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

• 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
• 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

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）：目前处方的胰岛素增敏药物（完全激动剂罗格列酮和吡格列酮）与过氧化物酶体增殖物激活受体（一种转录因子）结合，并改善正常血糖水平的维持，这有助于预防糖尿病的长期并发症，包括2500万美国糖尿病患者中的许多人的心脏病和中风。PPAR结合药物的抗糖尿病作用比其他药物如二甲双胍和格列本脲更持久（更长时间地防止糖尿病进展）和更有效，使得PPA相互作用药物成为糖尿病的有价值的治疗。然而，这些药物的使用是有限的，因为它们会导致女性骨折增加，体重增加，心力衰竭和水肿。需要有效的靶向PPAR的抗糖尿病药物，其具有较少的不希望的作用。PPAR是一种转录因子，它与许多其他蛋白质相互作用以发挥其作用，它与其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依赖于存在于大的疏水性PPAR配体结合口袋中的特定配体。不知何故，配体的结合改变了PPAR相互作用表面的结构和/或动力学，以有利于或不利于与这些配偶体（即共调节剂和异源二聚化配偶体，类维生素A X受体，RXR）的相互作用。这种独特的配体诱导的（或无配体的）PPAR/配偶体复合物增加或减少许多基因的表达，这导致配体特异性体内效应。与许多不同种类的配体结合的PPAR晶体结构，无论是单独的还是与RXR、共调节蛋白和DNA结合的，都非常相似，并且不能解释观察到的不同种类的PPAR配体的功能差异。我们假设，这些晶体结构的运动信息将有助于相关的过氧化物酶体增殖物激活受体的区域和运动与体内不同类别的过氧化物酶体增殖物激活受体配体的影响。然后，这种相关性图可以用于推动更有效的PPAR药物开发。我们有证据表明，不同的配体类别（完全，部分和非激动剂）确实可以区分它们诱导的动力学。我们已经发现，一种结合PPAR的非激动剂和两种部分激动剂都以至少两种不同的方向结合PPAR，而完全激动剂则不结合。此外，我们的过氧化物酶体增殖物激活受体的运动数据提出了一种新的机制，部分激动过氧化物酶体增殖物激活受体。将PPAR结构和运动与功能效应联系起来将有助于改进新型PPAR药物的设计，更好地将不需要的效应（例如心力衰竭）与想要的效应（即抗糖尿病功效、抗炎）分开。这将改善糖尿病治疗，并为动脉粥样硬化和自身免疫性疾病的PPAR靶向治疗开辟可能性。 公共卫生相关性：目前的胰岛素增敏药物结合PPAR，改变其初级构象和内部运动，这有助于治疗糖尿病，但也会导致体重增加和心力衰竭。我们的建议将确定如何PPAR构象和内部运动的变化，因为它与配体相互作用，以及这些变化如何有助于PPAR功能。这将增加必要的信息，使开发有效的PPAR调节剂，副作用比目前处方药少。