Identification of Apj receptor agonists and antagonists

Apj 受体激动剂和拮抗剂的鉴定

• 批准号: 2110706
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2110706
• 关键词: Identification; Apj; receptor; agonists; antagonists

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.

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。在全世界范围内，PAH病例每年在100- 200 k之间。目前还没有治疗PAH的好药。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。有强有力的公开证据表明爱帕琳受体激动剂将提供疾病治疗。具体来说，我们将有兴趣在所谓的'偏'受体激动剂的发展。已发表的数据表明，偏向性激动剂将产生治疗效果，而没有毒副作用。目的：使用分子建模、生物筛选和药物化学鉴定apelin受体激动剂。优化激动剂，使其具有与口服药物一致的特性。通过分子建模和化学合成研究受体偏好在了解激动剂对受体作用方面的重要性。鉴定和优化apelin受体拮抗剂。该项目高度交叉学科，将涉及许多领域的技能发展，包括合成化学、与PAH治疗相关的分子建模和生物学筛选。首先，将研究已发表的爱帕琳受体激动剂，以开发用于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，还没有发表的激动剂显示出受体偏倚。我们的目的是通过分子建模来了解偏倚的起源，以指导第一种受体偏倚激动剂的设计。该项目的一个重要目标将是优化所谓的“药物样”特性的新激动剂。激动剂将通过药物化学方法进行优化，使用多轮合成化学和生物筛选，以改善与“药物样”化合物一致的效力，选择性和性质。将在剑桥大学合作者实验室提供的PAH大鼠模型中评估选定激动剂的有效性。目的是确定一种有效的和选择性的偏向激动剂，有可能发展成为一种治疗。将通过使用诱变研究（一种允许分析受体特定区域对产生偏倚的重要性的技术）研究受体偏倚的起源。了解受体偏好的起源将使我们能够开发更有效和更有选择性（毒性更小）的激动剂。