Novel Modulators of LDL Metabolism
低密度脂蛋白代谢的新型调节剂
基本信息
- 批准号:7822161
- 负责人:
- 金额:$ 1.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-06-01 至 2009-10-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdverse effectsAreaBindingBiochemicalBiologicalBiological AssayBloodCardiovascular DiseasesCardiovascular systemCatalytic DomainCause of DeathCell surfaceCellsCessation of lifeCharacteristicsCholesterolCholesterol HomeostasisClinical DataCodeComplexComputer SimulationComputersCoronary ArteriosclerosisDataDatabasesDegradation PathwayDevelopmentDockingDrug CompoundingEducationEndoplasmic ReticulumEnsureEnzyme PrecursorsEnzymesEpidermal Growth FactorEventFamilial HypercholesterolemiaFoundationsGenesGeneticGoalsHeart DiseasesIndividualInterventionIntestinal AbsorptionLDL Cholesterol LipoproteinsLeadLinkLipidsLiverLow Density Lipoprotein ReceptorLow-Density LipoproteinsMediatingMetabolismMethodsMolecularMorbidity - disease rateMusMutationNonsense MutationPatientsPeptide HydrolasesPharmaceutical PreparationsPharmacotherapyPhasePlasmaPopulationProcessPropertyProprotein ConvertasesProteinsRegulationResolutionRiskRisk FactorsScreening procedureSequence AnalysisSerine ProteaseSingle Nucleotide PolymorphismSiteStructureSubtilisin Like Proprotein ConvertasesSubtilisinsSurfaceTestingWomanWorkZinc Compoundsbasecost effectivedrug marketexperienceextracellulargain of functionhigh riskhypercholesterolemiain vitro Assaykexinlipid disorderloss of functionloss of function mutationmeetingsmenmortalitynovelprematurepreventprogramspublic health relevancetherapeutic targetthree dimensional structuretraffickingvirtual
项目摘要
DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs achieve the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel drugs for cholesterol lowering. Our therapeutic target is the interface between the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) and the low density lipoprotein receptor (LDLR), where we propose to identify and develop compounds that prevent PCSK9 from binding to the LDLR. PCSK9 regulates the degradation of the LDLR in the liver by binding to LDLR on the cell surface, and thereby contributes to cholesterol homeostasis. PCSK9 is made as a zymogen that requires autocatalytic processing for proper secretion; the secreted enzyme is known to bind to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Our attempts to interfere with the interface between PCSK9 and the LDLR will be facilitated by the availability of the crystal structure of the PCSK9/LDLR-EGF-A complex. To achieve our goal, we will integrate virtual (computer) screening methods and in vitro assays to identify lead compounds that can potentially be optimized to produce cholesterol lowering drugs. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen million of compounds to identify a small set to be purchased and tested in a biological, biophysical or biochemical assay. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind to PCSK9 and block its binding to the LDLR. 2. Use in vitro assays to confirm the ability of the selected compounds to bind to PCSK9 and prevent its binding to the LDLR. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a segment of the population with very high cholesterol. Our goal is to develop new cholesterol lowering drugs that have an effect on all individuals with high cholesterol levels, including that segment of the population having very high cholesterol levels.
描述(由申请人提供):心脏病是美国男性和女性的主要死亡原因,占所有年死亡的近40%。高胆固醇水平是心脏病的众所周知的危险因素。尽管可以使用多种销售药物降低血液胆固醇,其中他汀类药物是主要药物,但服用这些药物的患者中只有38%实现了由国家胆固醇教育计划(NCEP)设定的低密度脂蛋白胆固醇目标。此外,纯合性家族高胆固醇血症的患者对当前药物治疗的反应较差,并且患心血管早熟的风险很高。这些和其他患者将受益于高胆固醇血症的积极治疗。这项工作的长期目标是开发降低胆固醇的新药物。我们的治疗靶标是蛋白酶前蛋白转化酶枯草蛋白样的KEXIN类型9(PCSK9)与低密度脂蛋白受体(LDLR)之间的接口,我们建议在其中识别和开发防止PCSK9与LDLR结合的化合物。 PCSK9通过与细胞表面上的LDLR结合,从而调节LDLR在肝脏中的降解,从而导致胆固醇稳态。 PCSK9是一种Zymogen,需要进行自催化处理以进行适当的分泌。已知分泌的酶与LDLR的表皮生长因子样重复A(EGF-A)结构结合。我们试图通过PCSK9/LDLR-EGF-A复合物的晶体结构的可用性来促进PCSK9和LDLR之间的接口。为了实现我们的目标,我们将整合虚拟(计算机)筛选方法和体外测定法,以识别有可能优化以生产胆固醇降低药物的铅化合物。虚拟筛选需要靶蛋白的原子分辨率3D结构的可用性,它为筛选百万种化合物的成本有效方法提供了识别要在生物,生物物理或生化测定中购买和测试的小型集合。这项工作的具体目的是:1。使用虚拟筛选方法识别与PCSK9结合并阻止其与LDLR结合的化合物。 2。使用体外测定法确认所选化合物与PCSK9结合并防止其与LDLR结合的能力。公共卫生相关性:心脏病是美国男女死亡的主要原因。高胆固醇水平是心脏病的众所周知的危险因素。尽管可以使用多种销售药物来降低血液胆固醇,但这些药物并不能以非常高的胆固醇治疗一部分人群。我们的目标是开发新的胆固醇降低药物,这些药物对所有胆固醇水平较高的人都有影响,包括胆固醇水平很高的人群。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(4)
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Nabil A Elshourbagy其他文献
Nabil A Elshourbagy的其他文献
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Oral PCSK9/LDLR antagonist direction to the clinic
口服 PCSK9/LDLR 拮抗剂临床指导
- 批准号:
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- 资助金额:
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$ 1.75万 - 项目类别:
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