JP5789515B2 - インスリン類似体 - Google Patents
インスリン類似体 Download PDFInfo
- Publication number
- JP5789515B2 JP5789515B2 JP2011542482A JP2011542482A JP5789515B2 JP 5789515 B2 JP5789515 B2 JP 5789515B2 JP 2011542482 A JP2011542482 A JP 2011542482A JP 2011542482 A JP2011542482 A JP 2011542482A JP 5789515 B2 JP5789515 B2 JP 5789515B2
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- Japan
- Prior art keywords
- seq
- insulin
- chain
- amino acid
- sequence
- 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.)
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- 230000008901 benefit Effects 0.000 description 1
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- 230000000975 bioactive effect Effects 0.000 description 1
- 229920001222 biopolymer Polymers 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940084891 byetta Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000021257 carbohydrate digestion Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940089126 diabeta Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
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- BOVGTQGAOIONJV-UHFFFAOYSA-N gliclazide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CC2CCCC2C1 BOVGTQGAOIONJV-UHFFFAOYSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
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- 125000005252 haloacyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 102000047882 human INSR Human genes 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 102000019758 lipid binding proteins Human genes 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011976 maleic acid Substances 0.000 description 1
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- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 238000001906 matrix-assisted laser desorption--ionisation mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 102000044158 nucleic acid binding protein Human genes 0.000 description 1
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- 206010033675 panniculitis Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 1
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- 229960003611 pramlintide Drugs 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
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- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 229940014800 succinic anhydride Drugs 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229940035266 tolinase Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
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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
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
Landscapes
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Endocrinology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
GIVEQCCX1SICSLYQLENX2CX3(配列番号3)
を含み、B鎖が配列:
X4LCGX5X6LVEALYLVCGERGFF(配列番号4)
を含むインスリン類似体が提供される。
[配列中、
X1は、トレオニンおよびヒスチジンから成る群より選択され;
X2は、一般式:
のアミノ酸であり;
X3は、アスパラギンまたはグリシンであり;
X4は、ヒスチジンおよびトレオニンから成る群より選択され;
X5は、アラニン、グリシンおよびセリンから成る群より選択され;
X6は、ヒスチジン、アスパラギン酸、グルタミン酸、ホモシステイン酸およびシステイン酸から成る群より選択される]
さらなる実施形態では、B鎖は、配列X11VNQX4LCGX5X6LVEALYLVCGERGFFYTX9X10(配列番号5)
を含む。
[配列中、
X4は、ヒスチジンおよびトレオニンから成る群より選択され;
X5は、アラニン、グリシンおよびセリンから成る群より選択され;
X6は、ヒスチジン、アスパラギン酸、グルタミン酸、ホモシステイン酸およびシステイン酸から成る群より選択され;
X9は、アスパラギン酸塩−リシンジペプチド、リシン−プロリンジペプチドまたはプロリン−リシンジペプチドであり;
X10は、トレオニン、アラニンまたはトレオニン−アルギニン−アルギニントリペプチドであり;
X11は、フェニルアラニンおよびデスアミノ−フェニルアラニンから成る群より選択される]
[配列中、X2は、一般式:
本出願は、その開示が全体として参照により明白に本明細書に組み込まれる、2008年12月19日出願の米国特許出願第61/139,221号の優先権を主張する。
本発明を説明し、特許請求する際に、以下の用語を以下で述べる定義に従って使用する。
I.小型の脂肪族の非極性またはわずかに極性の残基:
Ala、Ser、Thr、Pro、Gly;
II.極性の負に荷電した残基およびそれらのアミド:
Asp、Asn、Glu、Gln;
III.極性の正に荷電した残基:
His、Arg、Lys;オルニチン(Orn)
IV.大型の脂肪族の非極性残基:
Met、Leu、Ile、Val、Cys、ノルロイシン(Nle)、ホモシステイン
V.大型の芳香族残基:
Phe、Tyr、Trp、アセチルフェニルアラニン。
[配列中、
X1は、トレオニンおよびヒスチジンから成る群より選択され;
X2は、一般式
のアミノ酸であり;そして
X3は、アスパラギン、グリシンもしくはアラニンである]
1つの実施形態では、R4は、NH2である。別の実施形態では、X1は、トレオニンであり、X3は、アスパラギンであり、R4は、NH2である。
[配列中、
X1は、トレオニンおよびヒスチジンから成る群より選択され;
X2は、一般式
のアミノ酸であり;
X3は、アスパラギンもしくはグリシンであり;
X4は、ヒスチジンおよびトレオニンから成る群より選択され;
X5は、アラニン、グリシンおよびセリンから成る群より選択され;
X6は、ヒスチジン、アスパラギン酸、グルタミン酸、ホモシステイン酸およびシステイン酸から成る群より選択される]
[配列中、
X1は、トレオニン、ヒスチジン、アルギニンおよびリシンから成る群より選択され;
X2は、一般式
X3は、アスパラギンまたはグリシンであり;
X4は、ヒスチジンおよびトレオニンから成る群より選択され;
X5は、アラニン、グリシンおよびセリンから成る群より選択され;
X6は、ヒスチジン、アスパラギン酸、グルタミン酸、ホモシステイン酸およびシステイン酸から成る群より選択され;
X9は、アスパラギン酸塩−リシンジペプチド、リシン−プロリンジペプチドまたはプロリン−リシンジペプチドであり;
X10は、トレオニンまたはトレオニン−アルギニン−アルギニントリペプチドであり;
X11は、フェニルアラニンおよびデスアミノ−フェニルアラニンから成る群より選択される]
1つの実施形態では、B鎖配列は、配列HLCGSHLVEALYLVCGERGFF(配列番号7)を含み、さらなる実施形態では、B鎖は、FVNQHLCGSHLVEALYLVCGERGFFYTPKT(配列番号8)、FVNQHLCGSHLVEALYLVCGERGFFYTKPT(配列番号9)およびFVNQHLCGSHLVEALYLVCGERGFFYTPKTRR(配列番号10)から成る群より選択される。さらなる実施形態では、GIVEQCCX1SICSLYQLENX2CX3(配列番号3)のA鎖配列ならびに配列番号7、配列番号8および配列番号9から成る群より選択される配列を含有するB鎖配列を含むA19インスリン類似体が提供される。
[配列中、X1は、トレオニンおよびヒスチジンから成る群より選択され、X2は、一般式
[配列中、
X1は、トレオニンおよびヒスチジンから成る群より選択され;
X2は、一般式
のアミノ酸であり;そして
X3は、アスパラギンまたはグリシンである]
さらなる実施形態では、R4はNH2であり、そしてX3はアスパラギンであり、また1つの実施形態では、R4はNH2であり、X1はトレオニンであり、そしてX3はアスパラギンである。
[式中、R4は、NH2またはOCH3である]
1つの実施形態によれば、一本鎖インスリン類似体は、式:B−P−A19の化合物を含む[式中、Bは、インスリンのB鎖またはその機能的類似体を表し、A19は、本明細書で開示されるA19 A鎖類似体を表し、そしてPは、A鎖のアミノ末端をB鎖のカルボキシ末端に共有結合で連結する、ペプチドリンカーを含むリンカーを表す]。1つの実施形態では、リンカーは、約5〜約18、または約10〜約14、または約4〜約8、または約6アミノ酸のペプチドリンカーである。
[式中、
Bは、X4LCGX5X6LVEALYLVCGERGFF(配列番号4)の配列を含有するB鎖配列を表し;
A19は、GIVEQCCX1SICSLYQLENX2CX3(配列番号3)の配列を含有するA鎖配列を表し;そして
Pは、4〜8アミノ酸のペプチドリンカーを表し、さらに配列中、
X1は、トレオニンおよびヒスチジンから成る群より選択され;
X2は、一般式
のアミノ酸であり;
X3は、アスパラギンまたはグリシンであり;
X4は、ヒスチジンおよびトレオニンから成る群より選択され;
X5は、アラニン、グリシンおよびセリンから成る群より選択され;
X6は、ヒスチジン、アスパラギン酸、グルタミン酸、ホモシステイン酸およびシステイン酸から成る群より選択される]
1つの実施形態によれば、ペプチドリンカーは、5〜18アミノ酸長であり、Gly−Gly−Gly−Pro−Gly−Lys−Arg(配列番号11)、Gly−Tyr−Gly−Ser−Ser−Ser−Arg−Arg−Ala−Pro−Gln−Thr(配列番号12)、Arg−Arg−Gly−Pro−Gly−Gly−Gly(配列番号21)、Gly−Gly−Gly−Gly−Gly−Lys−Arg(配列番号13)、Arg−Arg−Gly−Gly−Gly−Gly−Gly(配列番号14)、Gly−Gly−Ala−Pro−Gly−Asp−Val−Lys−Arg (配列番号15)、Arg−Arg−Ala−Pro−Gly−Asp−Val−Gly−Gly(配列番号16)、Gly−Gly−Tyr−Pro−Gly−Asp−Val−Lys−Arg(配列番号17)、Arg−Arg−Tyr−Pro−Gly−Asp−Val−Gly−Gly(配列番号18)、Gly−Gly−His−Pro−Gly−Asp−Val−Lys−Arg(配列番号19)およびArg−Arg−His−Pro−Gly−Asp−Val−Gly−Gly(配列番号20)から成る群より選択される配列を含む。
Phe−Val−Asn−Gln−His−Leu−Cys−Gly−Ser−His−Leu−Val−Glu−Ala−Leu−Tyr−Leu−Val−Cys−Gly−Glu−Arg−Gly−Phe−Phe−Tyr−Thr−Pro−Lys−Thr−Gln−Pro−Leu−Ala−Leu−Glu−Gly−Ser−Leu−Gln−Lys−Arg−Gly−Ile−Val−Glu−Gln−Cys−Cys−Thr−Ser−Ile−Cys−Ser−Leu−Tyr−Gln−Leu−Glu−Asn−Xaa−Cys−Asn(配列番号23)を有する。
[配列中、Xaaは、一般式
のアミノ酸である]
==インスリンAおよびB鎖の合成==
インスリンAおよびB鎖を、Boc化学を用いて4−メチルベンズヒドリルアミン(MBHA)樹脂または4−ヒドロキシメチルフェニルアセトアミドメチル(PAM)樹脂上で合成した。95:5のHF/p−クレゾールを使用して0℃で1時間、ペプチドを樹脂から切断した。HFの除去およびエーテル沈殿後、ペプチドを50%酢酸水溶液に溶解し、凍結乾燥した。あるいは、Fmoc化学を用いてペプチドを合成した。これらのペプチドは、トリフルオロ酢酸(TFA)/トリイソプロピルシラン(TIS)/H2O(95:2.5:2.5)を使用して室温で2時間インキュベートし、樹脂から切断した。過剰量のジエチルエーテルを添加してペプチドを沈殿させ、ペレットを酸性緩衝水溶液に可溶化した。ペプチドの品質をRP−HPLCによってモニターし、質量分析(ESIまたはMALDI)によって確認した。
表1:天然インスリンと比較した合成インスリンの活性
==還元的アルキル化によるアミン基(N末端およびリシン)のペグ化==
a.合成
インスリン(またはインスリン類似体)、mPEG20k−アルデヒドおよびNaBH3CNを1:2:30のモル比でpH4.1〜4.4の酢酸緩衝液に溶解した。反応溶液は、0.1N NaCl、0.2N酢酸および0.1N Na2CO3から成る。インスリンペプチド濃度は約0.5mg/mlであった。反応は室温で6時間にわたって行った。反応完了の程度をRP−HPLCによってモニターし、反応の収率は約50%であった。
反応混合物を0.1%TFAで2〜5倍に希釈し、準備ておいたRP−HPLCカラムに供した。HPLC条件:C4カラム;流速10ml/分;A緩衝液、水中10%ACNおよび0.1%TFA;B緩衝液、ACN中0.1%TFA;Bの直線勾配(%)が0〜40%(0〜80分);PEG−インスリンまたは類似体は約35%のB緩衝液で溶出した。加硫分解またはトリプシン分解を介した化学修飾後、所望化合物をMALDI−TOFによって確認した。
a.合成
インスリン(またはインスリン類似体)をmPEG20k−NHSと共に0.1Nビシン緩衝液(pH8.0)に1:1のモル比で溶解した。インスリンペプチド濃度は約0.5mg/mlであった。反応の進行をHPLCによってモニターした。反応の収率は、室温で2時間後に約90%であった。
反応混合物を2〜5倍に希釈し、RP−HPLCに供した。HPLC条件:C4カラム;流速10ml/分;A緩衝液、水中10%ACNおよび0.1%TFA;B緩衝液、ACN中0.1%TFA;Bの直線勾配(%)が0〜40%(0〜80分);PEG−インスリンまたは類似体を約35%Bで収集した。加硫分解またはトリプシン分解を介した化学修飾後、所望化合物をMALDI−TOFによって確認した。
a.合成
インスリン(またはインスリン類似体)、mPEG20k−ヒドラジドおよびNaBH3CNを1:2:20のモル比で酢酸緩衝液(pH4.1〜4.4)に溶解した。反応溶液は、0.1N NaCl、0.2N酢酸および0.1N Na2CO3から成る。インスリンまたはインスリン類似体濃度は、室温で24時間、約0.5mg/mlであった。反応の経過をHPLCによってモニターした。反応の変換率は約50%であった(HPLCによって算定した)。
反応混合物を2〜5倍に希釈し、RP−HPLCに供した。HPLC条件:C4カラム;流速10ml/分;A緩衝液、水中10%ACNおよび0.1%TFA;B緩衝液、ACN中0.1%TFA;B直線勾配(%)が0〜40%(0〜80分);PEG−インスリンまたはPEG−インスリン類似体を約35%Bで収集した。加硫分解またはトリプシン分解を介した化学修飾後、所望化合物をMALDI−TOFによって確認した。
==インスリン受容体結合アッセイ==
インスリンまたはIGF−1受容体に対する各々のペプチドの親和性を、シンチレーション近接技術を利用した競合結合アッセイにおいて測定した。ペプチドの連続3倍希釈をTris−Cl緩衝液(0.05M Tris−HCl、pH7.5、0.15M NaCl、0.1%w/vウシ血清アルブミン)中で作製し、96穴プレート(Corning Inc.,Acton,MA)において0.05nM(3−[125I]−ヨードチロシル)A TyrA14インスリンまたは(3−[125I]−ヨードチロシル)IGF−1(Amersham Biosciences,Piscataway,NJ)と混合した。ヒトインスリンまたはIGF−1受容体を過剰発現する細胞から調製した形質膜フラグメントの1〜6μgを各ウエルに分注し、0.25mg/ウエルのポリエチレンイミン処理コムギ胚芽凝集素A型シンチレーション近接アッセイビーズ(Amersham Biosciences,Piscataway,NJ)を添加した。800rpmで5分間振とうした後、プレートを室温で12時間インキュベートし、MicroBeta1450液体シンチレーションカウンター(Perkin−Elmer,Wellesley,MA)で放射能を測定した。非特異的結合(NSB)の放射能を、試験試料の最高濃度よりも4倍高い濃度の「非放射性(コールド)」天然リガンドを含むウエルで測定した。競合物質を含まないウエルで総結合放射能を検出した。特異的結合のパーセントを以下のように計算した:特異的結合%=(結合−NSB/総結合−NSB)×100。IC50値は、Originソフトウエア(OriginLab,Northampton,MA)を用いて決定した。
==インスリン受容体リン酸化アッセイ==
インスリンまたはインスリン類似体の受容体リン酸化を測定するため、受容体をトランスフェクトしたHEK293細胞を96穴組織培養プレート(Costar No.3596,Cambridge,MA)に播種し、100IU/mlペニシリン、100μg/mlストレプトマイシン、10mM HEPESおよび0.25%ウシ増殖血清(HyClone SH30541,Logan,UT)を添加したダルベッコ改変イーグル培地(DMEM)中、37℃、5%CO2および90%湿度で16〜20時間培養した。インスリンまたはインスリン類似体の連続希釈を、0.5%ウシ血清アルブミン(Roche Applied Science No.100350,Indianapolis,IN)を添加したDMEM中で調製し、接着した細胞を含むウエルに添加した。5%CO2の加湿条件下で37℃で15分間インキュベートした後、細胞を5%パラホルムアルデヒドにより室温で20分間固定し、リン酸緩衝食塩水pH7.4で2回洗浄して、PBS中2%ウシ血清アルブミンで1時間ブロックした。次にプレートを3回洗浄し、製造者の推奨に従って2%ウシ血清アルブミン含有PBS中で再構成したホスホチロシンに対するホースラディッシュペルオキシダーゼ結合抗体(Upstate biotechnology No.16−105,Temecula,CA)で満たした。室温で3時間インキュベートした後、プレートを4回洗浄し、TMB single solution substrate(Invitrogen,No.00−2023,Carlbad,CA)0.1mlを各々のウエルに添加した。1N HCl 0.05mlを添加することによって5分後に発色を停止させた。450nmの吸光度をTitertek Multiscan MCC340(ThermoFisher,Pittsburgh,PA)で測定した。吸光度に対するペプチド濃度用量反応曲線をプロットし、Originソフトウエア(OriginLab,Northampton,MA)を用いてEC50値を決定した。
A19のインスリンの特定類似体を合成し、インスリン受容体におけるそれらの活性に関して特徴づけた。2つの活性の高い構造類似体がA19で同定されたが、2番目の活性部位の芳香族残基(B24)での同程度の構造変化により、同様の完全な活性のインスリン類似体は同定されなかった。表2および3は、インスリン受容体における完全な活性のために、A19位が高度に構造保存されていることを例示する。表2は、A19に修飾を有する2つのインスリン類似体だけが天然インスリンと同様の受容体結合活性を有することを明らかにする。4−アミノフェニルアラニンインスリン類似体に関して、3つの別々の実験からのデータを提示する。「活性(本試験)」と表示された欄は、同時に実施された2つの別々の実験における、天然インスリンに比較したインスリン類似体の結合パーセントを比較する。「活性(0.60nM)」と表示された欄は、このアッセイを用いてインスリン結合に関して得られた過去平均値と比較したインスリン類似体の相対的結合パーセントである。どちらの分析においても、2つのA19インスリン類似体(4−アミノフェニルアラニンおよび4−メトキシフェニルアラニン)は天然インスリンにおおよそ等しい受容体結合を示す。図3は、インスリン受容体への天然インスリンとA19インスリン類似体のそれぞれの特異的結合を示すグラフである。表3は、天然インスリンと等しい結合活性を示す2つのA19インスリン類似体(4−アミノおよび4−メトキシ)が、同時にインスリン受容体における等しいリン酸化活性も示すことを説明するデータを提示する。
表2:A19インスリン類似体のインスリン受容体結合活性
表3:A19インスリン類似体のインスリン受容体リン酸化活性
Claims (9)
- 前記B鎖のN末端のアミノ酸に連結されているポリエチレングリコール鎖を含むようにさらに修飾されている、請求項3に記載のインスリン類似体。
- 前記B鎖の前記N末端アミノ酸または配列番号8の29位の前記アミノ酸のいずれかに連結されているポリエチレングリコール鎖を含むようにさらに修飾されている、請求項3に記載のインスリン類似体。
- 前記B鎖の前記N末端アミノ酸または配列番号9の28位の前記アミノ酸のいずれかに連結されているポリエチレングリコール鎖を含むようにさらに修飾されている、請求項3に記載のインスリン類似体。
- 式:B−P−A19の化合物からなる一本鎖インスリン類似体。
[式中、
Bは、FVNQHLCGSHLVEALYLVCGERGFFYTPKT(配列番号8)またはFVNQHLCGSHLVEALYLVCGERGFFYTKPT(配列番号9)からなる配列を表し;
A19は、GIVEQCCTSICSLYQLENX2CN(配列番号6)からなる配列を表し;そして
Pは、Gly−Gly−Gly−Pro−Gly−Lys−Arg(配列番号11)、AGRGSGK(配列番号24)、AGLGSGK(配列番号25)、AGMGSGK(配列番号26)、ASWGSGK(配列番号27)、TGLGSGQ(配列番号28)、TGLGRGK(配列番号29)、TGLGSGK(配列番号30)、HGLYSGK(配列番号31)、KGLGSGQ(配列番号32)、VGLMSGK(配列番号33)、VGLSSGQ(配列番号34)、VGLYSGK(配列番号35)、VGLSSGK(配列番号36)、VGMSSGK(配列番号37)、VWSSSGK(配列番号38)、VGSSSGK(配列番号39)、VGMSSGK(配列番号40)からなる群から選択されるペプチドリンカーを表し、さらに、
配列中、
X2は、一般式:
のアミノ酸である] - 有効成分として請求項3に記載のインスリン類似体を含有する、医薬組成物。
- 有効成分として請求項3に記載のインスリン類似体を含有する、糖尿病治療用薬剤。
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CA2747490A1 (en) | 2010-07-15 |
AU2009335712B2 (en) | 2015-09-17 |
EP2376520A1 (en) | 2011-10-19 |
CN102256992B (zh) | 2015-04-22 |
US20110257091A1 (en) | 2011-10-20 |
CN102256992A (zh) | 2011-11-23 |
EP2376520B1 (en) | 2014-02-12 |
US8481485B2 (en) | 2013-07-09 |
CA2747490C (en) | 2017-02-14 |
JP2012512899A (ja) | 2012-06-07 |
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