Identification of Apj receptor agonists and antagonists

肺动脉高压(PAH)是一种危及生命的血压升高，可导致心力衰竭。在世界范围内，多环芳烃的病例每年在100-20万例之间。目前还没有治疗PAH的良药。因此，需要新的治疗方法。apelin受体是治疗PAH的一个有前途的新靶点。有强有力的已发表的证据表明，APELIN受体激动剂可以提供疾病治疗。具体地说，我们对开发一种所谓的“有偏向的”受体激动剂感兴趣。已发表的数据表明，偏向激动剂将产生没有毒副作用的治疗效果。目标：利用分子建模、生物筛选和药物化学来鉴定apelin受体激动剂。优化激动剂的性质与口服药物的性质一致。通过分子建模和化学合成研究受体偏向在了解激动剂在受体上的作用的重要性。识别和优化apelin受体的拮抗剂。该项目是高度交叉的，将涉及多个领域的技能发展，包括合成化学、分子建模和与治疗PAH相关的生物筛选。最初，将对已发表的apelin受体激动剂进行研究，以开发一个预测激动剂与受体结合的计算模型。该模型将用于指导新的激动剂的设计。到目前为止，还没有已发表的激动剂显示出受体偏向。我们的目的将是通过分子建模来了解偏倚的起源，以指导第一个受体偏向激动剂的设计。该项目的一个重要目标是优化新的激动剂，使其具有所谓的“类药物”特性。激动剂将通过药物化学方法进行优化，使用几轮合成化学和生物筛选来提高效力、选择性和与“类药物”化合物一致的性能。选定的激动剂将在剑桥大学合作者实验室提供的PAH大鼠模型中进行有效性评估。其目的是确定一种有效的、选择性的有偏向的激动剂，具有发展成为治疗性药物的潜力。受体偏倚的来源将通过突变研究(一种技术，应允许分析特定区域的受体对授予偏向的重要性)来调查。了解受体偏向的来源将使我们能够开发更有效、更具选择性(毒性较低)的激动剂。

Pulmonary arterial hypertension (PAH) is a life-threatening elevation of blood pressure which can lead to heart failure. Across the world, the cases of PAH are in the range of 100-200k per year. There are currently no good medicines for treatment of PAH. Consequently, there is a need for new therapies.The apelin receptor is a promising new target for treatment of PAH. There is strong published evidence that an apelin receptor agonist would offer disease therapy. Specifically, we would be interested in the development of a so-called 'biased' receptor agonist. Published data suggests that a biased agonist would generate a therapeutic effect without toxic side effects.Objectives:Identify an apelin receptor agonist using molecular modelling, biological screening & medicinal chemistry.Optimise the agonist for properties consistent with an orally delivered drug.Investigate through molecular modelling and chemical synthesis the importance of receptor bias in understanding the action of the agonist at the receptor.Identify and optimize an antagonist of the apelin receptor.The project is highly cross disciplinary and will involve development of skills in a number of areas, including synthetic chemistry, molecular modelling and biological screening of relevance to treatment of PAH. Initially, the published apelin receptor agonists will be investigated to develop a computational model for prediction of agonist binding to the receptor. The model will be used to guide the design of new agonists. As yet no published agonists have been shown to demonstrate receptor bias. Our intention will be to understand the origin of bias by molecular modelling to guide the design of the first receptor biased agonist. A significant aim of the project will be optimise the new agonists for so-called 'drug-like' properties. Agonists will be optimised by medicinal chemistry approaches using rounds of synthetic chemistry and biological screening for improvement in potency, selectivity and properties consistent with a 'drug-like' compound. Selected agonists will be assessed for effectiveness in rat models for PAH available in a collaborator's lab at the University of Cambridge. The intention is to identify a potent and selective biased agonist with potential for development into a therapeutic. The origin of receptor bias will be investigated by use of mutagenesis studies (a technique which should allow for analysis of the importance of specific areas of the receptor for conferring bias). Understanding the origin of receptor bias will allow us to develop more potent and more selective (less toxic) agonists.