CZ2004710A3 - Inzulínová sloučenina s protrahovaným účinkem - Google Patents

Info

Publication number

CZ2004710A3

CZ2004710A3 CZ2004710A CZ2004710A CZ2004710A3 CZ 2004710 A3 CZ2004710 A3 CZ 2004710A3 CZ 2004710 A CZ2004710 A CZ 2004710A CZ 2004710 A CZ2004710 A CZ 2004710A CZ 2004710 A3 CZ2004710 A3 CZ 2004710A3

Authority

CZ

Czechia

Prior art keywords

lys

arg

insulin

xaa

homoarginine

Prior art date

2001-12-20

Links

• Espacenet
• Global Dossier
• Discuss

• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Substances 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 abstract description 726
• 229940125396 insulin Drugs 0.000 title claims abstract description 533
• 102000004877 Insulin Human genes 0.000 title claims abstract description 344
• 108090001061 Insulin Proteins 0.000 title claims abstract description 343
• -1 Insulin compound Chemical class 0.000 title claims description 197
• 230000000694 effects Effects 0.000 title description 34
• 230000001747 exhibiting effect Effects 0.000 title 1
• 238000000034 method Methods 0.000 claims abstract description 54
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 25
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 463
• 150000001413 amino acids Chemical group 0.000 claims description 124
• 239000000203 mixture Substances 0.000 claims description 100
• QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 claims description 87
• QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 claims description 60
• 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 50
• 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 49
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 47
• 239000008103 glucose Substances 0.000 claims description 45
• 239000004026 insulin derivative Substances 0.000 claims description 35
• 150000001875 compounds Chemical class 0.000 claims description 33
• 102000007327 Protamines Human genes 0.000 claims description 32
• 108010007568 Protamines Proteins 0.000 claims description 32
• LKRMSSDDHQZQHJ-ZETCQYMHSA-N (2s)-2-amino-5-(diaminomethylideneamino)-2-methylpentanoic acid Chemical compound OC(=O)[C@](N)(C)CCCN=C(N)N LKRMSSDDHQZQHJ-ZETCQYMHSA-N 0.000 claims description 28
• UKUBCVAQGIZRHL-UHFFFAOYSA-N delta-Guanidinovaleric acid Chemical compound NC(N)=NCCCCC(O)=O UKUBCVAQGIZRHL-UHFFFAOYSA-N 0.000 claims description 28
• 239000011701 zinc Substances 0.000 claims description 28
• 229910052751 metal Inorganic materials 0.000 claims description 23
• 239000002184 metal Substances 0.000 claims description 23
• 229940048914 protamine Drugs 0.000 claims description 23
• 229910052725 zinc Inorganic materials 0.000 claims description 23
• 150000001768 cations Chemical class 0.000 claims description 22
• AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 21
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 21
• 210000004369 blood Anatomy 0.000 claims description 21
• 239000008280 blood Substances 0.000 claims description 21
• 238000002360 preparation method Methods 0.000 claims description 21
• 125000003277 amino group Chemical group 0.000 claims description 18
• 239000013081 microcrystal Substances 0.000 claims description 18
• NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 9
• 230000015572 biosynthetic process Effects 0.000 claims description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 150000001412 amines Chemical class 0.000 claims description 7
• 239000003125 aqueous solvent Substances 0.000 claims description 7
• 201000001421 hyperglycemia Diseases 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 150000003862 amino acid derivatives Chemical class 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract description 460
• 239000004472 Lysine Substances 0.000 abstract description 17
• 230000004048 modification Effects 0.000 abstract description 13
• 238000012986 modification Methods 0.000 abstract description 13
• 230000009471 action Effects 0.000 abstract description 6
• ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 378
• 235000001014 amino acid Nutrition 0.000 description 127
• 229940024606 amino acid Drugs 0.000 description 124
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 108
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 103
• 239000000243 solution Substances 0.000 description 91
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 76
• 239000011550 stock solution Substances 0.000 description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
• XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• 239000000047 product Substances 0.000 description 51
• MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 45
• 150000002148 esters Chemical class 0.000 description 44
• 239000011780 sodium chloride Substances 0.000 description 43
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 41
• 238000002474 experimental method Methods 0.000 description 40
• 108010076181 Proinsulin Proteins 0.000 description 38
• 108090000623 proteins and genes Proteins 0.000 description 37
• 210000004027 cell Anatomy 0.000 description 36
• 108090000765 processed proteins & peptides Proteins 0.000 description 34
• 102000004169 proteins and genes Human genes 0.000 description 33
• 238000005917 acylation reaction Methods 0.000 description 31
• 235000018102 proteins Nutrition 0.000 description 31
• 230000010933 acylation Effects 0.000 description 30
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 29
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• 125000003275 alpha amino acid group Chemical group 0.000 description 27
• 239000013078 crystal Substances 0.000 description 26
• 239000011787 zinc oxide Substances 0.000 description 26
• 239000000725 suspension Substances 0.000 description 25
• 238000006243 chemical reaction Methods 0.000 description 24
• 239000012153 distilled water Substances 0.000 description 24
• 239000000872 buffer Substances 0.000 description 22
• 238000009472 formulation Methods 0.000 description 22
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 21
• 239000000463 material Substances 0.000 description 21
• 238000000746 purification Methods 0.000 description 21
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 19
• 239000002953 phosphate buffered saline Substances 0.000 description 19
• 238000004007 reversed phase HPLC Methods 0.000 description 19
• 239000012071 phase Substances 0.000 description 18
• RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 17
• 150000003839 salts Chemical class 0.000 description 16
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
• 239000001488 sodium phosphate Substances 0.000 description 15
• 229910000162 sodium phosphate Inorganic materials 0.000 description 15
• 235000011008 sodium phosphates Nutrition 0.000 description 15
• RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 15
• 229960003742 phenol Drugs 0.000 description 13
• 239000002244 precipitate Substances 0.000 description 13
• 102000004196 processed proteins & peptides Human genes 0.000 description 13
• 238000002821 scintillation proximity assay Methods 0.000 description 13
• 238000012360 testing method Methods 0.000 description 13
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
• 239000003153 chemical reaction reagent Substances 0.000 description 12
• 239000002609 medium Substances 0.000 description 12
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 11
• DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 11
• 239000013598 vector Substances 0.000 description 11
• GVIXTVCDNCXXSH-AWEZNQCLSA-N (2s)-2-amino-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C GVIXTVCDNCXXSH-AWEZNQCLSA-N 0.000 description 10
• WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 10
• 238000004458 analytical method Methods 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 239000003755 preservative agent Substances 0.000 description 10
• 229950008679 protamine sulfate Drugs 0.000 description 10
• 241000894007 species Species 0.000 description 10
• WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 9
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 9
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
• 239000012528 membrane Substances 0.000 description 9
• 238000006467 substitution reaction Methods 0.000 description 9
• CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 8
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
• CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
• 108091028043 Nucleic acid sequence Proteins 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 8
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
• 229910052799 carbon Inorganic materials 0.000 description 8
• 239000001963 growth medium Substances 0.000 description 8
• 230000004044 response Effects 0.000 description 8
• 239000004475 Arginine Substances 0.000 description 7
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 7
• ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
• MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 7
• KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 7
• 125000001931 aliphatic group Chemical group 0.000 description 7
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 7
• 235000011180 diphosphates Nutrition 0.000 description 7
• 238000000338 in vitro Methods 0.000 description 7
• 230000002335 preservative effect Effects 0.000 description 7
• 239000001632 sodium acetate Substances 0.000 description 7
• 235000017281 sodium acetate Nutrition 0.000 description 7
• 239000007787 solid Substances 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• 229910021653 sulphate ion Inorganic materials 0.000 description 7
• ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 7
• 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 6
• 108010075254 C-Peptide Proteins 0.000 description 6
• 102000003746 Insulin Receptor Human genes 0.000 description 6
• 108010001127 Insulin Receptor Proteins 0.000 description 6
• QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
• ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
• COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
• 239000002253 acid Substances 0.000 description 6
• 235000004279 alanine Nutrition 0.000 description 6
• 238000004108 freeze drying Methods 0.000 description 6
• 125000000524 functional group Chemical group 0.000 description 6
• 235000011187 glycerol Nutrition 0.000 description 6
• JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
• LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• 102000005962 receptors Human genes 0.000 description 6
• 108020003175 receptors Proteins 0.000 description 6
• 239000001509 sodium citrate Substances 0.000 description 6
• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 6
• DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 5
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
• COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine 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)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(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 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 5
• 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 5
• AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 5
• KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 5
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
• 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 5
• 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 5
• AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 5
• 239000004473 Threonine Substances 0.000 description 5
• 239000007983 Tris buffer Substances 0.000 description 5
• 150000001408 amides Chemical class 0.000 description 5
• 229960001230 asparagine Drugs 0.000 description 5
• 235000009582 asparagine Nutrition 0.000 description 5
• 235000003704 aspartic acid Nutrition 0.000 description 5
• 239000011324 bead Substances 0.000 description 5
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
• 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 5
• 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 5
• 238000005277 cation exchange chromatography Methods 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 238000001727 in vivo Methods 0.000 description 5
• 238000001802 infusion Methods 0.000 description 5
• 230000000670 limiting effect Effects 0.000 description 5
• 229910000403 monosodium phosphate Inorganic materials 0.000 description 5
• 235000019799 monosodium phosphate Nutrition 0.000 description 5
• 239000011541 reaction mixture Substances 0.000 description 5
• AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 5
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
• 239000007790 solid phase Substances 0.000 description 5
• 238000007920 subcutaneous administration Methods 0.000 description 5
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
• 230000001550 time effect Effects 0.000 description 5
• 239000004474 valine Substances 0.000 description 5
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
• 241000282472 Canis lupus familiaris Species 0.000 description 4
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
• 239000004471 Glycine Substances 0.000 description 4
• 239000007995 HEPES buffer Substances 0.000 description 4
• 108010057186 Insulin Glargine Proteins 0.000 description 4
• 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
• HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
• ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
• 108010076504 Protein Sorting Signals Proteins 0.000 description 4
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
• 125000002252 acyl group Chemical group 0.000 description 4
• 230000037396 body weight Effects 0.000 description 4
• 230000021235 carbamoylation Effects 0.000 description 4
• 238000007385 chemical modification Methods 0.000 description 4
• 229960002242 chlorocresol Drugs 0.000 description 4
• 238000002425 crystallisation Methods 0.000 description 4
• 230000008025 crystallization Effects 0.000 description 4
• 230000004069 differentiation Effects 0.000 description 4
• 210000003527 eukaryotic cell Anatomy 0.000 description 4
• 238000001914 filtration Methods 0.000 description 4
• 235000013922 glutamic acid Nutrition 0.000 description 4
• 239000004220 glutamic acid Substances 0.000 description 4
• ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
• HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
• 229960002869 insulin glargine Drugs 0.000 description 4
• 239000003446 ligand Substances 0.000 description 4
• 230000002503 metabolic effect Effects 0.000 description 4
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
• 230000002297 mitogenic effect Effects 0.000 description 4
• COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
• 229920001184 polypeptide Polymers 0.000 description 4
• 210000001236 prokaryotic cell Anatomy 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
• 230000003248 secreting effect Effects 0.000 description 4
• 238000003786 synthesis reaction Methods 0.000 description 4
• 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 4
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
• 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 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• 241000283690 Bos taurus Species 0.000 description 3
• WEDIKSVWBUKTRA-WTKGVUNUSA-N CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=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](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=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](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC WEDIKSVWBUKTRA-WTKGVUNUSA-N 0.000 description 3
• LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 3
• 108020004414 DNA Proteins 0.000 description 3
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
• 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 3
• 229930182816 L-glutamine Natural products 0.000 description 3
• 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 3
• UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 3
• 229910019142 PO4 Inorganic materials 0.000 description 3
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
• QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
• 230000002378 acidificating effect Effects 0.000 description 3
• APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 3
• 239000012131 assay buffer Substances 0.000 description 3
• 210000004899 c-terminal region Anatomy 0.000 description 3
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
• 230000001276 controlling effect Effects 0.000 description 3
• 229960003067 cystine Drugs 0.000 description 3
• 230000002354 daily effect Effects 0.000 description 3
• 238000012217 deletion Methods 0.000 description 3
• 230000037430 deletion Effects 0.000 description 3
• 229960003957 dexamethasone Drugs 0.000 description 3
• UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
• VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 3
• 230000029087 digestion Effects 0.000 description 3
• 238000007865 diluting Methods 0.000 description 3
• 238000010790 dilution Methods 0.000 description 3
• 239000012895 dilution Substances 0.000 description 3
• 238000004090 dissolution Methods 0.000 description 3
• 239000013604 expression vector Substances 0.000 description 3
• 230000037406 food intake Effects 0.000 description 3
• 235000012631 food intake Nutrition 0.000 description 3
• 239000000499 gel Substances 0.000 description 3
• 238000001990 intravenous administration Methods 0.000 description 3
• 229960000310 isoleucine Drugs 0.000 description 3
• AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 3
• 238000012417 linear regression Methods 0.000 description 3
• 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
• 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
• 229960002216 methylparaben Drugs 0.000 description 3
• 238000007911 parenteral administration Methods 0.000 description 3
• 239000010452 phosphate Substances 0.000 description 3
• 235000011007 phosphoric acid Nutrition 0.000 description 3
• 229920000642 polymer Polymers 0.000 description 3
• 108091033319 polynucleotide Proteins 0.000 description 3
• 102000040430 polynucleotide Human genes 0.000 description 3
• 239000002157 polynucleotide Substances 0.000 description 3
• 239000002243 precursor Substances 0.000 description 3
• 239000013014 purified material Substances 0.000 description 3
• UCQFSGCWHRTMGG-UHFFFAOYSA-N pyrazole-1-carboximidamide Chemical compound NC(=N)N1C=CC=N1 UCQFSGCWHRTMGG-UHFFFAOYSA-N 0.000 description 3
• 230000009257 reactivity Effects 0.000 description 3
• 239000006228 supernatant Substances 0.000 description 3
• 229940095064 tartrate Drugs 0.000 description 3
• 238000002560 therapeutic procedure Methods 0.000 description 3
• OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
• BGOFOVHACSQSIE-ZDUSSCGKSA-N (2s)-5-[bis[(2-methylpropan-2-yl)oxycarbonylamino]methylideneamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCNC(NC(=O)OC(C)(C)C)=NC(=O)OC(C)(C)C BGOFOVHACSQSIE-ZDUSSCGKSA-N 0.000 description 2
• BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 2
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
• QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 2
• WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
• APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
• XUUXCWCKKCZEAW-YFKPBYRVSA-N Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N XUUXCWCKKCZEAW-YFKPBYRVSA-N 0.000 description 2
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
• 239000005711 Benzoic acid Substances 0.000 description 2
• QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
• 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
• 241000588724 Escherichia coli Species 0.000 description 2
• CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
• 229930182566 Gentamicin Natural products 0.000 description 2
• 108010051815 Glutamyl endopeptidase Proteins 0.000 description 2
• 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 2
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
• 108010081368 Isophane Insulin Proteins 0.000 description 2
• 102000005237 Isophane Insulin Human genes 0.000 description 2
• ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 2
• FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
• 241000124008 Mammalia Species 0.000 description 2
• 229930195725 Mannitol Natural products 0.000 description 2
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• 239000012901 Milli-Q water Substances 0.000 description 2
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
• 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
• 108091005804 Peptidases Proteins 0.000 description 2
• ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
• 239000004365 Protease Substances 0.000 description 2
• 241000700159 Rattus Species 0.000 description 2
• 101000930457 Rattus norvegicus Albumin Proteins 0.000 description 2
• 108020004511 Recombinant DNA Proteins 0.000 description 2
• SBMNPABNWKXNBJ-BQBZGAKWSA-N Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CO SBMNPABNWKXNBJ-BQBZGAKWSA-N 0.000 description 2
• 240000005038 Spathoglottis aurea Species 0.000 description 2
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
• 241000209140 Triticum Species 0.000 description 2
• 235000021307 Triticum Nutrition 0.000 description 2
• ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 2
• 239000000853 adhesive Substances 0.000 description 2
• 230000001070 adhesive effect Effects 0.000 description 2
• 125000000217 alkyl group Chemical group 0.000 description 2
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
• 239000000908 ammonium hydroxide Substances 0.000 description 2
• 229960003942 amphotericin b Drugs 0.000 description 2
• 230000000843 anti-fungal effect Effects 0.000 description 2
• 229940121375 antifungal agent Drugs 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• 238000003556 assay Methods 0.000 description 2
• 239000012911 assay medium Substances 0.000 description 2
• 235000010233 benzoic acid Nutrition 0.000 description 2
• 229960004365 benzoic acid Drugs 0.000 description 2
• 230000003115 biocidal effect Effects 0.000 description 2
• 210000004204 blood vessel Anatomy 0.000 description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
• 150000007942 carboxylates Chemical group 0.000 description 2
• 150000001735 carboxylic acids Chemical class 0.000 description 2
• 238000004113 cell culture Methods 0.000 description 2
• 230000001413 cellular effect Effects 0.000 description 2
• 238000005119 centrifugation Methods 0.000 description 2
• 230000008859 change Effects 0.000 description 2
• 125000003636 chemical group Chemical group 0.000 description 2
• OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
• NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
• 238000004587 chromatography analysis Methods 0.000 description 2
• 210000000349 chromosome Anatomy 0.000 description 2
• 238000012875 competitive assay Methods 0.000 description 2
• 230000000536 complexating effect Effects 0.000 description 2
• 229910052802 copper Inorganic materials 0.000 description 2
• 239000010949 copper Substances 0.000 description 2
• 238000005859 coupling reaction Methods 0.000 description 2
• 229940013361 cresol Drugs 0.000 description 2
• 229930003836 cresol Natural products 0.000 description 2
• 238000012258 culturing Methods 0.000 description 2
• 230000006240 deamidation Effects 0.000 description 2
• 230000007423 decrease Effects 0.000 description 2
• 238000001514 detection method Methods 0.000 description 2
• 239000008121 dextrose Substances 0.000 description 2
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
• 201000010099 disease Diseases 0.000 description 2
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
• 235000019441 ethanol Nutrition 0.000 description 2
• 230000003203 everyday effect Effects 0.000 description 2
• 210000001105 femoral artery Anatomy 0.000 description 2
• IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 2
• 229960002518 gentamicin Drugs 0.000 description 2
• 230000004190 glucose uptake Effects 0.000 description 2
• 125000005842 heteroatom Chemical group 0.000 description 2
• 102000047882 human INSR Human genes 0.000 description 2
• 229960000890 hydrocortisone Drugs 0.000 description 2
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
• 230000002218 hypoglycaemic effect Effects 0.000 description 2
• 239000004615 ingredient Substances 0.000 description 2
• 150000007529 inorganic bases Chemical class 0.000 description 2
• 150000002500 ions Chemical class 0.000 description 2
• 238000001155 isoelectric focusing Methods 0.000 description 2
• 238000002372 labelling Methods 0.000 description 2
• 239000008101 lactose Substances 0.000 description 2
• 239000000594 mannitol Substances 0.000 description 2
• 235000010355 mannitol Nutrition 0.000 description 2
• 229930182817 methionine Natural products 0.000 description 2
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
• 150000007522 mineralic acids Chemical class 0.000 description 2
• 238000002156 mixing Methods 0.000 description 2
• 230000007935 neutral effect Effects 0.000 description 2
• QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
• 150000007524 organic acids Chemical class 0.000 description 2
• 235000005985 organic acids Nutrition 0.000 description 2
• 230000020477 pH reduction Effects 0.000 description 2
• 239000002245 particle Substances 0.000 description 2
• 238000010647 peptide synthesis reaction Methods 0.000 description 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
• 230000001817 pituitary effect Effects 0.000 description 2
• 239000013612 plasmid Substances 0.000 description 2
• 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
• 230000002035 prolonged effect Effects 0.000 description 2
• QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
• 238000000164 protein isolation Methods 0.000 description 2
• 239000002287 radioligand Substances 0.000 description 2
• 230000010076 replication Effects 0.000 description 2
• 239000011347 resin Substances 0.000 description 2
• 229920005989 resin Polymers 0.000 description 2
• 230000002441 reversible effect Effects 0.000 description 2
• 230000028327 secretion Effects 0.000 description 2
• 229960002668 sodium chloride Drugs 0.000 description 2
• 238000010186 staining Methods 0.000 description 2
• 238000003756 stirring Methods 0.000 description 2
• 239000000126 substance Substances 0.000 description 2
• 208000024891 symptom Diseases 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• 238000013518 transcription Methods 0.000 description 2
• 230000035897 transcription Effects 0.000 description 2
• 229910052723 transition metal Inorganic materials 0.000 description 2
• 150000003624 transition metals Chemical class 0.000 description 2
• 230000002792 vascular Effects 0.000 description 2
• 230000002618 waking effect Effects 0.000 description 2
• 238000005303 weighing Methods 0.000 description 2
• 239000004246 zinc acetate Substances 0.000 description 2
• 239000011592 zinc chloride Substances 0.000 description 2
• 235000005074 zinc chloride Nutrition 0.000 description 2
• 229960001296 zinc oxide Drugs 0.000 description 2
• NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 2
• 229960001763 zinc sulfate Drugs 0.000 description 2
• 229910000368 zinc sulfate Inorganic materials 0.000 description 2
• HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
• DEIYNDIFGSDDCY-QMMMGPOBSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-6-[(2,2,2-trifluoroacetyl)amino]hexanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCCNC(=O)C(F)(F)F DEIYNDIFGSDDCY-QMMMGPOBSA-N 0.000 description 1
• HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
• CVFXPOKENLGCID-KRWDZBQOSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC1=C(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C(C)=C2CC(C)(C)OC2=C1C CVFXPOKENLGCID-KRWDZBQOSA-N 0.000 description 1
• JYEVQYFWINBXJU-QFIPXVFZSA-N (2s)-6-(9h-fluoren-9-ylmethoxycarbonylamino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 JYEVQYFWINBXJU-QFIPXVFZSA-N 0.000 description 1
• YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
• WPRAXAOJIODQJR-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)ethanone Chemical compound CC(=O)C1=CC=C(C)C(C)=C1 WPRAXAOJIODQJR-UHFFFAOYSA-N 0.000 description 1
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
• HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
• JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 description 1
• QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
• APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
• QXDQMDLSSYBBCY-UHFFFAOYSA-N 4-benzyl-3-chloro-2-methylphenol Chemical compound CC1=C(O)C=CC(CC=2C=CC=CC=2)=C1Cl QXDQMDLSSYBBCY-UHFFFAOYSA-N 0.000 description 1
• SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
• OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
• NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
• 241000251468 Actinopterygii Species 0.000 description 1
• PHHRSPBBQUFULD-UWVGGRQHSA-N Arg-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N PHHRSPBBQUFULD-UWVGGRQHSA-N 0.000 description 1
• 238000012935 Averaging Methods 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• 102000003670 Carboxypeptidase B Human genes 0.000 description 1
• 108090000087 Carboxypeptidase B Proteins 0.000 description 1
• GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• 206010053567 Coagulopathies Diseases 0.000 description 1
• 108020004705 Codon Proteins 0.000 description 1
• 241000699800 Cricetinae Species 0.000 description 1
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
• 102000053602 DNA Human genes 0.000 description 1
• 241000721047 Danaus plexippus Species 0.000 description 1
• 208000002249 Diabetes Complications Diseases 0.000 description 1
• 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
• 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
• 206010012655 Diabetic complications Diseases 0.000 description 1
• 206010012689 Diabetic retinopathy Diseases 0.000 description 1
• 108010016626 Dipeptides Proteins 0.000 description 1
• 206010059866 Drug resistance Diseases 0.000 description 1
• 206010052804 Drug tolerance Diseases 0.000 description 1
• 102000004190 Enzymes Human genes 0.000 description 1
• 108090000790 Enzymes Proteins 0.000 description 1
• 102400001368 Epidermal growth factor Human genes 0.000 description 1
• 101800003838 Epidermal growth factor Proteins 0.000 description 1
• YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
• 241000283073 Equus caballus Species 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
• 239000004366 Glucose oxidase Substances 0.000 description 1
• 108010015776 Glucose oxidase Proteins 0.000 description 1
• IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-N 0.000 description 1
• CLNSYANKYVMZNM-UWVGGRQHSA-N Gly-Lys-Arg Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N CLNSYANKYVMZNM-UWVGGRQHSA-N 0.000 description 1
• 102000009465 Growth Factor Receptors Human genes 0.000 description 1
• 108010009202 Growth Factor Receptors Proteins 0.000 description 1
• 239000012981 Hank's balanced salt solution Substances 0.000 description 1
• 101500025353 Homo sapiens Insulin A chain Proteins 0.000 description 1
• 101500025354 Homo sapiens Insulin B chain Proteins 0.000 description 1
• 208000013016 Hypoglycemia Diseases 0.000 description 1
• 108010065920 Insulin Lispro Proteins 0.000 description 1
• 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
• AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-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
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
• 241000699666 Mus <mouse, genus> Species 0.000 description 1
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
• 238000007126 N-alkylation reaction Methods 0.000 description 1
• 101800000135 N-terminal protein Proteins 0.000 description 1
• 229930193140 Neomycin Natural products 0.000 description 1
• 101100326804 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) arg-2 gene Proteins 0.000 description 1
• DPFJMEQFOFSXBG-UHFFFAOYSA-N OC(C(O)C(O)=O)C(O)=O.OS(=O)(=O)C1=CC=CC2=CC=CC=C12 Chemical compound OC(C(O)C(O)=O)C(O)=O.OS(=O)(=O)C1=CC=CC2=CC=CC=C12 DPFJMEQFOFSXBG-UHFFFAOYSA-N 0.000 description 1
• AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
• UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
• 101800001452 P1 proteinase Proteins 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 102000035195 Peptidases Human genes 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
• 239000004793 Polystyrene Substances 0.000 description 1
• 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
• 239000008156 Ringer's lactate solution Substances 0.000 description 1
• 229920002684 Sepharose Polymers 0.000 description 1
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
• 102000005157 Somatostatin Human genes 0.000 description 1
• 108010056088 Somatostatin Proteins 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
• 241000282898 Sus scrofa Species 0.000 description 1
• 239000004098 Tetracycline Substances 0.000 description 1
• HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
• 108090000631 Trypsin Proteins 0.000 description 1
• 102000004142 Trypsin Human genes 0.000 description 1
• ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• 239000008351 acetate buffer Substances 0.000 description 1
• PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 230000003213 activating effect Effects 0.000 description 1
• 230000004913 activation Effects 0.000 description 1
• 239000013543 active substance Substances 0.000 description 1
• 210000001789 adipocyte Anatomy 0.000 description 1
• 238000001042 affinity chromatography Methods 0.000 description 1
• 150000001298 alcohols Chemical class 0.000 description 1
• 239000003513 alkali Substances 0.000 description 1
• 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
• 229910052783 alkali metal Inorganic materials 0.000 description 1
• 150000001340 alkali metals Chemical class 0.000 description 1
• 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
• 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
• 150000001342 alkaline earth metals Chemical class 0.000 description 1
• 125000005907 alkyl ester group Chemical group 0.000 description 1
• 230000029936 alkylation Effects 0.000 description 1
• 238000005804 alkylation reaction Methods 0.000 description 1
• HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
• 230000009435 amidation Effects 0.000 description 1
• 238000007112 amidation reaction Methods 0.000 description 1
• 125000006242 amine protecting group Chemical group 0.000 description 1
• 125000000539 amino acid group Chemical group 0.000 description 1
• 229910021529 ammonia Inorganic materials 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
• 229960000723 ampicillin Drugs 0.000 description 1
• AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
• LSNWBKACGXCGAJ-UHFFFAOYSA-N ampiroxicam Chemical group CN1S(=O)(=O)C2=CC=CC=C2C(OC(C)OC(=O)OCC)=C1C(=O)NC1=CC=CC=N1 LSNWBKACGXCGAJ-UHFFFAOYSA-N 0.000 description 1
• 239000003708 ampul Substances 0.000 description 1
• 238000012435 analytical chromatography Methods 0.000 description 1
• 238000010171 animal model Methods 0.000 description 1
• 239000004599 antimicrobial Substances 0.000 description 1
• 239000012062 aqueous buffer Substances 0.000 description 1
• 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
• CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical group N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
• 230000001580 bacterial effect Effects 0.000 description 1
• 230000003385 bacteriostatic effect Effects 0.000 description 1
• 239000007640 basal medium Substances 0.000 description 1
• 229960000686 benzalkonium chloride Drugs 0.000 description 1
• 229960003872 benzethonium Drugs 0.000 description 1
• 229940050390 benzoate Drugs 0.000 description 1
• 239000012964 benzotriazole Substances 0.000 description 1
• 235000019445 benzyl alcohol Nutrition 0.000 description 1
• 229960004217 benzyl alcohol Drugs 0.000 description 1
• CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
• 230000027455 binding Effects 0.000 description 1
• 230000000903 blocking effect Effects 0.000 description 1
• 238000007664 blowing Methods 0.000 description 1
• 238000006664 bond formation reaction Methods 0.000 description 1
• 210000000069 breast epithelial cell Anatomy 0.000 description 1
• KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
• 229940067596 butylparaben Drugs 0.000 description 1
• 229910052793 cadmium Inorganic materials 0.000 description 1
• BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
• 244000309466 calf Species 0.000 description 1
• 238000005251 capillar electrophoresis Methods 0.000 description 1
• BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
• 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
• 125000002843 carboxylic acid group Chemical group 0.000 description 1
• 210000000170 cell membrane Anatomy 0.000 description 1
• 230000004663 cell proliferation Effects 0.000 description 1
• 239000007795 chemical reaction product Substances 0.000 description 1
• 229960005091 chloramphenicol Drugs 0.000 description 1
• WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
• 229960003260 chlorhexidine Drugs 0.000 description 1
• KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
• 229960004926 chlorobutanol Drugs 0.000 description 1
• 230000002759 chromosomal effect Effects 0.000 description 1
• 239000007979 citrate buffer Substances 0.000 description 1
• 230000035602 clotting Effects 0.000 description 1
• 229910017052 cobalt Inorganic materials 0.000 description 1
• 239000010941 cobalt Substances 0.000 description 1
• GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
• 238000011109 contamination Methods 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 230000008878 coupling Effects 0.000 description 1
• 239000007822 coupling agent Substances 0.000 description 1
• 238000010168 coupling 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
• GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
• 230000007547 defect Effects 0.000 description 1
• 238000001212 derivatisation Methods 0.000 description 1
• 208000033679 diabetic kidney disease Diseases 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
• 239000003085 diluting agent Substances 0.000 description 1
• SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 description 1
• 235000006694 eating habits Nutrition 0.000 description 1
• 230000005684 electric field Effects 0.000 description 1
• 238000001962 electrophoresis Methods 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• 230000007613 environmental effect Effects 0.000 description 1
• 229940088598 enzyme Drugs 0.000 description 1
• 229940116977 epidermal growth factor Drugs 0.000 description 1
• 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
• 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
• 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
• NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
• 239000012467 final product Substances 0.000 description 1
• 235000013305 food Nutrition 0.000 description 1
• 239000012634 fragment Substances 0.000 description 1
• 239000012458 free base Substances 0.000 description 1
• 230000002538 fungal effect Effects 0.000 description 1
• 238000001502 gel electrophoresis Methods 0.000 description 1
• 238000001641 gel filtration chromatography Methods 0.000 description 1
• 238000002523 gelfiltration Methods 0.000 description 1
• 230000002068 genetic effect Effects 0.000 description 1
• 239000011521 glass Substances 0.000 description 1
• 230000010030 glucose lowering effect Effects 0.000 description 1
• 229940116332 glucose oxidase Drugs 0.000 description 1
• 235000019420 glucose oxidase Nutrition 0.000 description 1
• 230000006377 glucose transport Effects 0.000 description 1
• 229930195712 glutamate Natural products 0.000 description 1
• 108010015792 glycyllysine Proteins 0.000 description 1
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
• 230000036541 health Effects 0.000 description 1
• 230000002440 hepatic effect Effects 0.000 description 1
• MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
• KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
• FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
• 102000044162 human IGF1 Human genes 0.000 description 1
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
• 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
• 229940071870 hydroiodic acid Drugs 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• 230000003345 hyperglycaemic effect Effects 0.000 description 1
• 125000002883 imidazolyl group Chemical group 0.000 description 1
• 238000011534 incubation Methods 0.000 description 1
• 229940060367 inert ingredients Drugs 0.000 description 1
• 239000012442 inert solvent Substances 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 239000002198 insoluble material Substances 0.000 description 1
• 229960001382 insulin argine Drugs 0.000 description 1
• 230000002473 insulinotropic effect Effects 0.000 description 1
• 230000002452 interceptive effect Effects 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 239000007928 intraperitoneal injection Substances 0.000 description 1
• 238000010253 intravenous injection Methods 0.000 description 1
• 238000004255 ion exchange chromatography Methods 0.000 description 1
• 229910052742 iron Inorganic materials 0.000 description 1
• KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
• 229960000318 kanamycin Drugs 0.000 description 1
• 229930027917 kanamycin Natural products 0.000 description 1
• SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
• 229930182823 kanamycin A Natural products 0.000 description 1
• 150000002576 ketones Chemical class 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 239000007791 liquid phase Substances 0.000 description 1
• 108010054155 lysyllysine Proteins 0.000 description 1
• 125000003717 m-cresyl group Chemical group [H]C1=C([H])C(O*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 210000004962 mammalian cell Anatomy 0.000 description 1
• IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
• 239000003550 marker Substances 0.000 description 1
• 238000004949 mass spectrometry Methods 0.000 description 1
• 150000002739 metals Chemical class 0.000 description 1
• 125000005341 metaphosphate group Chemical group 0.000 description 1
• 229940098779 methanesulfonic acid Drugs 0.000 description 1
• 229960000485 methotrexate Drugs 0.000 description 1
• IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
• 229940095102 methyl benzoate Drugs 0.000 description 1
• 229940050176 methyl chloride Drugs 0.000 description 1
• 102000035118 modified proteins Human genes 0.000 description 1
• 108091005573 modified proteins Proteins 0.000 description 1
• 238000012544 monitoring process Methods 0.000 description 1
• 150000002772 monosaccharides Chemical class 0.000 description 1
• 210000003205 muscle Anatomy 0.000 description 1
• KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
• 229960004927 neomycin Drugs 0.000 description 1
• 229910052759 nickel Inorganic materials 0.000 description 1
• 229910052757 nitrogen Inorganic materials 0.000 description 1
• 150000007523 nucleic acids Chemical group 0.000 description 1
• 235000021231 nutrient uptake Nutrition 0.000 description 1
• 235000015097 nutrients Nutrition 0.000 description 1
• WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
• 239000011368 organic material Substances 0.000 description 1
• 239000003960 organic solvent Substances 0.000 description 1
• 229960003104 ornithine Drugs 0.000 description 1
• 235000006408 oxalic acid Nutrition 0.000 description 1
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
• 230000037361 pathway Effects 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• 150000002989 phenols Chemical class 0.000 description 1
• 229960005323 phenoxyethanol Drugs 0.000 description 1
• DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
• WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
• 229950009215 phenylbutanoic acid Drugs 0.000 description 1
• 229940067107 phenylethyl alcohol Drugs 0.000 description 1
• 239000008363 phosphate buffer Substances 0.000 description 1
• 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
• XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
• 230000008488 polyadenylation Effects 0.000 description 1
• 229920002223 polystyrene Polymers 0.000 description 1
• 229910000027 potassium carbonate Inorganic materials 0.000 description 1
• 230000001376 precipitating effect Effects 0.000 description 1
• 238000001556 precipitation Methods 0.000 description 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
• 230000035755 proliferation Effects 0.000 description 1
• 230000001902 propagating effect Effects 0.000 description 1
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
• 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
• 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
• 229960003415 propylparaben Drugs 0.000 description 1
• UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
• 230000009145 protein modification Effects 0.000 description 1
• 238000000734 protein sequencing Methods 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• 238000003127 radioimmunoassay Methods 0.000 description 1
• 238000005215 recombination Methods 0.000 description 1
• 230000006798 recombination Effects 0.000 description 1
• 230000003362 replicative effect Effects 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
• YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
• 229940116351 sebacate Drugs 0.000 description 1
• CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
• UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1
• 239000004017 serum-free culture medium Substances 0.000 description 1
• 150000003384 small molecules Chemical class 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• 238000010532 solid phase synthesis reaction Methods 0.000 description 1
• NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound 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 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• 238000011895 specific detection Methods 0.000 description 1
• 238000010183 spectrum analysis Methods 0.000 description 1
• 238000013222 sprague-dawley male rat Methods 0.000 description 1
• 230000000087 stabilizing effect Effects 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• 239000007858 starting material Substances 0.000 description 1
• 230000000638 stimulation Effects 0.000 description 1
• 239000007929 subcutaneous injection Substances 0.000 description 1
• TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 150000005846 sugar alcohols Polymers 0.000 description 1
• BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
• 230000006103 sulfonylation Effects 0.000 description 1
• 238000005694 sulfonylation reaction Methods 0.000 description 1
• 238000007910 systemic administration Methods 0.000 description 1
• 229960002180 tetracycline Drugs 0.000 description 1
• 229930101283 tetracycline Natural products 0.000 description 1
• 235000019364 tetracycline Nutrition 0.000 description 1
• 150000003522 tetracyclines Chemical class 0.000 description 1
• UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
• RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
• 229940033663 thimerosal Drugs 0.000 description 1
• 229940104230 thymidine Drugs 0.000 description 1
• 231100000701 toxic element Toxicity 0.000 description 1
• 230000002103 transcriptional effect Effects 0.000 description 1
• 238000013519 translation Methods 0.000 description 1
• 108700019014 tri-Lys- insulin Proteins 0.000 description 1
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
• PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
• 229960000281 trometamol Drugs 0.000 description 1
• 239000012588 trypsin Substances 0.000 description 1
• 238000000825 ultraviolet detection Methods 0.000 description 1
• VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
• 239000003981 vehicle Substances 0.000 description 1
• 238000012795 verification Methods 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 239000003643 water by type Substances 0.000 description 1
• 229940071104 xylenesulfonate Drugs 0.000 description 1
• 210000005253 yeast cell Anatomy 0.000 description 1
• 150000003751 zinc Chemical class 0.000 description 1