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保健问题。随着每年越来越多的人变得超重或肥胖，美国受糖尿病影响的总人数预计将增加，并导致医疗费用显着增加。PPARG是一种配体调节的核受体转录因子，是胰岛素增敏药物的有效分子靶点。安全性问题严重限制了PPARG靶向药物的临床使用，因为它有严重的副作用，包括骨质流失、液体潴留和充血性心力衰竭。最近的工作已经导致了一种理解，即配体差异地影响PPARG与不同的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，一个表面相对于另一个表面的靶向稳定化可以导致新一代PPARG结合抗糖尿病药物的开发，其副作用更少。驱动当前PPARG药物开发的中心原则是合成配体与天然内源性配体（包括脂肪酸和脂质）竞争结合到配体结合结构域的核心中的典型配体结合口袋，以间接调节PPARG活性。我们的初步工作表明，许多合成的配体，被设计为结合到典型的配体结合口袋PPARG也可以结合到一个替代的结合位点。详细说明这种替代结合位点的结构和功能可以改善靶向该位点的更有效药物的开发，如果研究表明它增强抗糖尿病功效，或者如果它有助于副作用，则限制与该位点的结合。使用多学科的方法，结合结构和化学生物学与生物化学和细胞检测，我们将表征交替位点配体结合对PPARG结构，功能和细胞结果与抗糖尿病疗效和副作用的影响。这些研究的结果将提供第一个结构和功能的了解替代网站配体结合PPARG。这些发现将扩大PPARG功能和PPARG活性的配体调节的一般理解。这些知识可能会导致开发出更好的抗糖尿病PPARG靶向药物，减少不必要的副作用。

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.