DE19735711C2 - Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken - Google Patents
Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen CystinbrückenInfo
- Publication number
- DE19735711C2 DE19735711C2 DE19735711A DE19735711A DE19735711C2 DE 19735711 C2 DE19735711 C2 DE 19735711C2 DE 19735711 A DE19735711 A DE 19735711A DE 19735711 A DE19735711 A DE 19735711A DE 19735711 C2 DE19735711 C2 DE 19735711C2
- Authority
- DE
- Germany
- Prior art keywords
- cysteine
- insulin
- amino acid
- precursor
- chaotropic
- 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.)
- Expired - Lifetime
Links
- 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 title claims description 102
- 102000004877 Insulin Human genes 0.000 title claims description 42
- 108090001061 Insulin Proteins 0.000 title claims description 42
- 229940125396 insulin Drugs 0.000 title claims description 36
- 238000000034 method Methods 0.000 title claims description 36
- 239000002243 precursor Substances 0.000 title claims description 32
- 229960003067 cystine Drugs 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000000243 solution Substances 0.000 claims description 38
- 235000018417 cysteine Nutrition 0.000 claims description 31
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 31
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 31
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 30
- 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 description 28
- 230000003196 chaotropic effect Effects 0.000 claims description 28
- 229960002433 cysteine Drugs 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 21
- 239000004026 insulin derivative Substances 0.000 claims description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 10
- 239000004202 carbamide Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 5
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007900 aqueous suspension Substances 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
- 229960004198 guanidine Drugs 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 description 50
- 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 47
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 46
- 108010076181 Proinsulin Proteins 0.000 description 34
- 125000003275 alpha amino acid group Chemical group 0.000 description 27
- 108020001507 fusion proteins Proteins 0.000 description 25
- 102000037865 fusion proteins Human genes 0.000 description 25
- 108090000765 processed proteins & peptides Proteins 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 15
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 15
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000000855 fermentation Methods 0.000 description 12
- 230000004151 fermentation Effects 0.000 description 12
- 241000588724 Escherichia coli Species 0.000 description 11
- 210000003000 inclusion body Anatomy 0.000 description 10
- 239000004475 Arginine Substances 0.000 description 9
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 9
- 238000005119 centrifugation Methods 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102000004142 Trypsin Human genes 0.000 description 7
- 108090000631 Trypsin Proteins 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 239000012588 trypsin Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 108090000087 Carboxypeptidase B Proteins 0.000 description 5
- 102000003670 Carboxypeptidase B Human genes 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000011097 chromatography purification Methods 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000010353 genetic engineering Methods 0.000 description 4
- 238000000265 homogenisation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000001810 trypsinlike Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 108010075254 C-Peptide Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- -1 Halogen cyanide Chemical class 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 108010068380 arginylarginine Proteins 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 101500021084 Locusta migratoria 5 kDa peptide Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 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 2
- 238000010979 pH adjustment 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
- BMLMGCPTLHPWPY-REOHCLBHSA-N (4R)-2-oxo-4-thiazolidinecarboxylic acid Chemical compound OC(=O)[C@@H]1CSC(=O)N1 BMLMGCPTLHPWPY-REOHCLBHSA-N 0.000 description 1
- 241000283690 Bos taurus Species 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
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 102000018389 Exopeptidases Human genes 0.000 description 1
- 108010091443 Exopeptidases Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 101710186643 Insulin-2 Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-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
- 241001655322 Streptomycetales Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 235000004279 alanine Nutrition 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
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 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 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000164 protein isolation 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-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)
- Medicinal Chemistry (AREA)
- Diabetes (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Endocrinology (AREA)
- Analytical Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Priority Applications (38)
| 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 |
| ES99115386T ES2177178T3 (es) | 1997-08-18 | 1998-08-11 | Procedimiento mejorado para la obtencion de precursores de insulina con puentes cistina correctamente unidos. |
| EP98115048A EP0906918B1 (de) | 1997-08-18 | 1998-08-11 | Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| DE59803985T DE59803985D1 (de) | 1997-08-18 | 1998-08-11 | Verbessertes Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| AT99115386T ATE217012T1 (de) | 1997-08-18 | 1998-08-11 | Verbessertes verfahren zur gewinnung von insulinvorläufern mit korrekt verbundenen cystinbrücken |
| PT99115386T PT980874E (pt) | 1997-08-18 | 1998-08-11 | Processo melhorado para a obtencao de percursores da insulina com as pontes de cistina correctamente ligadas |
| EP99115386A EP0980874B1 (de) | 1997-08-18 | 1998-08-11 | Verbessertes Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| PT98115048T PT906918E (pt) | 1997-08-18 | 1998-08-11 | Processo para a recuperacao de produtos intermediarios previos de insulina com pontes de cistina correctamente ligadas |
| AT98115048T ATE217636T1 (de) | 1997-08-18 | 1998-08-11 | Verfahren zur gewinnung von insulinvorläufern mit korrekt verbundenen cystinbrücken |
| DK98115048T DK0906918T3 (da) | 1997-08-18 | 1998-08-11 | Fremgangsmåde til udvinding af insulinforstadier med korrekt forbundne cystinbroer |
| ES98115048T ES2176870T3 (es) | 1997-08-18 | 1998-08-11 | Procedimiento para la obtencion de precusores de la insulina con puentes de cistina correctamente ligados. |
| DK99115386T DK0980874T3 (da) | 1997-08-18 | 1998-08-11 | Forbedret fremgangsmåde til udvinding af insulinforstadier med korrekt forbundne cysteinbroer |
| DE59804121T DE59804121D1 (de) | 1997-08-18 | 1998-08-11 | Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| ARP980104052A AR016821A1 (es) | 1997-08-18 | 1998-08-14 | Procedimiento mejorado para la obtencion de precursores de insulina con puentes de cistina correctamente unidos |
| IDP981136A ID20717A (id) | 1997-08-18 | 1998-08-14 | Proses yang diperbaiki untuk memperoleh prekursor-prekursor insulin yang mempunyai jembatan-jembatan sistin yang terikat dengan tepat |
| CA002245151A CA2245151C (en) | 1997-08-18 | 1998-08-14 | Improved process for obtaining insulin precursors having correctly bonded cystine bridges |
| HU0600287A HU228203B1 (en) | 1997-08-18 | 1998-08-17 | Process for production of insulin or indulin-derivatne having correctly linked cystine bridges |
| CZ19982598A CZ295679B6 (cs) | 1997-08-18 | 1998-08-17 | Způsob získávání inzulinu nebo derivátů inzulinu se správně spojenými cysteinovými můstky |
| AU80763/98A AU744824B2 (en) | 1997-08-18 | 1998-08-17 | Improved process for obtaining insulin precursors having correctly bonded cystine bridges |
| BR9803755-2A BR9803755A (pt) | 1997-08-18 | 1998-08-17 | Processo aperfeiçoado para obtenção de precursores de insulina tendo pontes de cistina corretamente ligadas. |
| CN98117909A 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 |
| US09/134,836 US5986048A (en) | 1997-08-18 | 1998-08-17 | Process for obtaining insulin precursors having correctly bonded cystine bridges |
| BRPI9816233A BRPI9816233B8 (pt) | 1997-08-18 | 1998-08-17 | processo de preparação de insulinas ou de um derivado de insulina |
| TR1998/01587A TR199801587A3 (tr) | 1997-08-18 | 1998-08-17 | Insülin öncü moleküllerinin elde edilmesine yönelik yöntem. |
| CN2006101000625A 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 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 |
| HU9801886A HU228161B1 (en) | 1997-08-18 | 1998-08-17 | Improved process for producing inzulin precurzors and-derivatives having with availably bonded cystin-bride |
| JP23036898A JP4291900B2 (ja) | 1997-08-18 | 1998-08-17 | 正しく結合したシスチン橋を有するインスリン前駆体を取得するための改良された方法 |
| RU98116259/04A RU2205836C2 (ru) | 1997-08-18 | 1998-08-17 | Усовершенствованный способ получения предшественника инсулина с правильно соединенными цистиновыми мостиками |
| PL328108A PL191901B1 (pl) | 1997-08-18 | 1998-08-18 | Sposób wytwarzania prekursorów insuliny i pochodnych insuliny |
| KR1019980033384A KR100537842B1 (ko) | 1997-08-18 | 1998-08-18 | 정확하게 결합된 시스틴 브릿지를 갖는 인슐린 전구체를 수득하는 방법 |
| HK99103399.3A HK1018464B (en) | 1997-08-18 | 1999-08-06 | Improved process for obtaining insulin precursors haveing correctly bonded cystine bridges |
| US09/386,303 US6380355B1 (en) | 1997-08-18 | 1999-08-31 | Process for obtaining insulin precursors having correctly bonded cystine bridges |
| US09/947,563 US6727346B2 (en) | 1997-08-18 | 2001-09-07 | Process for obtaining insulin precursors having correctly bonded cystine bridges |
| RU2002126598/15A RU2302882C2 (ru) | 1997-08-18 | 2002-10-07 | Способ получения инсулина или производных инсулина с правильно соединенными цистиновыми мостиками |
| HK04104835.7A HK1061870B (en) | 1997-08-18 | 2004-07-06 | Improved process for obtaining insulin precursors having correctly bonded cystine bridges |
| KR1020050044974A KR100574580B1 (ko) | 1997-08-18 | 2005-05-27 | 정확하게 결합된 시스틴 브릿지를 갖는 인슐린 또는 인슐린유도체를 수득하는 방법 |
| HK08107963.0A HK1119449B (en) | 1997-08-18 | 2008-07-18 | Process for obtaining insulin or insulin derivatives having correctly bonded cystine bridges |
Applications Claiming Priority (1)
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE19735711A1 DE19735711A1 (de) | 1999-02-25 |
| DE19735711C2 true DE19735711C2 (de) | 2001-04-26 |
Family
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| DE59803985T Expired - Lifetime DE59803985D1 (de) | 1997-08-18 | 1998-08-11 | Verbessertes Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| DE59804121T Expired - Lifetime DE59804121D1 (de) | 1997-08-18 | 1998-08-11 | Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
Family Applications After (2)
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| DE59803985T Expired - Lifetime DE59803985D1 (de) | 1997-08-18 | 1998-08-11 | Verbessertes Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
| DE59804121T Expired - Lifetime DE59804121D1 (de) | 1997-08-18 | 1998-08-11 | Verfahren zur Gewinnung von Insulinvorläufern mit korrekt verbundenen Cystinbrücken |
Country Status (20)
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| EP (2) | EP0980874B1 (enExample) |
| JP (1) | JP4291900B2 (enExample) |
| KR (2) | KR100537842B1 (enExample) |
| CN (3) | CN101186940B (enExample) |
| AR (1) | AR016821A1 (enExample) |
| AT (2) | ATE217636T1 (enExample) |
| AU (1) | AU744824B2 (enExample) |
| BR (2) | BR9803755A (enExample) |
| CA (1) | CA2245151C (enExample) |
| CZ (1) | CZ295679B6 (enExample) |
| DE (3) | DE19735711C2 (enExample) |
| DK (2) | DK0980874T3 (enExample) |
| ES (2) | ES2176870T3 (enExample) |
| HU (2) | HU228161B1 (enExample) |
| ID (1) | ID20717A (enExample) |
| PL (1) | PL191901B1 (enExample) |
| PT (2) | PT980874E (enExample) |
| RU (2) | RU2205836C2 (enExample) |
| TR (1) | TR199801587A3 (enExample) |
Families Citing this family (34)
| 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 |
| JP5036727B2 (ja) | 2005-12-22 | 2012-09-26 | ジェネンテック， インコーポレイテッド | ヘパリン結合タンパク質の組み換え体産生 |
| CN101506222B (zh) * | 2006-07-14 | 2013-10-02 | 健泰科生物技术公司 | 重组蛋白的重折叠 |
| CA2692585A1 (en) * | 2007-07-03 | 2010-01-04 | Amgen Inc. | Measurement of protein using inclusion body dry weight |
| RU2451750C2 (ru) * | 2007-09-24 | 2012-05-27 | Общество С Ограниченной Ответственностью "Герофарм" | Способ получения рекомбинантного с-пептида проинсулина человека |
| BRPI0907371A2 (pt) | 2008-01-09 | 2015-11-24 | Sanofi Aventis Deutschland | derivados de insulina com um perfil de tempo-ação muito retardado |
| US9296806B2 (en) * | 2008-04-30 | 2016-03-29 | Wockhardt Limited | Processes for refolding of insulin |
| RS59913B1 (sr) | 2008-10-17 | 2020-03-31 | Sanofi Aventis Deutschland | Kombinacija insulina i glp-1-agonista |
| CA2780043C (en) | 2009-11-13 | 2019-01-29 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| 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 |
| SG187904A1 (en) | 2010-08-30 | 2013-04-30 | Sanofi Aventis Deutschland | Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 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 |
| AR087744A1 (es) | 2011-09-01 | 2014-04-16 | Sanofi Aventis Deutschland | Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa |
| US12157766B2 (en) * | 2012-08-05 | 2024-12-03 | Absci Corporation | Cytoplasmic expression system |
| US10421795B2 (en) | 2012-12-17 | 2019-09-24 | Merck Sharp & Dohme Corp. | Process for purifying insulin and analogues thereof |
| WO2014133324A1 (ko) * | 2013-02-26 | 2014-09-04 | 한미약품 주식회사 | 신규한 인슐린 아날로그 및 이의 용도 |
| CN103694339B (zh) * | 2013-12-04 | 2017-10-13 | 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 |
| US10407483B2 (en) | 2014-03-14 | 2019-09-10 | Merck Sharp & Dohme Corp. | Purifying insulin using cation exchange and reverse phase chromatography in the presence of an organic modifier and elevated temperature |
| SI3229828T1 (sl) | 2014-12-12 | 2023-06-30 | Sanofi-Aventis Deutschland Gmbh | Formulacija s fiksnim razmerjem inzulin glargin/liksisenatid |
| 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 |
| 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 |
| 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 |
| 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 |
| JP7749397B2 (ja) * | 2021-09-30 | 2025-10-06 | キヤノン株式会社 | 超音波ファントム及び超音波ファントムの製造方法 |
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| EP0668292A2 (de) * | 1994-02-18 | 1995-08-23 | Hoechst Aktiengesellschaft | Verfahren zur Gewinnung von Insulin mit korrekt verbundenen Cystinbrücken |
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| 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. |
| RU2045535C1 (ru) * | 1991-06-18 | 1995-10-10 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | Способ получения проинсулина человека |
| ES2097426T3 (es) * | 1992-12-02 | 1997-04-01 | Hoechst Ag | Procedimiento para la obtencion de proinsulina con puentes de cistina correctamente unidos. |
| RU2081122C1 (ru) * | 1994-06-16 | 1997-06-10 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | Способ выделения и очистки инсулина или его биотехнологических предшественников |
| PT871474E (pt) * | 1994-12-29 | 2007-02-28 | Ferring Int Ct Sa | Produção de insulina humana |
| DE19735711C2 (de) | 1997-08-18 | 2001-04-26 | Aventis Pharma Gmbh | Verfahren zur Herstellung eines Vorläufers von Insulin oder Insulinderivaten mit korrekt verbundenen Cystinbrücken |
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1997
- 1997-08-18 DE DE19735711A patent/DE19735711C2/de not_active Expired - Lifetime
-
1998
- 1998-08-11 DE DE59803985T patent/DE59803985D1/de not_active Expired - Lifetime
- 1998-08-11 AT AT98115048T patent/ATE217636T1/de active
- 1998-08-11 EP EP99115386A patent/EP0980874B1/de not_active Expired - Lifetime
- 1998-08-11 DE DE59804121T patent/DE59804121D1/de not_active Expired - Lifetime
- 1998-08-11 PT PT99115386T patent/PT980874E/pt unknown
- 1998-08-11 ES ES98115048T patent/ES2176870T3/es not_active Expired - Lifetime
- 1998-08-11 ES ES99115386T patent/ES2177178T3/es not_active Expired - Lifetime
- 1998-08-11 AT AT99115386T patent/ATE217012T1/de active
- 1998-08-11 DK DK99115386T patent/DK0980874T3/da active
- 1998-08-11 PT PT98115048T patent/PT906918E/pt unknown
- 1998-08-11 EP EP98115048A patent/EP0906918B1/de not_active Expired - Lifetime
- 1998-08-11 DK DK98115048T patent/DK0906918T3/da active
- 1998-08-14 AR ARP980104052A patent/AR016821A1/es active IP Right Grant
- 1998-08-14 ID IDP981136A patent/ID20717A/id unknown
- 1998-08-14 CA CA002245151A patent/CA2245151C/en not_active Expired - Lifetime
- 1998-08-17 BR BR9803755-2A patent/BR9803755A/pt not_active Application Discontinuation
- 1998-08-17 CN CN2006101000625A patent/CN101186940B/zh not_active Expired - Lifetime
- 1998-08-17 US US09/134,836 patent/US5986048A/en not_active Expired - Lifetime
- 1998-08-17 RU RU98116259/04A patent/RU2205836C2/ru active
- 1998-08-17 CN CN98117909A patent/CN1132845C/zh not_active Expired - Lifetime
- 1998-08-17 AU AU80763/98A patent/AU744824B2/en not_active Expired
- 1998-08-17 HU HU9801886A patent/HU228161B1/hu unknown
- 1998-08-17 CZ CZ19982598A patent/CZ295679B6/cs not_active IP Right Cessation
- 1998-08-17 CN CN031523307A patent/CN1483831B/zh not_active Expired - Lifetime
- 1998-08-17 TR TR1998/01587A patent/TR199801587A3/tr unknown
- 1998-08-17 JP JP23036898A patent/JP4291900B2/ja not_active Expired - Lifetime
- 1998-08-17 BR BRPI9816233A patent/BRPI9816233B8/pt not_active IP Right Cessation
- 1998-08-17 HU HU0600287A patent/HU228203B1/hu unknown
- 1998-08-18 PL PL328108A patent/PL191901B1/pl unknown
- 1998-08-18 KR KR1019980033384A patent/KR100537842B1/ko not_active Expired - Lifetime
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1999
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| EP0668292A2 (de) * | 1994-02-18 | 1995-08-23 | Hoechst Aktiengesellschaft | Verfahren zur Gewinnung von Insulin mit korrekt verbundenen Cystinbrücken |
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