RU2003123109A - Ацетил-кофермент а-карбоксилаза 2 как мишень для регуляции сжигания жира, накопления жира, энергетичесеого гомеостаза и действия инсулина - Google Patents
Ацетил-кофермент а-карбоксилаза 2 как мишень для регуляции сжигания жира, накопления жира, энергетичесеого гомеостаза и действия инсулина Download PDFInfo
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- RU2003123109A RU2003123109A RU2003123109/15A RU2003123109A RU2003123109A RU 2003123109 A RU2003123109 A RU 2003123109A RU 2003123109/15 A RU2003123109/15 A RU 2003123109/15A RU 2003123109 A RU2003123109 A RU 2003123109A RU 2003123109 A RU2003123109 A RU 2003123109A
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- acetyl coa
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- 238000009825 accumulation Methods 0.000 title claims 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title 2
- 102000004877 Insulin Human genes 0.000 title 1
- 108090001061 Insulin Proteins 0.000 title 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title 1
- 230000033228 biological regulation Effects 0.000 title 1
- 230000006346 energetic homeostasis Effects 0.000 title 1
- 229940125396 insulin Drugs 0.000 title 1
- 108010018763 Biotin carboxylase Proteins 0.000 claims 16
- 238000000034 method Methods 0.000 claims 14
- 102100021641 Acetyl-CoA carboxylase 2 Human genes 0.000 claims 11
- 241000699666 Mus <mouse, genus> Species 0.000 claims 10
- 210000004027 cell Anatomy 0.000 claims 10
- 230000000694 effects Effects 0.000 claims 7
- 238000011830 transgenic mouse model Methods 0.000 claims 5
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims 4
- 102100039164 Acetyl-CoA carboxylase 1 Human genes 0.000 claims 3
- 241000699670 Mus sp. Species 0.000 claims 3
- 229940124682 acetyl-CoA carboxylase 2 inhibitor Drugs 0.000 claims 3
- 239000003112 inhibitor Substances 0.000 claims 3
- 108090000623 proteins and genes Proteins 0.000 claims 3
- 238000012216 screening Methods 0.000 claims 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 claims 2
- 108700024394 Exon Proteins 0.000 claims 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims 2
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 2
- 102000001708 Protein Isoforms Human genes 0.000 claims 2
- 108010029485 Protein Isoforms Proteins 0.000 claims 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 claims 2
- 230000001413 cellular effect Effects 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 206010012601 diabetes mellitus Diseases 0.000 claims 2
- 230000003647 oxidation Effects 0.000 claims 2
- 238000007254 oxidation reaction Methods 0.000 claims 2
- 230000004963 pathophysiological condition Effects 0.000 claims 2
- 102000004169 proteins and genes Human genes 0.000 claims 2
- 101150115324 ACC2 gene Proteins 0.000 claims 1
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 claims 1
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 claims 1
- LTYOQGRJFJAKNA-KKIMTKSISA-N Malonyl CoA Natural products S(C(=O)CC(=O)O)CCNC(=O)CCNC(=O)[C@@H](O)C(CO[P@](=O)(O[P@](=O)(OC[C@H]1[C@@H](OP(=O)(O)O)[C@@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C LTYOQGRJFJAKNA-KKIMTKSISA-N 0.000 claims 1
- 108090000143 Mouse Proteins Proteins 0.000 claims 1
- 241001529936 Murinae Species 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 claims 1
- 102000004357 Transferases Human genes 0.000 claims 1
- 108090000992 Transferases Proteins 0.000 claims 1
- 210000001789 adipocyte Anatomy 0.000 claims 1
- 239000000556 agonist Substances 0.000 claims 1
- 239000005557 antagonist Substances 0.000 claims 1
- 229960002685 biotin Drugs 0.000 claims 1
- 235000020958 biotin Nutrition 0.000 claims 1
- 239000011616 biotin Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 230000009260 cross reactivity Effects 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- 210000002064 heart cell Anatomy 0.000 claims 1
- 230000002779 inactivation Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 230000037356 lipid metabolism Effects 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 210000005229 liver cell Anatomy 0.000 claims 1
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 108020004999 messenger RNA Proteins 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 claims 1
- 238000012544 monitoring process Methods 0.000 claims 1
- 210000000663 muscle cell Anatomy 0.000 claims 1
- 235000020824 obesity Nutrition 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000028327 secretion Effects 0.000 claims 1
- 210000002027 skeletal muscle Anatomy 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 claims 1
- 230000004580 weight loss Effects 0.000 claims 1
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Claims (23)
1. Способ стимуляции окисления жирных кислот и потери в весе у индивидуума, включающий стадию ингибирования активности ацетил-КоА-карбоксилазы 2 у указанного индивидуума.
2. Способ по п.1, где указанная активность ингибируется путем введения указанному индивидууму ингибитора ацетил-КоА-карбоксилазы 2 (АСС2).
3. Способ по п.1, где указанный индивидуум страдает патофизиологическим состоянием.
4. Способ по п.3, где указанное патофизиологическое состояние выбрано из группы, состоящей из ожирения и диабета.
5. Способ снижения уровней сахара в крови индивидуума, включающий стадию введения указанному индивидууму ингибитора ацетил-КоА-карбоксилазы 2 (АСС2).
6. Способ по п.5, где указанный индивидуум страдает диабетом.
7. Трансгенная мышь, геном которой содержит гомозиготный разрыв в эндогенном гене АСС2 кодирующем изоформу ацетил-КоА-карбоксилазу 2 ацетил-КоА-карбоксилазы, где указанный разрыв приводит к инактивации указанного гена, и где указанная мышь не продуцирует какой-либо функциональной ацетил-КоА-карбоксилазы 2.
8. Мышь по п.7, где один или несколько экзонов указанного гена АСС2 были делетированы.
9. Мышь по п.8, где указанные экзоны были заменены гетерологичными ДНК-последовательностями.
10. Мышь по п.9, где указанные гетерологичные ДНК-последовательности содержат экспрессионный кластер гипоксантинфосфорилрибозилтрансферазы.
11. Мышь по п.10, где экзон, кодирующий биотин-связывающий мотив АСС2, заменен экспрессионным кластером гипоксантинфосфорилрибозилтрансферазы.
12. Мышь по п.7, которая имеет фенотип, характеризующийся снижением уровней метаболического продуцирования малонил-КоА в скелетной мышце и в сердце.
13. Мышь по п.12, которая, кроме того, имеет фенотип, характеризующийся неограниченным окислением жира и пониженным уровнем накопления жира в печени и в запасающих жир клетках.
14. Мышь по п.13, которая, кроме того, имеет фенотип, характеризующийся потреблением большего количества калорий, чем мышь дикого типа, но меньшим накоплением жира, чем мышь дикого типа.
15. Способ скрининга на ингибитор активности изоформы ацетил-КоА-карбоксилазы 2, включающий стадии: введения потенциальных ингибиторов мышам дикого типа и скрининг мышей, которые обладают фенотипом трансгенной мыши по п.14.
16. Ингибитор ацетил-КоА-карбоксилазы 2, идентифицированный способом по п.15.
17. Фармацевтическая композиция, содержащая ингибитор ацетил-КоА-карбоксилазы 2 по п.16 и фармацевтически приемлемый носитель.
18. Способ получения очищенного препарата белка ацетил-КоА-карбоксилазы 1, который не содержит ацетил-КоА-карбоксилазы 2, где указанный способ включает стадию очистки указанного белка ацетил-КоА-карбоксилазы 1 из тканей, полученных от трансгенной мыши по п.7.
19. Способ получения мышиных антител против ацетил-КоА-карбоксилазы 2, обладающих пониженной перекрестной реактивностью с ацетил-КоА-карбоксилазой 1 и с другими мышиными белками, где указанный способ включает стадию вырабатывания указанных антител у трансгенной мыши по п.7.
20. Клеточная линия, происходящая от трансгенной мыши по п.7.
21. Клеточная линия по п.20, происходящая от клеток, выбранных из группы, состоящей из клеток мышц, клеток сердца, жировых клеток и клеток печени.
22. Способ скрининга для выявления агонистов и антагонистов АСС2, включающий стадии введения соединения-кандидата в клеточную линию по п.20 и в клеточные линии, происходящие от мышей дикого типа, и мониторинга указанных клеточных линий на изменение клеточной активности, где соединение, которое специфически воздействует на АСС2, будет изменять клеточную активность в клетках дикого типа, но не будет оказывать влияние на клеточную линию по п.20.
23. Способ по п.22, где подвергаемые мониторингу клеточные активности выбраны из группы, состоящей из таких активностей, как экспрессия мРНК, экспрессия белка, секреция белка и липидный обмен.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| US09/749,109 US6548738B2 (en) | 2000-12-26 | 2000-12-26 | ACC2-knockout mice and uses thereof |
| US09/749,109 | 2000-12-26 | ||
| US09/929,575 US6734337B2 (en) | 2000-12-26 | 2001-08-14 | Acetyl-coenzyme A carboxylase 2 as a target in the regulation of fat burning, fat accumulation, energy homeostasis and insulin action |
| US09/929,575 | 2001-08-14 |
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| RU2003123109A true RU2003123109A (ru) | 2005-01-20 |
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| RU2003123109/15A RU2003123109A (ru) | 2000-12-26 | 2001-12-26 | Ацетил-кофермент а-карбоксилаза 2 как мишень для регуляции сжигания жира, накопления жира, энергетичесеого гомеостаза и действия инсулина |
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| JP (1) | JP2004523225A (ru) |
| CN (1) | CN1809750A (ru) |
| CA (1) | CA2432415A1 (ru) |
| IL (1) | IL156625A0 (ru) |
| NZ (1) | NZ526581A (ru) |
| RU (1) | RU2003123109A (ru) |
| WO (1) | WO2002051355A2 (ru) |
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| JP2005089384A (ja) * | 2003-09-18 | 2005-04-07 | Kao Corp | 持久力向上剤 |
| CA2641734A1 (en) | 2006-02-15 | 2007-08-23 | Abbott Laboratories | Acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome |
| EP1996567B1 (en) | 2006-02-15 | 2013-09-18 | AbbVie Inc. | Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome |
| CA2641766A1 (en) | 2006-02-15 | 2007-08-23 | Abbott Laboratories | Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome |
| US8389207B2 (en) | 2006-06-08 | 2013-03-05 | Salk Institute For Biological Studies | Methods for identifying candidate fat-mobilizing agents |
| US20120010285A1 (en) * | 2009-03-18 | 2012-01-12 | Kao Corporation | Agent for promoting energy consumption |
| MX2022014553A (es) * | 2020-05-21 | 2022-12-15 | Shionogi & Co | Composicion farmaceutica para tratar enfermedad de higado graso. |
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| DE69434939T2 (de) * | 1993-05-21 | 2007-11-29 | Astrazeneca Ab | Nukleinsäure für die AMP - aktivierte Proteinkinase |
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- 2001-12-26 EP EP01991510A patent/EP1356276A4/en not_active Withdrawn
- 2001-12-26 WO PCT/US2001/049910 patent/WO2002051355A2/en not_active Application Discontinuation
- 2001-12-26 IL IL15662501A patent/IL156625A0/xx unknown
- 2001-12-26 CA CA002432415A patent/CA2432415A1/en not_active Abandoned
- 2001-12-26 RU RU2003123109/15A patent/RU2003123109A/ru not_active Application Discontinuation
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- 2001-12-26 JP JP2002552503A patent/JP2004523225A/ja active Pending
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Also Published As
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|---|---|
| WO2002051355A2 (en) | 2002-07-04 |
| EP1356276A2 (en) | 2003-10-29 |
| JP2004523225A (ja) | 2004-08-05 |
| NZ526581A (en) | 2004-12-24 |
| US20040204338A1 (en) | 2004-10-14 |
| CN1809750A (zh) | 2006-07-26 |
| CA2432415A1 (en) | 2002-07-04 |
| EP1356276A4 (en) | 2005-02-02 |
| IL156625A0 (en) | 2004-01-04 |
| WO2002051355A3 (en) | 2003-01-30 |
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