Allostery-driven G protein selectivity in the adenosine A1 receptor

腺苷 A1 受体中变构驱动的 G 蛋白选择性

• 批准号: BB/W016974/1
• 负责人: Christopher Reynolds
• 金额: $ 50.72万
• 依托单位: Coventry University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW016974%2F1
• 关键词: Allostery; driven; protein; selectivity; adenosine

Lay SummaryG protein-coupled receptors, GPCRs, are a large family of receptors that are the target for 35% of prescription drugs. Everyday experiences of GPCRs include the anti-allergy effect of anti-histamines binding to the histamine receptor, the increase in the heart rate from caffeine blocking the adenosine receptor and pain relief from morphine binding to the opioid receptor. The adenosine receptor comes in multiple forms, labelled A1, A2A, A2B and A3. We are interested in the adenosine A1 receptor (A1R), which in principle is a target for a number of conditions where new drugs are needed, including glaucoma, type 2 diabetes mellitus, pain, epilepsy and cerebral ischemia. However, many scientists have rejected the adenosine A1R receptor as a drug target because of serious side effects intrinsically linked to the target rather than to any potential drug molecule. The problem arises because when a drug interacts with the A1R, a number of pathways are activated inside the cell, whether this be in the central nervous system (CNS) or in the cardiorespiratory system. The pathways in the CNS may lead to pain relief but the pathways in the cardiorespiratory system slow the heart, reduce blood pressure, and supress respiration; these pathways in the cardiorespiratory system lead to unacceptable side effects, and consequently to a loss in interest in the A1R as a drug target. These desirable and undesirable pathways arise because the A1R is a GPCR that couples to multiple G proteins; some G proteins give rise to favourable outcomes while simultaneously, other G proteins may give rise to unfavourable outcomes. Recently, we discovered, by chance, an agonist molecule called BnOCPA (BnO stands for oxybenzyl, CPA is cyclopentyladenosine), which has totally transformed the landscape with regards to the A1R as a drug target. (An agonist is a molecule that activates the receptor, as opposed to an antagonist, like caffeine, that blocks the receptor.) The BnOCPA agonist has totally shifted the paradigm as it only activates one G protein (Gob), through which it confers pain relief in vivo. It does not activate the very closely related G protein Goa and so there are no cardiovascular side effects. BnOCPA now allows us to propose a rational approach to designing A1R agonists that only activate one G protein. Having discovered BnOCPA by chance, we propose a programme of research aimed at rational design of similar compounds. We propose experimental studies of how BnOCPA and similar molecules interact with the A1R. We propose computational studies of how BnOCPA and related molecules interact with the receptor. We also propose studies of how these receptor/molecule combinations interact, or don't interact, with relevant G proteins. These studies will be supplemented by chemical synthesis of new molecules designed from the results. BnOCPA is a rather large molecule that extends beyond the main A1R binding site into the so called, allosteric binding site, where allosteric modulators can bind to help the natural adenosine agonist. These studies will therefore be guided by studies of agonists in the presence of allosteric modulators in the understanding that parts of the allosteric modulators may influence where the oxybenzyl group of BnOCPA binds and so the agonist/allosteric modulator combination may show similar properties to BnOCPA. The information gathered will be used to design BnOCPA analogues that can interact with only specified G proteins. The principles learned in these studies may open the door to the design of G protein selective agonists for other GPCRs besides the A1R.

Lay SummaryG蛋白偶联受体（gpcr）是一个大的受体家族，是35%的处方药的靶标。GPCRs的日常经验包括抗组胺结合组胺受体的抗过敏作用，咖啡因阻断腺苷受体的心率增加，吗啡结合阿片受体的疼痛缓解。腺苷受体有多种形式，分别标记为A1、A2A、A2B和A3。我们对腺苷A1受体（A1R）感兴趣，原则上，它是许多需要新药的病症的靶标，包括青光眼、2型糖尿病、疼痛、癫痫和脑缺血。然而，许多科学家拒绝将腺苷A1R受体作为药物靶标，因为其严重的副作用与靶标内在相关，而不是与任何潜在的药物分子。问题的出现是因为当药物与A1R相互作用时，细胞内的许多途径被激活，无论是在中枢神经系统（CNS）还是在心肺系统。中枢神经系统的通路可能导致疼痛缓解，但心肺系统的通路减慢心跳，降低血压，抑制呼吸；这些途径在心肺系统中导致不可接受的副作用，并因此失去对A1R作为药物靶点的兴趣。这些理想和不理想的途径之所以出现，是因为A1R是与多个G蛋白偶联的GPCR；一些G蛋白产生有利的结果，而同时，其他G蛋白可能产生不利的结果。最近，我们偶然发现了一种名为BnOCPA的激动剂分子（BnO代表oxybenzyl， CPA代表cyclopentyladenosine），它完全改变了A1R作为药物靶点的格局。（激动剂是一种激活受体的分子，与咖啡因等阻断受体的拮抗剂不同。）BnOCPA激动剂完全改变了这种模式，因为它只激活一种G蛋白（Gob），通过它在体内减轻疼痛。它不会激活密切相关的G蛋白Goa，因此没有心血管副作用。BnOCPA现在允许我们提出一种合理的方法来设计仅激活一种G蛋白的A1R激动剂。偶然发现BnOCPA后，我们提出了一项旨在合理设计类似化合物的研究计划。我们建议实验研究BnOCPA和类似分子如何与A1R相互作用。我们建议计算研究BnOCPA和相关分子如何与受体相互作用。我们还建议研究这些受体/分子组合如何与相关G蛋白相互作用或不相互作用。这些研究将通过化学合成根据结果设计的新分子来补充。BnOCPA是一个相当大的分子，它从主要的A1R结合位点延伸到所谓的变构结合位点，在那里变构调节剂可以结合以帮助天然腺苷激动剂。因此，这些研究将以在存在变构调节剂的情况下对激动剂的研究为指导，因为了解到部分变构调节剂可能影响BnOCPA的氧苄基结合的位置，因此激动剂/变构调节剂组合可能表现出与BnOCPA相似的性质。收集到的信息将用于设计仅能与特定G蛋白相互作用的BnOCPA类似物。在这些研究中学到的原理可能为设计除A1R之外的其他gpcr的G蛋白选择性激动剂打开了大门。