 0.000 description 4
- 238000000265 homogenisation Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010075254 C-Peptide Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- ARPVSMCNIDAQBO-YUMQZZPRSA-N Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ARPVSMCNIDAQBO-YUMQZZPRSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 3
- LHSGPCFBGJHPCY-STQMWFEESA-N Leu-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-STQMWFEESA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- -1 Serine Chemical compound 0.000 description 3
- 102000001400 Tryptase Human genes 0.000 description 3
- 108060005989 Tryptase Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 102220369447 c.1352G>A Human genes 0.000 description 3
- 230000000290 insulinogenic effect Effects 0.000 description 3
- 108010012058 leucyltyrosine Proteins 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 2
- AYKQJQVWUYEZNU-IMJSIDKUSA-N Cys-Asn Chemical compound SC[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O AYKQJQVWUYEZNU-IMJSIDKUSA-N 0.000 description 2
- ZUKPVRWZDMRIEO-VKHMYHEASA-N L-cysteinylglycine Chemical compound SC[C@H]([NH3+])C(=O)NCC([O-])=O ZUKPVRWZDMRIEO-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- NFDYGNFETJVMSE-BQBZGAKWSA-N Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CO NFDYGNFETJVMSE-BQBZGAKWSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 108010016616 cysteinylglycine Proteins 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- OMLWNBVRVJYMBQ-YUMQZZPRSA-N Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OMLWNBVRVJYMBQ-YUMQZZPRSA-N 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000006035 Tryptophane Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].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](CC3N=CN=C3)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(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)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N cystine group Chemical group C([C@@H](C(=O)O)N)SSC[C@@H](C(=O)O)N LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229960002989 glutamic acid 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
- 229960002743 glutamine Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/12—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by hydrolysis, i.e. solvolysis in general
-
- 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
- C07K14/62—Insulins
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Analytical Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (13)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19735711A DE19735711C2 (de) | 1997-08-18 | 1997-08-18 | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
DE19735711.3 | 1997-08-18 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006101000625A Division CN101186940B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
CN031523307A Division CN1483831B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1209437A true CN1209437A (zh) | 1999-03-03 |
CN1132845C CN1132845C (zh) | 2003-12-31 |
Family
ID=7839275
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98117909A Expired - Lifetime CN1132845C (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素前体的改进的方法 |
CN2006101000625A Expired - Lifetime CN101186940B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
CN031523307A Expired - Lifetime CN1483831B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006101000625A Expired - Lifetime CN101186940B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
CN031523307A Expired - Lifetime CN1483831B (zh) | 1997-08-18 | 1998-08-17 | 获得具有正确键合的胱氨酸键的胰岛素或胰岛素衍生物的方法 |
Country Status (21)
Country | Link |
---|---|
US (3) | US5986048A (zh) |
EP (2) | EP0980874B1 (zh) |
JP (1) | JP4291900B2 (zh) |
KR (2) | KR100537842B1 (zh) |
CN (3) | CN1132845C (zh) |
AR (1) | AR016821A1 (zh) |
AT (2) | ATE217636T1 (zh) |
AU (1) | AU744824B2 (zh) |
BR (2) | BRPI9816233B8 (zh) |
CA (1) | CA2245151C (zh) |
CZ (1) | CZ295679B6 (zh) |
DE (3) | DE19735711C2 (zh) |
DK (2) | DK0906918T3 (zh) |
ES (2) | ES2177178T3 (zh) |
HK (3) | HK1018464A1 (zh) |
HU (2) | HU228203B1 (zh) |
ID (1) | ID20717A (zh) |
PL (1) | PL191901B1 (zh) |
PT (2) | PT906918E (zh) |
RU (2) | RU2205836C2 (zh) |
TR (1) | TR199801587A3 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103694339A (zh) * | 2013-12-04 | 2014-04-02 | 珠海联邦制药股份有限公司 | 一种甘精胰岛素前体的复性方法 |
CN114989289A (zh) * | 2013-02-26 | 2022-09-02 | 韩美药品株式会社 | 新颖的胰岛素类似物及其用途 |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19735711C2 (de) | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
DE19930676B4 (de) * | 1999-07-02 | 2006-01-19 | Sanofi-Aventis Deutschland Gmbh | Verfahren zur Stabilisierung von Insulin, Insulinderivaten und/oder deren Vorläufer in komplexen Mischungen bei deren Lagerung in wäßrigen Lösungsmitteln |
JP2003530316A (ja) | 1999-12-22 | 2003-10-14 | ノボ ノルディスク アクティーゼルスカブ | スクランブルした一本鎖ポリペプチドの抽出的再生法 |
AU2001280436A1 (en) * | 2000-07-12 | 2002-01-21 | Eli Lilly And Company | Process to increase protein stability |
DE10235168A1 (de) * | 2002-08-01 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Verfahren zur Reinigung von Preproinsulin |
DE102004015965A1 (de) * | 2004-04-01 | 2005-10-20 | Aventis Pharma Gmbh | Verfahren zur Gewinnung von Insulinen durch verbesserte Luftbegasung der Faltung |
US20080032343A1 (en) | 2005-12-22 | 2008-02-07 | Genentech, Inc. | Recombinant Production of Heparin Binding Proteins |
RU2439076C2 (ru) | 2006-07-14 | 2012-01-10 | Дженентек, Инк. | Способ выделения повторно свернутого рекомбинантного белка из культуры прокариотических клеток (варианты) |
JP5244175B2 (ja) * | 2007-07-03 | 2013-07-24 | アムジエン・インコーポレーテツド | 封入体乾燥重量を用いたタンパク質の測定 |
RU2451750C2 (ru) * | 2007-09-24 | 2012-05-27 | Общество С Ограниченной Ответственностью "Герофарм" | Способ получения рекомбинантного с-пептида проинсулина человека |
KR20100111682A (ko) | 2008-01-09 | 2010-10-15 | 사노피-아벤티스 도이칠란트 게엠베하 | 극히 지연된 시간-작용 프로필을 갖는 신규 인슐린 유도체 |
EP2274318B1 (en) * | 2008-04-30 | 2014-08-13 | Wockhardt Limited | Processes for refolding of insulin |
KR101820024B1 (ko) | 2008-10-17 | 2018-01-18 | 사노피-아벤티스 도이칠란트 게엠베하 | 인슐린과 glp-1 효능제의 병용물 |
HUE037735T2 (hu) | 2009-11-13 | 2018-09-28 | Sanofi Aventis Deutschland | DesPro36exendin-4(1-39)-Lys6-NH2-t és metionint tartalmazó gyógyszerkészítmény |
ES2534191T3 (es) | 2009-11-13 | 2015-04-20 | Sanofi-Aventis Deutschland Gmbh | Composición farmacéutica que comprende un agonista de GLP-1, una insulina y metionina |
BR112013004756B1 (pt) | 2010-08-30 | 2020-04-28 | Sanofi Aventis Deutschland | uso de ave0010 para a fabricação de um medicamento para o tratamento da diabetes melito tipo 2 |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
US20180282405A1 (en) * | 2012-08-05 | 2018-10-04 | Absci, Llc | Cytoplasmic expression system |
US10421795B2 (en) | 2012-12-17 | 2019-09-24 | Merck Sharp & Dohme Corp. | Process for purifying insulin and analogues thereof |
WO2015138548A1 (en) | 2014-03-14 | 2015-09-17 | Merck Sharp & Dohme Corp. | Purifying insulin using cation exchange and reverse phase chromatography in the presence of an organic modifier and elevated temperature |
JP6970615B2 (ja) | 2014-12-12 | 2021-11-24 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | インスリングラルギン/リキシセナチド固定比処方 |
TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患治療 |
TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第2型糖尿病病患之治療 |
CN104911203A (zh) * | 2015-06-30 | 2015-09-16 | 成都易胜科生物科技有限公司 | 一种重组人胰岛素的工业制备方法 |
EP3344651B1 (en) | 2015-09-02 | 2022-03-02 | Merck Sharp & Dohme Corp. | A process for obtaining insulin with correctly formed disulfide bonds |
US10689430B2 (en) | 2016-05-25 | 2020-06-23 | Merck Sharp & Dohme Corp. | Insulin receptor partial agonists |
WO2018018613A1 (zh) | 2016-07-29 | 2018-02-01 | 广东东阳光药业有限公司 | 一种提高抗体纯度的细胞培养基和培养方法 |
CN113773391B (zh) * | 2020-06-09 | 2023-10-20 | 宁波鲲鹏生物科技有限公司 | 一种门冬胰岛素的制备方法 |
CN113773400B (zh) * | 2020-06-09 | 2023-08-18 | 宁波鲲鹏生物科技有限公司 | 一种门冬胰岛素衍生物及其应用 |
CN113773396A (zh) * | 2020-06-10 | 2021-12-10 | 宁波鲲鹏生物科技有限公司 | 一种地特胰岛素衍生物及其应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ199391A (en) * | 1981-01-02 | 1985-12-13 | Genentech Inc | Chimeric polypeptides comprising a proinsulin sequence,and preparation by recombinant dna technique;production of human insulin |
DE3501641A1 (de) * | 1985-01-19 | 1986-07-24 | Hoechst Ag, 6230 Frankfurt | Verfahren zur gewinnung von insulin-vorlaeufern aus reaktionsgemischen, die bei der faltung von insulin-vorlaeufern aus den entsprechenden s-sulfonaten anfallen |
GR1005153B (el) * | 1989-08-29 | 2006-03-13 | The General Hospital Corporation | Πρωτεινες συντηξεως, παρασκευη τους και χρηση τους. |
EP0600372B1 (de) * | 1992-12-02 | 1997-02-05 | Hoechst Aktiengesellschaft | Verfahren zur Gewinnung von Proinsulin mit korrekt verbundenen Cystinbrücken |
DE4405179A1 (de) * | 1994-02-18 | 1995-08-24 | Hoechst Ag | Verfahren zur Gewinnung von Insulin mit korrekt verbundenen Cystinbrücken |
JP4624495B2 (ja) * | 1994-12-29 | 2011-02-02 | フェリング・インターナショナル・センター・エス.・エー. | ヒト・インスリンの生成 |
DE19735711C2 (de) * | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
-
1997
- 1997-08-18 DE DE19735711A patent/DE19735711C2/de not_active Expired - Lifetime
-
1998
- 1998-08-11 PT PT98115048T patent/PT906918E/pt unknown
- 1998-08-11 EP EP99115386A patent/EP0980874B1/de not_active Expired - Lifetime
- 1998-08-11 EP EP98115048A patent/EP0906918B1/de not_active Expired - Lifetime
- 1998-08-11 AT AT98115048T patent/ATE217636T1/de active
- 1998-08-11 PT PT99115386T patent/PT980874E/pt unknown
- 1998-08-11 DK DK98115048T patent/DK0906918T3/da active
- 1998-08-11 DE DE59804121T patent/DE59804121D1/de not_active Expired - Lifetime
- 1998-08-11 DK DK99115386T patent/DK0980874T3/da active
- 1998-08-11 AT AT99115386T patent/ATE217012T1/de active
- 1998-08-11 ES ES99115386T patent/ES2177178T3/es not_active Expired - Lifetime
- 1998-08-11 ES ES98115048T patent/ES2176870T3/es not_active Expired - Lifetime
- 1998-08-11 DE DE59803985T patent/DE59803985D1/de not_active Expired - Lifetime
- 1998-08-14 CA CA002245151A patent/CA2245151C/en not_active Expired - Lifetime
- 1998-08-14 ID IDP981136A patent/ID20717A/id unknown
- 1998-08-14 AR ARP980104052A patent/AR016821A1/es active IP Right Grant
- 1998-08-17 JP JP23036898A patent/JP4291900B2/ja not_active Expired - Lifetime
- 1998-08-17 RU RU98116259/04A patent/RU2205836C2/ru active
- 1998-08-17 BR BRPI9816233A patent/BRPI9816233B8/pt not_active IP Right Cessation
- 1998-08-17 TR TR1998/01587A patent/TR199801587A3/tr unknown
- 1998-08-17 HU HU0600287A patent/HU228203B1/hu unknown
- 1998-08-17 US US09/134,836 patent/US5986048A/en not_active Expired - Lifetime
- 1998-08-17 CN CN98117909A patent/CN1132845C/zh not_active Expired - Lifetime
- 1998-08-17 CN CN2006101000625A patent/CN101186940B/zh not_active Expired - Lifetime
- 1998-08-17 HU HU9801886A patent/HU228161B1/hu unknown
- 1998-08-17 AU AU80763/98A patent/AU744824B2/en not_active Expired
- 1998-08-17 CN CN031523307A patent/CN1483831B/zh not_active Expired - Lifetime
- 1998-08-17 BR BR9803755-2A patent/BR9803755A/pt not_active Application Discontinuation
- 1998-08-17 CZ CZ19982598A patent/CZ295679B6/cs not_active IP Right Cessation
- 1998-08-18 PL PL328108A patent/PL191901B1/pl unknown
- 1998-08-18 KR KR1019980033384A patent/KR100537842B1/ko not_active IP Right Cessation
-
1999
- 1999-08-06 HK HK99103399A patent/HK1018464A1/xx not_active IP Right Cessation
- 1999-08-31 US US09/386,303 patent/US6380355B1/en not_active Expired - Lifetime
-
2001
- 2001-09-07 US US09/947,563 patent/US6727346B2/en not_active Expired - Lifetime
-
2002
- 2002-10-07 RU RU2002126598/15A patent/RU2302882C2/ru active
-
2004
- 2004-07-06 HK HK04104835.7A patent/HK1061870A1/xx not_active IP Right Cessation
-
2005
- 2005-05-27 KR KR1020050044974A patent/KR100574580B1/ko not_active IP Right Cessation
-
2008
- 2008-07-18 HK HK08107963.0A patent/HK1119449A1/xx not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114989289A (zh) * | 2013-02-26 | 2022-09-02 | 韩美药品株式会社 | 新颖的胰岛素类似物及其用途 |
CN103694339A (zh) * | 2013-12-04 | 2014-04-02 | 珠海联邦制药股份有限公司 | 一种甘精胰岛素前体的复性方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1132845C (zh) | 获得具有正确键合的胱氨酸键的胰岛素前体的改进的方法 | |
CN1144874C (zh) | 具酶活性的重组羧肽酶b的生产 | |
CN1158305C (zh) | 增强了锌结合力的胰岛素衍生物 | |
CN1193042C (zh) | 用于改进胰岛素和胰岛素类似物的制备方法的c肽 | |
CN101068833A (zh) | 产生羧基端酰胺化肽的方法 | |
CN1196061A (zh) | 胰岛素衍生物 | |
CN1110323A (zh) | 新多肽和编码它们的脱氧核糖核酸 | |
CN1265143A (zh) | 通过内源基因活化制备促红细胞生成素 | |
CN1529757A (zh) | 用于向细菌培养物上清液中分泌目的蛋白质的融合蛋白质 | |
CN1152955C (zh) | 生产蛋白酶的方法 | |
CN1303299A (zh) | 关于肽合成的方法以及组合物 | |
CN1916017A (zh) | 生产疏水多肽、蛋白质或肽的方法 | |
CN1055480C (zh) | 爪蟾抗菌肽的取代类似物 | |
CN1197876C (zh) | 含有分子内伴侣样序列的嵌合蛋白及其在胰岛素生产中的应用 | |
CN1865283A (zh) | 固相多肽合成鲑鱼降钙素的制备方法 | |
CN1111909A (zh) | 新多肽及编码该多肽的dna | |
CN1213146C (zh) | 从新的融合蛋白制造重组胰岛素的方法 | |
CN1765929A (zh) | 含有肽载体和表皮生长因子的融合蛋白和核酸及其用途 | |
CN1219883C (zh) | 改造合成的苏云金芽孢杆菌杀虫晶体蛋白基因CrylC* | |
CN1798569A (zh) | 用于治疗1型糖尿病的治疗性疫苗组合物 | |
CN1757739A (zh) | 一种表达肝素酶的方法及其专用表达载体 | |
CN1968961A (zh) | 制备肽的方法 | |
CN100339479C (zh) | 参与油菜素类固醇合成的基因 | |
CN1046559A (zh) | 制备胰高血糖素的方法 | |
CN1597698A (zh) | 阳离子抗菌肽 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Applicant after: Awentis Medicines Deutschland GmbH Applicant before: German Beh Chester Marie Applicant before: Searl Oro Co. Ltd. |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: HOECHST MARION GERMANY; MOSHIER LTD. TO: AVENTIS PHARMACY (GERMANY)INTERNATIONAL CO., LTD. |
|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: SANOFI- AVENTIS GERMAN CO., LTD. Free format text: FORMER NAME OR ADDRESS: AVENTIS PHARMACY (GERMANY)INTERNATIONAL CO., LTD. |
|
CP03 | Change of name, title or address |
Address after: Frankfurt, Federal Republic of Germany Patentee after: Aventis Pharma GmbH Address before: Frankfurt, Federal Republic of Germany Patentee before: Awentis Medicines Deutschland GmbH |
|
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20031231 |