Structural definition of biased agonism in the nuclear receptor PPAR gamma.

核受体 PPAR γ 偏向激动的结构定义。

• 批准号: 10667641
• 负责人: Travis Shane Hughes
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667641
• 关键词: Acute; Adipocytes; Adverse effects; Affect; Affinity; Agonist; Animals; Autoimmune Diseases; Automobile Driving; Binding; Cells; Characteristics; Clinic; Complex; Crystallography; Data; Deuterium; Development; Disease; Drug Prescriptions; Drug Receptors; Drug Targeting; Dyslipidemias; Encyclopedias; Evaluation; Family; Fluorescence Anisotropy; Fluorine; Fracture; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Heart failure; Human; Hydrogen; Investments; Knowledge; Lead; Ligands; Mass Spectrum Analysis; Measures; Mediating; Metabolic syndrome; Molecular; Mus; Mutagenesis; N-terminal; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Nuclear Receptors; Outcome; PPAR gamma; Pathway Analysis; Peptides; Pharmaceutical Preparations; Physiological; Proteins; Publishing; Reporting; Sales; Series; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Weight Gain; Work; antagonist; bone; chronic liver disease; clinically relevant; design; drug development; drug discovery; fracture risk; improved; improved outcome; molecular dynamics; novel; programs; receptor; receptor structure function; recruit; transcription factor; transcriptome sequencing

About 1 out of 6 prescription drugs produce therapeutic effects by binding to a family of transcription factors called nuclear receptors. Such nuclear receptor drugs often provide the best treatment option for many diseases; however, they also cause serious adverse effects. For example, agonists known as thiazolidinediones (TZDs) activate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) and are arguably the best treatment for type II diabetes; however, they cause weight gain and weak bones. Some PPARγ partial agonists produce fewer adverse effects but the same beneficial effects in mice compared to TZDs. While this new class of agonists is promising, they have not reached the clinic. A lack of understanding of how they produce different effects from TZDs impedes their development into drugs to treat type II diabetes and other diseases. We propose that such partial agonists are “biased agonists”. Like TZDs, a biased agonist would bind to and activate PPARγ; however, they would produce different effects by activating the receptor differently from TZDs. How biased agonists could activate the receptor differently is not known. We know that agonists produce effects by recruiting other proteins, known as coactivators, to PPARγ. The best-supported mechanism of biased agonism in nuclear receptors is that they induce what we term “coactivator bias”. Coactivator bias refers to the ability of an agonist to bias interaction of PPARγ toward certain coactivators or away from others relative to TZDs. It is well-documented that some agonists induce coactivator bias; however, such bias has never been well-quantified and the mechanism underlying bias is unknown. This lack of mechanistic understanding limits enthusiasm for and the ability to carry out further development of biased PPARγ agonists. This proposal will quantify and compare coactivator bias for a panel of agonists and measure the acute effects of those same agonists on cells. This will help determine how coactivator bias affects PPARγ signaling pathways. Comparison of bias with the published physiologic effects of these agonists may correlate bias with physiologic effects, including the desired and undesired effects of type II diabetes drugs. This proposal will also test structural mechanisms of coactivator bias. Our preliminary data show that there are two distinct structural classes of coactivators and suggest a clear mechanism by which biased agonists favor binding of one class. Completion of the aims of this proposal will define, in atomic detail, mechanisms of biased agonism in PPARγ. Such knowledge is critical to further development of drugs that produce less adverse effects, but maintain the powerful and unique beneficial effects of TZDs. Because PPARγ is structurally similar to other nuclear receptors, the knowledge gained in this proposal will impact biased drug development for other nuclear receptors.

大约六分之一的处方药通过与转录因子家族结合产生治疗效果 称为核受体的药物通常为许多人提供最佳的治疗选择。 疾病；然而，它们也会引起严重的副作用，例如，称为激动剂。 噻唑烷二酮类 (TZD) 激活核受体过氧化物酶体增殖物激活受体 γ (PPARγ) 可以说是治疗 II 型糖尿病的最佳方法；然而，它们会导致体重增加和骨骼脆弱。 一些 PPARγ 部分激动剂对小鼠产生较少的副作用，但产生相同的有益效果 与 TZD 相比，虽然这类新型激动剂很有前景，但尚未进入临床。 了解它们如何产生与 TZD 不同的作用会阻碍它们开发成治疗药物 II型糖尿病和其他疾病。 我们认为这种部分激动剂是“偏向激动剂”，就像 TZD 一样，偏向激动剂会与 TZD 结合。 并激活PPARγ；然而，它们通过不同方式激活受体而产生不同的效果； TZDs。偏向激动剂如何以不同的方式激活受体尚不清楚。 我们知道激动剂通过招募其他蛋白质（称为共激活剂）到 PPARγ 来产生作用。 核受体中偏向激动的最受支持的机制是它们诱导我们所说的 “共激活剂偏向”是指激动剂使 PPARγ 的相互作用偏向某些方向的能力。 有充分证据表明，某些激动剂可诱导共激活剂。 偏见；然而，这种偏见从未被充分量化，并且偏见背后的机制尚不清楚。 缺乏机械理解限制了进一步开发的热情和能力 偏向 PPARγ 激动剂。 该提案将量化和比较一组激动剂的共激活剂偏差，并测量急性 这些相同的激动剂对细胞的影响这将有助于确定共激活剂偏向如何影响 PPARγ 信号传导。 偏差与这些激动剂已发表的生理效应的比较可能会将偏差与相关联。 生理作用，包括 II 型糖尿病药物的预期和非预期作用。 该提案还将测试共激活剂偏差的结构机制。我们的初步数据表明： 共激活剂有两种不同的结构类别，并提出了一种明确的机制，通过该机制可以产生偏向性 激动剂倾向于结合一类。完成该提案的目标将在原子细节上定义： PPARγ 偏向激动机制的这些知识对于进一步开发药物至关重要。 产生较少的副作用，但保持 TZD 强大而独特的有益作用。 PPARγ在结构上与其他核受体相似，本提案中获得的知识将影响 针对其他核受体的偏向药物开发。