Linking partial and non-agonist induced dynamics to PPAR gamma functions

将部分和非激动剂诱导的动力学与 PPAR gamma 函数联系起来

基本信息

批准号：
8457348
负责人：
Travis Shane Hughes
金额：
$ 5.39万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8457348
关键词：
Adverse effects Affinity Agonist American Antidiabetic Drugs Atherosclerosis Autoimmune Diseases Binding Binding Sites Blood Glucose Complex Complications of Diabetes Mellitus DNA DNA Binding Data Deuterium Development Diabetes Mellitus Drug Prescriptions Drug usage Edema Estrogen Receptors Fracture Genes Glucocorticoid Receptor Glyburide-metformin Goals Heart Diseases Heart failure Heterodimerization Hydrogen Inflammation Insulin Knowledge Life Ligand Binding Ligands Link Location Maintenance Maps Mass Spectrum Analysis Molecular Conformation Movement Nuclear Receptors PPAR gamma Partner in relationship Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phosphorylation Pioglitazone Progesterone Receptors Protein Dynamics Proteins Proxy Publishing RXR Receptor Activation Solutions Stroke Structure Surface Testing Time Vitamin D3 Receptor Weight Gain Woman Work design diabetic drug development functional outcomes improved in vivo insulin sensitizing drugs next generation novel pre-clinical prevent rosiglitazone stoichiometry transcription factor

项目摘要

DESCRIPTION (provided by applicant): The currently prescribed insulin sensitizing drugs, (the full agonists rosiglitazone and pioglitazone), bind to peroxisome proliferators-activated receptor PPAR, a transcription factor) and improve maintenance of normal blood sugar levels, which helps prevent the long-term complications of diabetes, including heart disease and stroke for many of the 25 million diabetic Americans. The anti-diabetic effects of PPAR binding drugs are more durable (prevent diabetes progression for a longer time) and more effective than other drugs such as metformin and glyburide making PPA interacting drugs a valuable treatment for diabetes. However use of these drugs is limited because they cause increased bone fracture in women, weight gain, heart failure and edema. Effective PPAR targeted anti-diabetics with less unwanted effects are needed. PPAR is a transcription factor that interacts with many other proteins to carry out its effects, it interacts with these other proteins on its surface. Many of these interactions depend on a particular ligand being present in the large and hydrophobic PPAR ligand binding pocket. Somehow, binding of ligand changes the structure and/or dynamics of PPAR's interacting surfaces to favor or disfavor interaction with these partners (i.e. co regulators and heterodimerization partner, retinoid X receptor, RXR). This unique ligand induced (or ligand free) PPAR/partner complex increases or decreases the expression of many genes which leads to ligand specific in vivo effects. PPAR crystal structures bound to many different kinds of ligands, both alone and mated with RXR, co regulator proteins and DNA are very similar and do not explain the functional differences observed for different classes of PPAR ligands. We hypothesize that adding movement information to these crystal structures will help correlate PPAR regions and movements with in vivo effects of the distinct classes of PPAR ligands. This correlation map could then be used to drive more effective PPAR drug development. We have evidence that different ligand classes (full, partial and non agonists) can indeed be differentiated by the dynamics they induce. We have found that a PPAR binding non-agonist and two partial agonists all bind PPAR in at least two distinct orientations, while the ful agonist does not. Furthermore our PPAR movement data suggest a novel mechanism for partial agonism in PPAR. Connection of PPAR structure and movement to functional effects will help improve design of novel PPAR drugs with better separation of unwanted effects (e.g. heart failure) from wanted effects (i.e. anti-diabetic efficacy, anti-inflammation). This will improve diabetes treatment and open up possibilities for PPAR targeted therapies for atherosclerosis and autoimmune disorders. PUBLIC HEALTH RELEVANCE: Current insulin sensitizing drugs bind PPAR changing its primary conformation and its internal movements, which helps treat diabetes but also causes weight gain and heart failure. Our proposal will determine how PPAR conformations and internal movements change as it interacts with ligands and how these changes contribute to PPAR functions. This will add essential information that will allow development of effective PPAR modulators with less side effects than currently prescribed drugs.

描述（由申请人提供）：当前处方的胰岛素敏化药物（全部激动剂罗马列酮和吡格列酮）与过氧化物酶体增殖物激活受体PPAR的结合，转录因子，转录因子），并改善了正常血糖水平的维持，这有助于预防糖尿病的长期疾病，包括糖尿病和糖尿病的长期疾病，包括许多糖尿病，以获得许多25 corloke，这是25 corloke the 25 corper the 25 corper the 25 corper the 25 corloke。 PPAR结合药物的抗糖尿病作用更耐用（预防糖尿病的进展更长的时间），并且比其他药物（例如二甲甲曲蛋白和格列本叶植物）更有效，使PPA相互作用的药物成为对糖尿病的有价值治疗方法。但是，这些药物的使用受到限制，因为它们会导致女性骨折，体重增加，心力衰竭和水肿。需要有效的PPAR针对性抗糖尿病患者，其影响较小。 PPAR是一种与许多其他蛋白质相互作用以执行其作用的转录因子，它与表面上的这些其他蛋白质相互作用。这些相互作用中的许多相互作用取决于在大的和疏水的PPAR配体结合袋中存在的特定配体。某种程度上，配体的结合改变了PPAR相互作用表面的结构和/或动力学，以偏爱或不利于与这些伴侣的相互作用（即CO调节剂和异二聚体伴侣，类维生素类X受体，RXR）。这种独特的配体诱导的（或不含配体）PPAR/伴侣复合物增加或降低了许多基因的表达，从而导致体内效应的配体特异性。 PPAR晶体结构与许多不同种类的配体结合，无论是单独和与RXR，CO调节蛋白和DNA配合的配体非常相似，并且无法解释对不同类别的PPAR配体观察到的功能差异。我们假设在这些晶体结构中添加运动信息将有助于将PPAR区域和运动与不同类别的PPAR配体的体内效应相关联。然后可以使用此相关图来推动更有效的PPAR药物开发。我们有证据表明，不同的配体类（完全，部分和非激动剂）确实可以通过它们引起的动态来区分。我们发现，PPAR结合的非激动剂和两个部分激动剂都在至少两个不同的方向上结合了PPAR，而Ful激动剂则没有。此外，我们的PPAR运动数据表明了PPAR中部分激动剂的新型机制。 PPAR结构和运动与功能效应的连接将有助于改善新型PPAR药物的设计，并更好地将不良效应（例如心力衰竭）与通缉效应（即抗糖尿病功效，抗炎）分离。这将改善糖尿病治疗，并为PPAR针对性疾病和自身免疫性疾病的PPAR靶向疗法提供可能性。公共卫生相关性：当前的胰岛素敏化药物结合PPAR改变其主要构象和内部运动，这有助于治疗糖尿病，但也会导致体重增加和心力衰竭。我们的建议将决定PPAR构象和内部运动与配体相互作用以及这些变化如何促进PPAR功能时的变化。这将添加基本信息，从而允许开发有效的PPAR调节剂，其副作用比当前处方药更少。