Structure and Function of Alternate-Site Binding of Anti-Diabetic PPARG Ligands

抗糖尿病 PPARG 配体的交替位点结合的结构和功能

• 批准号: 9198540
• 负责人: Douglas Kojetin
• 金额: $ 42.72万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198540
• 关键词: Adverse effects; Affect; Antidiabetic Drugs; Area; Automobile Driving; Binding; Binding Sites; Biochemical; Biological Assay; Biology; Blood Glucose; Cell model; Cellular Assay; Chemicals; Clinical; Congestive Heart Failure; Crystallography; Deuterium; Development; Diabetes Mellitus; Disease; Drug Targeting; Edema; Fatty Acids; Fracture; Gene Expression; Generations; Healthcare; Hydrogen; Knowledge; Lead; Ligand Binding; Ligand Binding Domain; Ligands; Link; Lipid Binding; Liquid substance; Literature; Maintenance; Mass Spectrum Analysis; Medical; Molecular; Molecular Conformation; Molecular Target; Mutagenesis; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Outcome; Outcome Study; Overweight; PPARG gene; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Regulation; Role; Safety; Site; Specificity; Structure; Structure-Activity Relationship; Surface; Testing; United States; Weight Gain; Work; bone loss; cost; design; diabetic; drug development; improved; insulin sensitizing drugs; interdisciplinary approach; public health relevance; scaffold; structural biology; transcription factor

DESCRIPTION (provided by applicant): Diabetes represents a major healthcare problem for the United States. With more people becoming overweight or obese each year, the total number of people affected by diabetes in the United States is expected to increase and result in significantly higher medical costs. PPARG is a ligand-regulated nuclear receptor transcription factor and a validated molecular target for insulin sensitizing drugs. Safety concerns have severely restricted clinical use of PPARG-targeted drugs due to serious side effects, including loss of bone, fluid retention and congestive heart failure. Recent work has led to an understanding that ligands differentially affect the structural conformation of two distinct surfaces used by PPARG to interact with different functional interaction partners. It is thought that targeted stabilization of one surface over another can lead to the development of a new generation of PPARG-binding anti-diabetic drugs with fewer unwanted side effects. A central tenet driving current PPARG drug development is that synthetic ligands compete with natural endogenous ligands, including fatty acids and lipids, for binding to a canonical ligand-binding pocket in the core of the ligand-binding domain to pharmacologically regulate PPARG activity. Our preliminary work shows that many synthetic ligands that were designed to bind to the canonical ligand-binding pocket in PPARG can also bind to an alternate binding site. Detailing the structure and function of this alternate binding ste could improve development of more potent drugs that target this site if studies indicate it enhances anti-diabetic efficacy, or limit binding to this site if it contributes to side effects. Uing a multidisciplinary approach, combining structural and chemical biology with biochemical and cellular assays, we will characterize the effects of alternate-site ligand binding on PPARG structure, function and cellular outcomes associated with anti-diabetic efficacy and side effects. Outcomes from these studies will provide the first structural and functional understanding of alternate-site ligand binding to PPARG. These findings will expand the general understanding of PPARG function and regulation of PPARG activity by ligands. This knowledge could lead to the development of improved anti-diabetic PPARG-targeted drugs with fewer unwanted side effects.

描述（由申请人提供）： 糖尿病是美国的一个主要医疗问题。随着每年越来越多的人超重或肥胖，在美国受糖尿病影响的人数预计将增加，并导致医疗费用明显更高。 PPARG是配体调节的核受体转录因子，也是胰岛素敏化药物的经过验证的分子靶标。由于严重的副作用，包括骨骼损失，液体保留和充血性心力衰竭，安全问题严重限制了靶向PPARG靶向药物的临床使用。最近的工作导致人们的理解是，配体会差异地影响PPARG与不同功能相互作用伙伴相互作用的两个不同表面的结构构象。人们认为，一个表面靶向稳定在另一个表面上会导致新一代的PPARG结合抗糖尿病药物的发展，而副作用较少。驱动当前PPARG药物开发的中心宗旨是，合成配体与包括脂肪酸和脂质在内的天然内源配体竞争，以与配体结合结构域核心的规范配体结合口袋结合到药理学调节PPARG活性。我们的初步工作表明，许多旨在与PPARG中的规范配体结合口袋结合的合成配体也可以与替代结合位点结合。详细说明该替代结合的结构和功能可以改善针对该部位的更有效药物的开发，如果研究表明它会提高抗糖尿病的功效，或者如果副作用有助于该部位，则可以限制与该部位的结合。我们将采用多学科方法，将结构和化学生物学与生化和细胞测定法相结合，我们将表征与抗糖尿病功效和副作用相关的PPARG结构，功能和细胞结构的替代位置配体结合的影响。这些研究的结果将提供对替代位点配体与PPARG结合的第一个结构和功能理解。这些发现将扩大对PPARG功能的一般理解和配体对PPARG活性的调节。这些知识可能会导致改善抗糖尿病PPARG靶向药物的发展，而副作用较少。