JP5816097B2 - 安定な成長ホルモン化合物 - Google Patents
安定な成長ホルモン化合物 Download PDFInfo
- Publication number
- JP5816097B2 JP5816097B2 JP2011546797A JP2011546797A JP5816097B2 JP 5816097 B2 JP5816097 B2 JP 5816097B2 JP 2011546797 A JP2011546797 A JP 2011546797A JP 2011546797 A JP2011546797 A JP 2011546797A JP 5816097 B2 JP5816097 B2 JP 5816097B2
- Authority
- JP
- Japan
- Prior art keywords
- growth hormone
- hormone compound
- seq
- hgh
- compound according
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 240
- 102000018997 Growth Hormone Human genes 0.000 title claims description 210
- 108010051696 Growth Hormone Proteins 0.000 title claims description 210
- 239000000122 growth hormone Substances 0.000 title claims description 210
- 108010000521 Human Growth Hormone Proteins 0.000 claims description 146
- 102000002265 Human Growth Hormone Human genes 0.000 claims description 146
- 239000000854 Human Growth Hormone Substances 0.000 claims description 145
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 96
- 235000001014 amino acid Nutrition 0.000 claims description 79
- 150000001413 amino acids Chemical class 0.000 claims description 72
- 102200153349 rs104894823 Human genes 0.000 claims description 62
- 230000035772 mutation Effects 0.000 claims description 52
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 51
- 102220078630 rs61735992 Human genes 0.000 claims description 46
- 108091005804 Peptidases Proteins 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 38
- 102220047964 rs587783194 Human genes 0.000 claims description 38
- 229920001184 polypeptide Polymers 0.000 claims description 37
- 230000017854 proteolysis Effects 0.000 claims description 32
- 239000004365 Protease Substances 0.000 claims description 28
- 102200070479 rs28933693 Human genes 0.000 claims description 28
- 235000018417 cysteine Nutrition 0.000 claims description 26
- 102200083530 rs34382405 Human genes 0.000 claims description 24
- 102200124873 rs58730926 Human genes 0.000 claims description 24
- 230000001965 increasing effect Effects 0.000 claims description 21
- 102220259718 rs34120878 Human genes 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 108090000317 Chymotrypsin Proteins 0.000 claims description 17
- 229960002376 chymotrypsin Drugs 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 17
- 108010067372 Pancreatic elastase Proteins 0.000 claims description 13
- 102000016387 Pancreatic elastase Human genes 0.000 claims description 13
- 150000001945 cysteines Chemical class 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- -1 lipophilic group Substances 0.000 claims description 9
- 102200016458 rs104894274 Human genes 0.000 claims description 9
- 102220257167 rs1553408119 Human genes 0.000 claims description 9
- 102220062540 rs372619120 Human genes 0.000 claims description 9
- 108090000631 Trypsin Proteins 0.000 claims description 8
- 102000004142 Trypsin Human genes 0.000 claims description 8
- 230000015556 catabolic process Effects 0.000 claims description 8
- 238000006731 degradation reaction Methods 0.000 claims description 8
- 239000012588 trypsin Substances 0.000 claims description 8
- 108010006303 Carboxypeptidases Proteins 0.000 claims description 7
- 102000005367 Carboxypeptidases Human genes 0.000 claims description 7
- 125000006850 spacer group Chemical group 0.000 claims description 7
- 108010088751 Albumins Proteins 0.000 claims description 6
- 102000009027 Albumins Human genes 0.000 claims description 6
- 102000057297 Pepsin A Human genes 0.000 claims description 6
- 108090000284 Pepsin A Proteins 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- 229940111202 pepsin Drugs 0.000 claims description 6
- 229960001322 trypsin Drugs 0.000 claims description 6
- 239000003613 bile acid Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- 239000011782 vitamin Substances 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 230000008901 benefit Effects 0.000 claims description 4
- 150000001720 carbohydrates Chemical class 0.000 claims description 4
- 230000003054 hormonal effect Effects 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 2
- 108020001507 fusion proteins Proteins 0.000 claims description 2
- 102000037865 fusion proteins Human genes 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 4
- 108090000623 proteins and genes Proteins 0.000 description 50
- 235000018102 proteins Nutrition 0.000 description 44
- 102000004169 proteins and genes Human genes 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 42
- 102000035195 Peptidases Human genes 0.000 description 34
- 125000000539 amino acid group Chemical group 0.000 description 29
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 23
- 238000001727 in vivo Methods 0.000 description 23
- 230000000694 effects Effects 0.000 description 22
- 206010017076 Fracture Diseases 0.000 description 17
- 239000013598 vector Substances 0.000 description 17
- 210000000988 bone and bone Anatomy 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 239000000872 buffer Substances 0.000 description 15
- 206010056438 Growth hormone deficiency Diseases 0.000 description 14
- 108091028043 Nucleic acid sequence Proteins 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 13
- 208000020221 Short stature Diseases 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002202 Polyethylene glycol Substances 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 230000004071 biological effect Effects 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 235000019833 protease Nutrition 0.000 description 10
- 230000006337 proteolytic cleavage Effects 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- 238000007385 chemical modification Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 235000019419 proteases Nutrition 0.000 description 9
- 206010053759 Growth retardation Diseases 0.000 description 8
- 208000001132 Osteoporosis Diseases 0.000 description 8
- 201000010769 Prader-Willi syndrome Diseases 0.000 description 8
- 208000026928 Turner syndrome Diseases 0.000 description 8
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 208000014674 injury Diseases 0.000 description 8
- 210000003127 knee Anatomy 0.000 description 8
- 208000018773 low birth weight Diseases 0.000 description 8
- 231100000533 low birth weight Toxicity 0.000 description 8
- 230000007017 scission Effects 0.000 description 8
- 208000011580 syndromic disease Diseases 0.000 description 8
- 210000002303 tibia Anatomy 0.000 description 8
- 208000031886 HIV Infections Diseases 0.000 description 7
- 208000037357 HIV infectious disease Diseases 0.000 description 7
- 108090000190 Thrombin Proteins 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000003862 glucocorticoid Substances 0.000 description 7
- 210000001624 hip Anatomy 0.000 description 7
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 7
- 208000019423 liver disease Diseases 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 108010033419 somatotropin-binding protein Proteins 0.000 description 7
- 229960004072 thrombin Drugs 0.000 description 7
- 230000008733 trauma Effects 0.000 description 7
- 102000014914 Carrier Proteins Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000029087 digestion Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 210000000614 rib Anatomy 0.000 description 6
- 230000003248 secreting effect Effects 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 5
- 108091008324 binding proteins Proteins 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 5
- 239000000562 conjugate Substances 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 230000002797 proteolythic effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 4
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 4
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 4
- 208000004611 Abdominal Obesity Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 4
- 206010006895 Cachexia Diseases 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 206010007710 Cartilage injury Diseases 0.000 description 4
- 206010065941 Central obesity Diseases 0.000 description 4
- 201000003883 Cystic fibrosis Diseases 0.000 description 4
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 4
- 201000010374 Down Syndrome Diseases 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 108010088842 Fibrinolysin Proteins 0.000 description 4
- 208000001640 Fibromyalgia Diseases 0.000 description 4
- 208000003456 Juvenile Arthritis Diseases 0.000 description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 4
- 208000007466 Male Infertility Diseases 0.000 description 4
- 208000002720 Malnutrition Diseases 0.000 description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 description 4
- 208000021642 Muscular disease Diseases 0.000 description 4
- 201000009623 Myopathy Diseases 0.000 description 4
- 241001481166 Nautilus Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 206010029748 Noonan syndrome Diseases 0.000 description 4
- 238000012300 Sequence Analysis Methods 0.000 description 4
- 206010049416 Short-bowel syndrome Diseases 0.000 description 4
- 206010072610 Skeletal dysplasia Diseases 0.000 description 4
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- 230000032683 aging Effects 0.000 description 4
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 4
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 4
- 239000001099 ammonium carbonate Substances 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 210000001188 articular cartilage Anatomy 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 208000019069 chronic childhood arthritis Diseases 0.000 description 4
- 208000020832 chronic kidney disease Diseases 0.000 description 4
- 210000003109 clavicle Anatomy 0.000 description 4
- 238000001784 detoxification Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 210000002683 foot Anatomy 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 230000035876 healing Effects 0.000 description 4
- 210000002758 humerus Anatomy 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 210000001503 joint Anatomy 0.000 description 4
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 4
- 230000001071 malnutrition Effects 0.000 description 4
- 235000000824 malnutrition Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 206010027175 memory impairment Diseases 0.000 description 4
- 210000001872 metatarsal bone Anatomy 0.000 description 4
- 208000015380 nutritional deficiency disease Diseases 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 229940012957 plasmin Drugs 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 210000003625 skull Anatomy 0.000 description 4
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 4
- 210000001738 temporomandibular joint Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000014616 translation Effects 0.000 description 4
- 230000009529 traumatic brain injury Effects 0.000 description 4
- 210000000623 ulna Anatomy 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SNDPXSYFESPGGJ-UHFFFAOYSA-N 2-aminopentanoic acid Chemical compound CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 3
- 206010008723 Chondrodystrophy Diseases 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 208000032170 Congenital Abnormalities Diseases 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- 206010061619 Deformity Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 3
- 230000010799 Receptor Interactions Effects 0.000 description 3
- 208000008919 achondroplasia Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 229940000635 beta-alanine Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 108091007735 digestive proteases Proteins 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 235000003642 hunger Nutrition 0.000 description 3
- 208000003074 hypochondrogenesis Diseases 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 230000005976 liver dysfunction Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000510 mucolytic effect Effects 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 238000011499 palliative surgery Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 210000002832 shoulder Anatomy 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 230000037351 starvation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 229920002994 synthetic fiber Polymers 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001052 transient effect Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- 210000003857 wrist joint Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- RDFMDVXONNIGBC-UHFFFAOYSA-N 2-aminoheptanoic acid Chemical compound CCCCCC(N)C(O)=O RDFMDVXONNIGBC-UHFFFAOYSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 description 2
- 238000012492 Biacore method Methods 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 description 2
- 108090000227 Chymases Proteins 0.000 description 2
- 102000003858 Chymases Human genes 0.000 description 2
- 102000002029 Claudin Human genes 0.000 description 2
- 108050009302 Claudin Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108010067770 Endopeptidase K Proteins 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 108010013369 Enteropeptidase Proteins 0.000 description 2
- 102100029727 Enteropeptidase Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010054265 Factor VIIa Proteins 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 108010051815 Glutamyl endopeptidase Proteins 0.000 description 2
- 108060005986 Granzyme Proteins 0.000 description 2
- 102000001398 Granzyme Human genes 0.000 description 2
- 102100020948 Growth hormone receptor Human genes 0.000 description 2
- 101710099093 Growth hormone receptor Proteins 0.000 description 2
- 206010019114 Hand fracture Diseases 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101000684208 Homo sapiens Prolyl endopeptidase FAP Proteins 0.000 description 2
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- 150000008575 L-amino acids Chemical group 0.000 description 2
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 2
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000003939 Membrane transport proteins Human genes 0.000 description 2
- 108090000301 Membrane transport proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KSPIYJQBLVDRRI-UHFFFAOYSA-N N-methylisoleucine Chemical compound CCC(C)C(NC)C(O)=O KSPIYJQBLVDRRI-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- 108010003044 Placental Lactogen Proteins 0.000 description 2
- 239000000381 Placental Lactogen Substances 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- 102100024819 Prolactin Human genes 0.000 description 2
- 108700015930 Prolyl Oligopeptidases Proteins 0.000 description 2
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 description 2
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 2
- 108091006272 SLC5A6 Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102100027046 Sodium-dependent multivitamin transporter Human genes 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 108090000787 Subtilisin Proteins 0.000 description 2
- 108090001109 Thermolysin Proteins 0.000 description 2
- 108060008539 Transglutaminase Proteins 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 238000012382 advanced drug delivery Methods 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 108090001092 clostripain Proteins 0.000 description 2
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000001268 conjugating effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- 210000002310 elbow joint Anatomy 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 229940012414 factor viia Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 150000002433 hydrophilic molecules Chemical class 0.000 description 2
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 238000001597 immobilized metal affinity chromatography Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 210000000629 knee joint Anatomy 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 210000003041 ligament Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001906 matrix-assisted laser desorption--ionisation mass spectrometry Methods 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229960003104 ornithine Drugs 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000013600 plasmid vector Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 210000002320 radius Anatomy 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 210000000323 shoulder joint Anatomy 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 102000003601 transglutaminase Human genes 0.000 description 2
- 230000000472 traumatic effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- MRXDGVXSWIXTQL-HYHFHBMOSA-N (2s)-2-[[(1s)-1-(2-amino-1,4,5,6-tetrahydropyrimidin-6-yl)-2-[[(2s)-4-methyl-1-oxo-1-[[(2s)-1-oxo-3-phenylpropan-2-yl]amino]pentan-2-yl]amino]-2-oxoethyl]carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](NC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C=O)C1NC(N)=NCC1)C(O)=O)C1=CC=CC=C1 MRXDGVXSWIXTQL-HYHFHBMOSA-N 0.000 description 1
- DFZVZEMNPGABKO-ZETCQYMHSA-N (2s)-2-amino-3-pyridin-3-ylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CN=C1 DFZVZEMNPGABKO-ZETCQYMHSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- KDYAKYRBGLKMAK-ZETCQYMHSA-N (2s)-2-azaniumyl-3-cyclopentylpropanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])CC1CCCC1 KDYAKYRBGLKMAK-ZETCQYMHSA-N 0.000 description 1
- UYBWIEGTWASWSR-UHFFFAOYSA-N 1,3-diaminopropan-2-ol Chemical compound NCC(O)CN UYBWIEGTWASWSR-UHFFFAOYSA-N 0.000 description 1
- JHTPBGFVWWSHDL-UHFFFAOYSA-N 1,4-dichloro-2-isothiocyanatobenzene Chemical compound ClC1=CC=C(Cl)C(N=C=S)=C1 JHTPBGFVWWSHDL-UHFFFAOYSA-N 0.000 description 1
- MAEDLSNGVQYGPK-UHFFFAOYSA-N 2,2-diaminoacetic acid Chemical compound NC(N)C(O)=O MAEDLSNGVQYGPK-UHFFFAOYSA-N 0.000 description 1
- MSKSQCLPULZWNO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN MSKSQCLPULZWNO-UHFFFAOYSA-N 0.000 description 1
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GSWYUZQBLVUEPH-UHFFFAOYSA-N 3-(azaniumylmethyl)benzoate Chemical compound NCC1=CC=CC(C(O)=O)=C1 GSWYUZQBLVUEPH-UHFFFAOYSA-N 0.000 description 1
- XABCFXXGZPWJQP-UHFFFAOYSA-N 3-aminoadipic acid Chemical compound OC(=O)CC(N)CCC(O)=O XABCFXXGZPWJQP-UHFFFAOYSA-N 0.000 description 1
- KHABBYNLBYZCKP-UHFFFAOYSA-N 4-aminopiperidin-1-ium-4-carboxylate Chemical compound OC(=O)C1(N)CCNCC1 KHABBYNLBYZCKP-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- XRTHAPZDZPADIL-UHFFFAOYSA-N 8-[(5-chloro-2-hydroxybenzoyl)amino]octanoic acid Chemical compound OC(=O)CCCCCCCNC(=O)C1=CC(Cl)=CC=C1O XRTHAPZDZPADIL-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 102000035101 Aspartic proteases Human genes 0.000 description 1
- 108091005502 Aspartic proteases Proteins 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- OLVPQBGMUGIKIW-UHFFFAOYSA-N Chymostatin Natural products C=1C=CC=CC=1CC(C=O)NC(=O)C(C(C)CC)NC(=O)C(C1NC(N)=NCC1)NC(=O)NC(C(O)=O)CC1=CC=CC=C1 OLVPQBGMUGIKIW-UHFFFAOYSA-N 0.000 description 1
- 101710131551 Chymotrypsin-like serine proteinase Proteins 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 1
- 229930182847 D-glutamic acid Natural products 0.000 description 1
- ZDXPYRJPNDTMRX-GSVOUGTGSA-N D-glutamine Chemical compound OC(=O)[C@H](N)CCC(N)=O ZDXPYRJPNDTMRX-GSVOUGTGSA-N 0.000 description 1
- 229930195715 D-glutamine Natural products 0.000 description 1
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 1
- 229930182819 D-leucine Natural products 0.000 description 1
- 108020003215 DNA Probes Proteins 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 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 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
- 102000018389 Exopeptidases Human genes 0.000 description 1
- 108010091443 Exopeptidases Proteins 0.000 description 1
- 101710089384 Extracellular protease Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 102400001066 Growth hormone-binding protein Human genes 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 1
- 101001075374 Homo sapiens Gamma-glutamyl hydrolase Proteins 0.000 description 1
- 101000664737 Homo sapiens Somatotropin Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- JUQLUIFNNFIIKC-YFKPBYRVSA-N L-2-aminopimelic acid Chemical compound OC(=O)[C@@H](N)CCCCC(O)=O JUQLUIFNNFIIKC-YFKPBYRVSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 1
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- XIGSAGMEBXLVJJ-YFKPBYRVSA-N L-homocitrulline Chemical compound NC(=O)NCCCC[C@H]([NH3+])C([O-])=O XIGSAGMEBXLVJJ-YFKPBYRVSA-N 0.000 description 1
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- OLNLSTNFRUFTLM-UHFFFAOYSA-N N-ethylasparagine Chemical compound CCNC(C(O)=O)CC(N)=O OLNLSTNFRUFTLM-UHFFFAOYSA-N 0.000 description 1
- YPIGGYHFMKJNKV-UHFFFAOYSA-N N-ethylglycine Chemical compound CC[NH2+]CC([O-])=O YPIGGYHFMKJNKV-UHFFFAOYSA-N 0.000 description 1
- 108010065338 N-ethylglycine Proteins 0.000 description 1
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- BZQFBWGGLXLEPQ-UHFFFAOYSA-N O-phosphoryl-L-serine Natural products OC(=O)C(N)COP(O)(O)=O BZQFBWGGLXLEPQ-UHFFFAOYSA-N 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 101710118538 Protease Proteins 0.000 description 1
- 101710123874 Protein-glutamine gamma-glutamyltransferase Proteins 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 108020004518 RNA Probes Proteins 0.000 description 1
- 239000003391 RNA probe Substances 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001495137 Streptomyces mobaraensis Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 101710112791 Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- YOFPFYYTUIARDI-UHFFFAOYSA-N alpha-aminosuberic acid Chemical compound OC(=O)C(N)CCCCCC(O)=O YOFPFYYTUIARDI-UHFFFAOYSA-N 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 229960002684 aminocaproic acid Drugs 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
- 238000010171 animal model Methods 0.000 description 1
- 210000004198 anterior pituitary gland Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004323 caveolae Anatomy 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent 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
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 108010086192 chymostatin Proteins 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- VEVRNHHLCPGNDU-MUGJNUQGSA-O desmosine Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(CC[C@H](N)C(O)=O)=C(CCC[C@H](N)C(O)=O)C(CC[C@H](N)C(O)=O)=C1 VEVRNHHLCPGNDU-MUGJNUQGSA-O 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 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
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000023266 generation of precursor metabolites and energy Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000007773 growth pattern Effects 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-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
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 230000005499 meniscus Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 108010068617 neonatal Fc receptor Proteins 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940063137 norditropin Drugs 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940063149 nutropin Drugs 0.000 description 1
- 229940080527 omnitrope Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 238000012510 peptide mapping method Methods 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
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000007026 protein scission Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229920013730 reactive polymer Polymers 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 239000002824 redox indicator Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000002356 skeleton Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940045946 sodium taurodeoxycholate Drugs 0.000 description 1
- YXHRQQJFKOHLAP-FVCKGWAHSA-M sodium;2-[[(4r)-4-[(3r,5r,8r,9s,10s,12s,13r,14s,17r)-3,12-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 YXHRQQJFKOHLAP-FVCKGWAHSA-M 0.000 description 1
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- YSMODUONRAFBET-WHFBIAKZSA-N threo-5-hydroxy-L-lysine Chemical compound NC[C@@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-WHFBIAKZSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000031998 transcytosis Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/61—Growth hormone [GH], i.e. somatotropin
-
- 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
-
- 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
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
が含まれる。
a. hGH内にさらなるジスルフィド結合を導入するステップ
を含む方法。
a. hGH内の1つまたは複数のアミノ酸残基を、1つまたは複数のシステインで置換することにより、hGH内にさらなるジスルフィド結合を導入するステップ
を含む方法。
a. 1つまたは複数のシステイン残基を付加することにより、hGH内にさらなるジスルフィド結合を導入するステップ
を含む方法。
hGH化合物を調製するための一般的な方法
成長ホルモン化合物をコードする遺伝子を、組換えによりプラスミドベクター内へと挿入した。QuickChange部位指向性変異誘発キット(Stratagene社製)を用いることにより、システインの変異を導入した。その後、プラスミドベクターを用いて、適切な大腸菌株を形質転換した。タンパク質は、固定化金属アフィニティークロマトグラフィー精製に適する、N末端におけるヒスチジンに富むペプチドタグを伴う可溶性タンパク質として発現させた。
以下の溶液:
緩衝液A:トリエタノールアミン(119mg、0.8ミリモル)を水(40mL)に溶解させ、pHを8.5に調整した。
緩衝液B: 20mMトリエタノールアミン; 0.2M NaCl
を調製した。
hGH(8.64g)を、撹拌しながら、緩衝液A(500mL)に溶解させた。この溶液に、緩衝液A(50mL)中の1,3-ジアミノ-2-プロパノール(DAP)(8.1g; Fluka社製33262)の混合物をゆっくりと添加した。HCl水溶液を添加することにより、結果として得られる混合物のpHを8.5へと調整した。混合しながら、mTGアーゼ(2.8mL、1.3mg/mL)を添加した。最終混合物を、室温で一晩にわたり撹拌した。
緩衝液A:トリエタノールアミン(119mg、0.8ミリモル)を水(40mL)に溶解させ、pHを8.5に調整した。
緩衝液B: 3-メチルチオ-1-プロパノール(725mg、7.1ミリモル)を緩衝液A(10mL)に溶解させた。
緩衝液C: HEPES(5.96g)を水(1.0L)に溶解させ、pHを7.0に調整した。
過ヨウ素酸: NaIO4(48.1mg、0.225ミリモル)を水(1.0mL)に溶解させた。
(B)からの最終溶液(1mL、0.45マイクロモル)を、pH7.0の25mM HEPES緩衝液中において、PEG-アミン溶液(2mL、0.3マイクロモル)と混合し、結果として得られる混合物を、室温で1時間にわたりゆっくりと回転させた。1時間後に、NaCNBH3(水(0.5mL)中に100μLのNaCNBH3溶液(20mg))を、分割して(10回に分割して)添加した。混合物を、暗所内室温で18〜24時間にわたり静置した。MonoQ上において混合物を精製し、緩衝液を交換し、濃縮した。mPEG-アミン試薬は、市販されている。
精製された成長ホルモン化合物に対するタンパク質化学による特徴づけ
MALDI-MSを用いて、完全精製タンパク質を解析した。観察された質量は、アミノ酸配列から推定される理論的質量と符合した。
精製された成長ホルモン化合物の生物学的活性についての解析
細胞ベースの受容体能による増殖アッセイ、すなわちBAFアッセイにより、hGH化合物の生物学的活性を測定した。該方法は、hGH化合物に対する一般性を示す。
下垂体切除Sprague Dawleyラットにおける、in vivo用量-反応試験(アッセイ3A)
雄の下垂体切除Sprague Dawleyラットにおいて、in vivoの用量-反応関係を調べた。下垂体切除ラットは、よく知られて認知された、成長ホルモン欠損の動物モデルであり、手術により下垂体を除去した後では、成長ホルモンの生成が生じない。これはまた、ヒトにおける成長ホルモン欠損の別の重要な臨床特徴である、循環インスリン様成長因子1(IGF-1)レベルの低下ももたらす。
表面プラズモン共鳴解析による受容体相互作用試験
表面プラズモン共鳴解析を用いて、hGH化合物の受容体相互作用について解析した。この方法は、hGH化合物について一般性があり、Q84C/Y143C hGH化合物はこれを例示する。
プロテアーゼによる野生型hGHおよびhGH化合物の分解速度を測定するアッセイ
37℃で最長24時間にわたり、適切な緩衝液(例えば、PBSまたは重炭酸アンモニウム)中における関与性のプロテアーゼ(トリプシン、キモトリプシン、ペプシン、エラスターゼ、因子VIIa、因子Xa、プロテイナーゼK、カルボキシペプチダーゼ、DPPIV、中性エンドペプチダーゼ、グランザイムB、プロリンエンドペプチダーゼ、ブドウ球菌ペプチダーゼI、テルモリシン、トロンビン、Arg-Cプロテイナーゼ、Asp-Nエンドペプチダーゼ、カスパーゼ1〜10、クロストリパイン、エンテロキナーゼ、グルタミルエンドペプチダーゼ、LysC、およびLysN、または組織抽出物)により、対象の化合物を消化させた。タンパク質分解は、HPLCアッセイにより評価する。
タンパク質分解による消化:
重炭酸アンモニウム緩衝液中1mg/mlの被験化合物溶液100μLを、37℃で最長24時間にわたり、酵素により分解させる。各時点に対応する部分試料を採取し、1%TFA中への10倍希釈を介して該試料を酸化させることにより、タンパク質分解反応を停止させる。逆相HPLCによりこれらの希釈試料を解析して、タンパク質分解による消化の程度を推定する。
水中に0.1%TFA〜0.1%TFA含有100%アセトニトリルの直線勾配により溶出させる2×150mmのVydac C4逆相カラム上に、30分間にわたり、0.2ml/分の流速で、10μLの上記溶液を注射する。214nmにおけるUV吸収により、ピークの検出を実施する。時点t=Tにおけるピーク面積(AT)と、時点t=0におけるピーク面積(A0)とから、(AT/A0)×100%として、時点t=Tにおける完全化合物(%)を計算する。本明細書下記のtable 6(表9)に示す結果は、4時間後(上式におけるT=4)に得られた。
100μgのwthGHを、13ngのキモトリプシンを含む100μLの緩衝液中においてインキュベートした(T1/2=3.6時間)。
100μgのwthGHを、135ngのエラスターゼを含む100μLの緩衝液中においてインキュベートした(T1/2=1.6時間)。
100μgのhGH(Q84C、Y143C)を、135ngのエラスターゼを含む100μLの緩衝液中においてインキュベートした(T1/2=6.2時間)。
100μgのhGH(A17C、E174C)を、13ngのキモトリプシンを含む100μLの緩衝液中においてインキュベートした(T1/2=7.5時間)。
100μgのhGH(H21C、M170C)を、13ngのキモトリプシンを含む100μLの緩衝液中でインキュベートした(T1/2=22時間)。
100μgのhGH(R94C、D107C)を、13ngのキモトリプシンを含む100μLの緩衝液中でインキュベートした(T1/2=2.5時間)。
100μgのhGH(Q84C、Y143C)を、13ngのキモトリプシンを含む100μLの50mM重炭酸アンモニウム緩衝液中でインキュベートした。分解が観察されないので、T1/2を計算することはできない。
BAFアッセイ、ならびに実施例3および実施例5に記載したタンパク質分解による消化を介する、選択された化合物についての解析
Claims (20)
- 配列番号1中にさらなるジスルフィド結合を含む成長ホルモン化合物であって、前記さらなるジスルフィド結合が、ヘリックスH1とH4、ヘリックスH1とループL2、ループL1とL3、ヘリックスH2とループ3、または、ヘリックスH2とH3との間を連結する、成長ホルモン化合物。
- ポリペプチド配列が、配列番号1により定義されるhGHと少なくとも95%同一である、請求項1に記載の成長ホルモン化合物。
- 配列番号1中に、R16C/L117C、H21C/M170C、D26C/V102C、D26C/Y103C、N47C/T50C、Q49C/G161C、F54C/Y143C、F54C/S144C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、P61C/E66C、P61C/T67C、S71C/S132C、L73C/S132C、L73C/F139C、R77C/I138C、R77C/F139C、L81C/Q141C、L81C/Y143C、Q84C/Y143C、Q84C/S144C、S85C/Y143C、S85C/S144C、P89C/F146C、F92C/F146C、F92C/T148C、R94C/D107C、V102C/A105C、L156C/F146C、L156C/T148C、またはV185C/S188Cに対応する1対の変異を含む、請求項1または2のいずれかに記載の成長ホルモン化合物。
- 配列番号1中に、H21C/M170C、D26C/V102C、D26C/Y103C、F54C/Y143C、F54C/S144C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、S71C/S132C、L81C/Y143C、Q84C/Y143C、S85C/Y143C、S85C/S144C、F92C/T148C、またはR94C/D107Cに対応する1対の変異を含む、請求項3に記載の成長ホルモン化合物。
- 前記さらなるジスルフィド結合を形成するシステインのうちの少なくとも1つが、配列番号1中のアミノ酸128〜154に対応するループ3(L3)内に存在する、請求項1から4のいずれか一項に記載の成長ホルモン化合物。
- 前記さらなるジスルフィド結合を形成するシステインのうちの少なくとも1つが、配列番号1中のアミノ酸135〜148に対応する領域内に存在する、請求項5に記載の成長ホルモン化合物。
- 配列番号1中に、F54C/Y143C、F54C/S144C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、S71C/S132C、L73C/S132C、L73C/F139C、R77C/I138C、R77C/F139C、L81C/Q141C、L81C/Y143C、Q84C/Y143C、Q84C/S144C、S85C/Y143C、S85C/S144C、P89C/F146C、F92C/F146C、またはF92C/T148Cに対応する1対の変異を含む、請求項5に記載の成長ホルモン化合物。
- 前記さらなるジスルフィド結合が、L3をヘリックス2(H2)またはループ1(L1)と連結する、請求項5に記載の成長ホルモン化合物。
- プロテアーゼによる分解に対して安定化されている、請求項1から8のいずれか一項に記載の成長ホルモン化合物。
- プロテアーゼが消化性プロテアーゼである、請求項9に記載の成長ホルモン化合物。
- 消化性プロテアーゼが、ペプシン、トリプシン、キモトリプシン、カルボキシペプチダーゼ、キモトリプシンおよびエラスターゼからなる群から選択される、請求項10に記載の成長ホルモン化合物。
- 配列番号1中に、H21C/M170C、D26C/V102C、D26C/Y103C、F54C/Y143C、F54C/S144C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、S71C/S132C、L81C/Y143C、Q84C/Y143C、S85C/Y143C、S85C/S144C、F92C/T148C、またはR94C/D107Cに対応する1対の変異を含む、請求項6から11のいずれか一項に記載の成長ホルモン化合物。
- 配列番号1で定義されるヒト成長ホルモンと比較して、正確に2つのさらなるシステインを含む、請求項1から12のいずれか一項に記載の成長ホルモン化合物。
- 融合タンパク質である、請求項1から13のいずれか一項に記載の成長ホルモン化合物。
- 化学的に修飾されている、請求項1から14のいずれか一項に記載の成長ホルモン化合物。
- 成長ホルモン化合物の側鎖または主鎖への結合部分を介して化学的に修飾されている、請求項1から15のいずれか一項に記載の成長ホルモン化合物。
- 前記結合部分が、PEG、炭水化物、アルブミン結合剤、脂肪酸、アルキル鎖、親油性基、ビタミン、胆汁酸、またはスペーサーから選択される、請求項16に記載の成長ホルモン化合物。
- タンパク質分解に対する安定性を増大させた成長ホルモン化合物を調製する方法であって、
a.配列番号1で定義されるhGH内に、さらなるジスルフィド結合を導入するステップ
を含み、
前記さらなるジスルフィド結合が、ヘリックスH1とH4、ヘリックスH1とループL2、ループL1とL3、ヘリックスH2とループ3、または、ヘリックスH2とH3との間を連結する、方法。 - 請求項1から17のいずれかに記載の成長ホルモン化合物と、薬学的に許容される担体とを含む医薬組成物。
- 循環成長ホルモン化合物量の増大から患者が利益を得る疾患または状態を治療するのに成長ホルモン活性を用いることができる疾患または状態を治療するための、請求項19に記載の医薬組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09151108 | 2009-01-22 | ||
EP09151108.9 | 2009-01-22 | ||
US14811909P | 2009-01-29 | 2009-01-29 | |
US61/148,119 | 2009-01-29 | ||
PCT/EP2010/050725 WO2010084173A1 (en) | 2009-01-22 | 2010-01-22 | Stable growth hormone compounds |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015133685A Division JP2015193636A (ja) | 2009-01-22 | 2015-07-02 | 安定な成長ホルモン化合物 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012515748A JP2012515748A (ja) | 2012-07-12 |
JP2012515748A5 JP2012515748A5 (ja) | 2013-01-17 |
JP5816097B2 true JP5816097B2 (ja) | 2015-11-18 |
Family
ID=40521462
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011546797A Active JP5816097B2 (ja) | 2009-01-22 | 2010-01-22 | 安定な成長ホルモン化合物 |
JP2015133685A Withdrawn JP2015193636A (ja) | 2009-01-22 | 2015-07-02 | 安定な成長ホルモン化合物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015133685A Withdrawn JP2015193636A (ja) | 2009-01-22 | 2015-07-02 | 安定な成長ホルモン化合物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US8513192B2 (ja) |
EP (1) | EP2389389B1 (ja) |
JP (2) | JP5816097B2 (ja) |
KR (1) | KR20110122100A (ja) |
CN (1) | CN102292349B (ja) |
AU (1) | AU2010207725B2 (ja) |
CA (1) | CA2747825A1 (ja) |
ES (1) | ES2542202T3 (ja) |
IL (1) | IL213686A0 (ja) |
MX (1) | MX2011007736A (ja) |
RU (1) | RU2539797C2 (ja) |
TW (1) | TWI504405B (ja) |
WO (1) | WO2010084173A1 (ja) |
ZA (1) | ZA201105419B (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2733200A1 (en) | 2008-08-06 | 2010-02-11 | Novo Nordisk Health Care Ag | Conjugated proteins with prolonged in vivo efficacy |
CN102292349B (zh) | 2009-01-22 | 2016-04-13 | 诺沃—诺迪斯克保健股份有限公司 | 稳定的生长激素化合物 |
CN102612376A (zh) | 2009-08-06 | 2012-07-25 | 诺沃-诺迪斯克保健股份有限公司 | 具有延长的体内功效的生长激素 |
AU2011208625C1 (en) * | 2010-01-22 | 2022-08-18 | Novo Nordisk Health Care Ag | Growth hormones with prolonged in-vivo efficacy |
AU2011208620B2 (en) * | 2010-01-22 | 2015-04-16 | Novo Nordisk Health Care Ag | Stable growth hormone compounds |
WO2012010516A1 (en) * | 2010-07-22 | 2012-01-26 | Novo Nordisk Health Care Ag | Growth hormone conjugates |
WO2014166836A1 (en) | 2013-04-05 | 2014-10-16 | Novo Nordisk A/S | Growth hormone compound formulation |
Family Cites Families (104)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
GB8610551D0 (en) | 1986-04-30 | 1986-06-04 | Hoffmann La Roche | Polypeptide & protein derivatives |
JPH0665280B2 (ja) | 1987-03-04 | 1994-08-24 | 味の素株式会社 | タンパクゲル化剤及びそれを用いるタンパクのゲル化方法 |
EP0355460B1 (en) * | 1988-08-24 | 2000-12-27 | American Cyanamid Company | Stabilization of somatotropins by modification of cysteine residues utilizing site directed mutagenesis or chemical derivatization |
US6780613B1 (en) | 1988-10-28 | 2004-08-24 | Genentech, Inc. | Growth hormone variants |
US5534617A (en) | 1988-10-28 | 1996-07-09 | Genentech, Inc. | Human growth hormone variants having greater affinity for human growth hormone receptor at site 1 |
US5750373A (en) | 1990-12-03 | 1998-05-12 | Genentech, Inc. | Enrichment method for variant proteins having altered binding properties, M13 phagemids, and growth hormone variants |
CA2345497A1 (en) | 1988-10-28 | 1990-04-28 | Genentech, Inc. | Growth hormone variants and method for forming growth hormone variants |
EP0464022B1 (en) | 1989-03-20 | 2000-05-31 | The General Hospital Corporation | Insulinotropic hormone |
US5101018A (en) * | 1989-06-12 | 1992-03-31 | International Minerals & Chemical Corp. | Method for recovering recombinant proteins |
DE3930696A1 (de) | 1989-09-14 | 1991-03-28 | Hoechst Ag | Gallensaeurederivate, verfahren zu ihrer herstellung, verwendung als arzneimittel |
JP3262329B2 (ja) | 1990-01-24 | 2002-03-04 | アイ. バックレイ,ダグラス | 糖尿病治療に有用なglp―1アナログ |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
US5951972A (en) | 1990-05-04 | 1999-09-14 | American Cyanamid Company | Stabilization of somatotropins and other proteins by modification of cysteine residues |
JP2849773B2 (ja) | 1990-08-27 | 1999-01-27 | 天野製薬株式会社 | ストレプトミセス属由来のトランスグルタミナーゼの製造法 |
DK220890D0 (da) | 1990-09-14 | 1990-09-14 | Ole Buchardt | Fremgangsmaade til fremstilling af c-terminalt amiderede peptider |
IT1251895B (it) | 1991-09-27 | 1995-05-26 | Eniricerche Spa | Mutanti dell'ormone della crescita umano e loro impiego |
EP0555649B1 (en) | 1992-01-14 | 2004-12-08 | Ajinomoto Co., Inc. | Gene encoding transglutaminase derived from fish |
ZA936811B (en) | 1992-10-28 | 1995-03-15 | Upjohn Co | Somatotropin modifications |
US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
US5736356A (en) | 1994-01-28 | 1998-04-07 | Ajinomoto Co., Inc. | Transglutaminase originating from Crassostrea gigas |
WO1996006931A1 (en) | 1994-08-26 | 1996-03-07 | Novo Nordisk A/S | Microbial transglutaminases, their production and use |
WO1996010089A1 (fr) | 1994-09-29 | 1996-04-04 | Ajinomoto Co., Inc. | Modification d'un peptide et d'une proteine |
DE4437604A1 (de) | 1994-10-21 | 1996-04-25 | Basf Ag | Konjugate aus einem Poly- oder Oligopeptid und einer niedermolekularen lipophilen Verbindung |
DE69629719T2 (de) | 1995-01-19 | 2004-07-08 | Novozymes A/S | Transglutaminasen aus oomyzeten |
JP3669390B2 (ja) | 1995-02-09 | 2005-07-06 | 味の素株式会社 | バチルス属細菌由来のトランスグルタミナーゼ |
US5869602A (en) | 1995-03-17 | 1999-02-09 | Novo Nordisk A/S | Peptide derivatives |
CA2230492C (en) | 1995-09-21 | 2009-05-26 | Genentech, Inc. | Human growth hormone variants |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
CA2468374C (en) | 1996-08-30 | 2010-12-21 | Novo-Nordisk A/S | Glp-1 derivatives |
EP0929576A1 (en) | 1996-08-30 | 1999-07-21 | Novo Nordisk A/S | Glp-2 derivatives |
WO1998013381A1 (fr) | 1996-09-26 | 1998-04-02 | Ajinomoto Co., Inc. | Proteines modifiees physiologiquement actives et compositions medicamenteuses les contenant |
US5985627A (en) | 1997-02-28 | 1999-11-16 | Carlsberg Laboratory | Modified carboxypeptidase |
JPH1156378A (ja) * | 1997-06-11 | 1999-03-02 | Nippon Chem Res Kk | 変異型ヒト成長ホルモンとその用途 |
DE69841063D1 (de) * | 1997-06-25 | 2009-09-24 | Merck Serono Sa Coinsins | Disulfid-vernetzte Glycoprotein-Hormone, ihre Herstellung und Verwendung |
CA2296770A1 (en) * | 1997-07-14 | 1999-01-28 | Bolder Biotechnology, Inc. | Derivatives of growth hormone and related proteins |
US6136536A (en) | 1997-10-29 | 2000-10-24 | Genetics Institute, Inc. | Rapid generation of stable mammalian cell lines producing high levels of recombinant proteins |
EP1060192A2 (en) | 1998-02-27 | 2000-12-20 | Novo Nordisk A/S | Glp-2 derivatives with helix-content exceeding 25 %, forming partially structured micellar-like aggregates |
EP1056774A1 (en) | 1998-02-27 | 2000-12-06 | Novo Nordisk A/S | N-terminally truncated glp-1 derivatives |
DE69942307D1 (de) | 1998-02-27 | 2010-06-10 | Novo Nordisk As | N-terminal veränderte glp-1 abkömmlinge |
EP1056775B1 (en) | 1998-02-27 | 2010-04-28 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
DE69916811T2 (de) | 1998-02-27 | 2005-04-14 | Novo Nordisk A/S | Glp-1 derivate mit einem helix-gehalt über 25 %, die partiell strukturierte mizellenartige aggregate bilden |
US6656922B2 (en) | 1998-05-28 | 2003-12-02 | Mediplex Corporation, Korea | Oral delivery of macromolecules |
US6358705B1 (en) | 1998-07-16 | 2002-03-19 | Novo Nordisk A/S | Method of making proteins in transformed yeast cells |
CA2353574C (en) | 1998-12-07 | 2012-05-08 | Zheng Xin Dong | Analogues of glp-1 |
ATE252601T1 (de) | 1999-05-17 | 2003-11-15 | Conjuchem Inc | Lang wirkende insulinotrope peptide |
US6309663B1 (en) | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
AU5805500A (en) | 1999-07-07 | 2001-01-30 | Maxygen Aps | A method for preparing modified polypeptides |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
GB2355009A (en) | 1999-07-30 | 2001-04-11 | Univ Glasgow | Peptides conjugated to bile acids/salts |
US20040001827A1 (en) | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
AU2353701A (en) | 2000-01-11 | 2001-07-24 | Novo Nordisk A/S | Transepithelial delivery of glp-1 derivatives |
DE60138364D1 (de) | 2000-02-11 | 2009-05-28 | Bayer Healthcare Llc | Gerinnungsfaktor vii oder viia konjugate |
US20020142964A1 (en) | 2000-11-02 | 2002-10-03 | Nissen Torben Lauesgaard | Single-chain polypeptides |
AU2002226897B2 (en) | 2000-12-07 | 2007-10-25 | Eli Lilly And Company | GLP-1 fusion proteins |
AU2002219021A1 (en) | 2001-01-11 | 2002-07-24 | Maxygen Aps | Variant growth hormone molecules conjugated with macromolecular compounds |
US20060183197A1 (en) | 2001-01-11 | 2006-08-17 | Andersen Kim V | Variant growth hormone molecules conjugated with macromolecules compounds |
FR2819810B1 (fr) | 2001-01-23 | 2004-05-28 | Pf Medicament | Peptides non glycosyles derives de la proteine g du vrs et leur utilisation dans un vaccin |
US6858580B2 (en) | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
WO2002103024A2 (en) * | 2001-06-14 | 2002-12-27 | The Scripps Research Institute | Stabilized proteins with engineered disulfide bonds |
ES2298378T3 (es) | 2001-06-28 | 2008-05-16 | Novo Nordisk A/S | Formulacion estable de glp-1 modificado. |
JP2004537580A (ja) | 2001-08-10 | 2004-12-16 | エピックス メディカル, インコーポレイテッド | 延長された循環半減期を有するポリペプチド結合体 |
AR036711A1 (es) | 2001-10-05 | 2004-09-29 | Bayer Corp | Peptidos que actuan como agonistas del receptor del glp-1 y como antagonistas del receptor del glucagon y sus metodos de uso farmacologico |
RS53104A (en) | 2001-11-20 | 2006-10-27 | Pharmacia Corporation | Chemically-modified human growth hormone conjugates |
JP2003199569A (ja) | 2001-12-17 | 2003-07-15 | Food Industry Research & Development Inst | ストレプトベルティシリウム・ラダカヌムのトランスグルタミナーゼ遺伝子及び該遺伝子によってコードされるトランスグルタミナーゼ |
WO2004065621A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
KR20040098063A (ko) | 2002-04-10 | 2004-11-18 | 일라이 릴리 앤드 캄파니 | 위마비의 치료 |
CA2483478A1 (en) | 2002-04-30 | 2003-11-13 | Maxygen Holdings Ltd. | Factor vii or viia polypeptide variants |
US7611700B2 (en) | 2002-09-09 | 2009-11-03 | Hanall Pharmaceuticals, Co., Ltd. | Protease resistant modified interferon alpha polypeptides |
ES2336563T3 (es) | 2003-02-19 | 2010-04-14 | Ipsen Pharma | Analogos de glp-1. |
EP1625158A2 (en) | 2003-05-09 | 2006-02-15 | Novo Nordisk A/S | Peptides for use in treating obesity |
EP1654004A2 (en) | 2003-08-08 | 2006-05-10 | Novo Nordisk A/S | Synthesis and application of new structural well defined branched polymers as conjugating agents for peptides |
JP2007537981A (ja) | 2003-09-19 | 2007-12-27 | ノボ ノルディスク アクティーゼルスカブ | 新規の血漿タンパク質親和性タグ |
RU2401276C2 (ru) | 2003-09-19 | 2010-10-10 | Ново Нордиск А/С | Производные глюкагон-подобного пептида-1 (glp-1) |
SI2932981T1 (sl) | 2003-09-19 | 2021-11-30 | Novo Nordisk A/S | Albumin-vezavni derivati GLP-1 |
JP2008502301A (ja) | 2003-10-10 | 2008-01-31 | ノボ ノルディスク アクティーゼルスカブ | ペプチドの抱合 |
BRPI0417684A (pt) | 2003-12-18 | 2007-03-20 | Novo Nordisk As | composto, composição farmacêutica, e, uso de um composto |
EP1704165B1 (en) | 2003-12-18 | 2010-03-17 | Novo Nordisk A/S | Glp-1 compounds |
CN1909930B (zh) | 2004-01-21 | 2015-12-16 | 诺和诺德医疗保健公司 | 转谷氨酰胺酶介导的肽的接合 |
CA2553040A1 (en) * | 2004-02-02 | 2005-08-18 | Ambrx, Inc. | Modified human four helical bundle polypeptides and their uses |
US7906137B2 (en) | 2004-05-21 | 2011-03-15 | Mediplex Corporation, Korea | Delivery agents for enhancing mucosal absorption of therapeutic agents |
US20090111730A1 (en) | 2004-07-08 | 2009-04-30 | Novo Nordisk A/S | Polypeptide protracting tags |
WO2006013202A2 (en) | 2004-08-02 | 2006-02-09 | Novo Nordisk Health Care Ag | Conjugation of fvii |
EP1799710A2 (en) | 2004-10-07 | 2007-06-27 | Novo Nordisk A/S | Protracted glp-1 compounds |
US7998930B2 (en) | 2004-11-04 | 2011-08-16 | Hanall Biopharma Co., Ltd. | Modified growth hormones |
CN101128214A (zh) | 2005-03-18 | 2008-02-20 | 诺和诺德公司 | 长效glp-1化合物 |
JP2008533104A (ja) | 2005-03-18 | 2008-08-21 | ノボ ノルディスク アクティーゼルスカブ | Glp−1受容体の二量体ペプチドアゴニスト |
TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
JP5335422B2 (ja) | 2005-06-17 | 2013-11-06 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 少なくとも1つの非天然のシステインを含んでいる操作されたタンパク質の選択的な還元および誘導体化 |
US20090117640A1 (en) | 2005-08-18 | 2009-05-07 | Novo Nordisk Health Care Ag | Transglutaminase Variants with Improved Specificity |
ES2546282T3 (es) | 2006-02-14 | 2015-09-22 | Novo Nordisk Health Care Ag | Acoplamiento de polipéptidos en el extremo C-terminal |
BRPI0713963A2 (pt) | 2006-07-07 | 2012-11-27 | Novo Nordisk Healthcare Ag | conjugados de proteìna e métodos para sua preparação |
CA2672267C (en) | 2006-07-27 | 2016-05-31 | Emisphere Technologies, Inc. | Arylsulfanyl compounds and compositions for delivering active agents |
EP2054435A1 (en) | 2006-08-18 | 2009-05-06 | Novo Nordisk Health Care AG | Transglutaminase variants with improved specificity |
US20080095837A1 (en) | 2006-08-31 | 2008-04-24 | Emisphere Technologies, Inc. | Human growth hormone formulations |
KR101524880B1 (ko) | 2006-08-31 | 2015-06-01 | 노파르티스 아게 | Hgh를 포함하는 경구 전달용 제약 조성물 |
WO2008101240A1 (en) | 2007-02-16 | 2008-08-21 | Emisphere Technologies, Inc. | Compounds having a cyclic moiety and compositions for delivering active agents |
WO2008112836A2 (en) | 2007-03-15 | 2008-09-18 | Novartis Ag | Pharmaceutical composition comprising human growth hormon |
CN101842109B (zh) | 2007-09-05 | 2014-01-29 | 诺沃-诺迪斯克有限公司 | 用a-b-c-d-衍生的肽和它们的治疗用途 |
CA2733200A1 (en) | 2008-08-06 | 2010-02-11 | Novo Nordisk Health Care Ag | Conjugated proteins with prolonged in vivo efficacy |
ES2561208T3 (es) | 2008-09-12 | 2016-02-25 | Novo Nordisk A/S | Método de acilación de un péptido o una proteína |
CN102292349B (zh) | 2009-01-22 | 2016-04-13 | 诺沃—诺迪斯克保健股份有限公司 | 稳定的生长激素化合物 |
-
2010
- 2010-01-22 CN CN201080005067.4A patent/CN102292349B/zh active Active
- 2010-01-22 ES ES10701015.9T patent/ES2542202T3/es active Active
- 2010-01-22 KR KR1020117016169A patent/KR20110122100A/ko not_active Application Discontinuation
- 2010-01-22 US US13/144,757 patent/US8513192B2/en active Active
- 2010-01-22 MX MX2011007736A patent/MX2011007736A/es active IP Right Grant
- 2010-01-22 JP JP2011546797A patent/JP5816097B2/ja active Active
- 2010-01-22 CA CA2747825A patent/CA2747825A1/en not_active Withdrawn
- 2010-01-22 EP EP10701015.9A patent/EP2389389B1/en active Active
- 2010-01-22 TW TW099101707A patent/TWI504405B/zh not_active IP Right Cessation
- 2010-01-22 RU RU2011133926/10A patent/RU2539797C2/ru not_active IP Right Cessation
- 2010-01-22 AU AU2010207725A patent/AU2010207725B2/en not_active Ceased
- 2010-01-22 WO PCT/EP2010/050725 patent/WO2010084173A1/en active Application Filing
-
2011
- 2011-06-21 IL IL213686A patent/IL213686A0/en unknown
- 2011-07-22 ZA ZA2011/05419A patent/ZA201105419B/en unknown
-
2015
- 2015-07-02 JP JP2015133685A patent/JP2015193636A/ja not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
CN102292349B (zh) | 2016-04-13 |
AU2010207725A1 (en) | 2011-07-21 |
AU2010207725B2 (en) | 2015-06-11 |
JP2012515748A (ja) | 2012-07-12 |
ZA201105419B (en) | 2012-04-25 |
CN102292349A (zh) | 2011-12-21 |
EP2389389A1 (en) | 2011-11-30 |
ES2542202T3 (es) | 2015-08-03 |
IL213686A0 (en) | 2011-07-31 |
RU2011133926A (ru) | 2013-02-27 |
TW201032819A (en) | 2010-09-16 |
MX2011007736A (es) | 2011-09-06 |
KR20110122100A (ko) | 2011-11-09 |
JP2015193636A (ja) | 2015-11-05 |
WO2010084173A1 (en) | 2010-07-29 |
US8513192B2 (en) | 2013-08-20 |
TWI504405B (zh) | 2015-10-21 |
CA2747825A1 (en) | 2010-07-29 |
RU2539797C2 (ru) | 2015-01-27 |
EP2389389B1 (en) | 2015-04-15 |
US20110306548A1 (en) | 2011-12-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5980689B2 (ja) | 安定な成長ホルモン化合物 | |
CN102834109B (zh) | 稳定的生长激素化合物 | |
JP2015193636A (ja) | 安定な成長ホルモン化合物 | |
JP5635531B2 (ja) | グルカゴン類似体 | |
JP5635532B2 (ja) | グルカゴン類似体 | |
JP5635529B2 (ja) | グルカゴン類似体 | |
JP5635530B2 (ja) | グルカゴン類似体 | |
US20130143815A1 (en) | Growth hormone conjugates | |
JP6018129B2 (ja) | グルカゴン類似体 | |
JP5912151B2 (ja) | グルカゴン類似体 | |
JP2015006186A (ja) | グルカゴン類似体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121116 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20121116 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140519 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140819 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20150302 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150702 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20150714 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150831 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150925 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5816097 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |