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

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，美国受糖尿病影响的总人数预计会增加，并导致医疗费用大幅上升。PPARG是一种配体调节的核受体转录因子，也是胰岛素增敏药物的有效分子靶点。由于严重的副作用，包括骨质丢失、液体滞留和充血性心力衰竭，安全性问题严重限制了PPARG靶向药物的临床使用。最近的工作导致了一种理解，即配体不同地影响PPARG用来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，靶向稳定一种表面而不是另一种表面，可以开发出新一代与PPARG结合的抗糖尿病药物，而且副作用更少。目前推动PPARG药物开发的一个核心原则是，合成配体与包括脂肪酸和脂类在内的天然内源性配体竞争，与位于配体结合结构域核心的规范配体结合口袋结合，从药理上调节PPARG活性。我们的初步工作表明，许多设计用于与PPARG中的正则配体结合口袋结合的合成配体也可以结合到另一个结合位点。如果研究表明它增强了抗糖尿病疗效，详细说明这种替代结合STE的结构和功能可能会促进针对该位点的更有效药物的开发，或者如果它导致副作用，则限制与该位点的结合。利用多学科方法，结合结构和化学生物学以及生化和细胞分析，我们将表征交替位点配体结合对PPARG结构、功能和与抗糖尿病疗效和副作用相关的细胞结果的影响。这些研究的结果将提供第一个结构和功能上的理解替代位点配体结合PPARG。这些发现将扩大对PPARG功能和配体对PPARG活性调节的一般理解。这一知识可能导致开发具有更少不良副作用的改进的抗糖尿病PPARG靶向药物。

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.