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是一个大型受体家族，是35％的处方药的靶标。 GPCR的日常经历包括与组胺受体结合的抗抗素胺的抗过敏作用，咖啡因可阻断腺苷受体的心率增加，以及从吗啡结合到阿片类受体中的疼痛缓解。腺苷受体有多种形式，标记为A1，A2A，A2B和A3。我们对腺苷A1受体（A1R）感兴趣，该腺苷A1受体原则上是需要新药的靶标，包括青光眼，2型糖尿病，疼痛，癫痫，癫痫和脑缺血。但是，许多科学家拒绝了腺苷A1R受体作为药物靶标，因为与靶标有严重的副作用，而不是与任何潜在的药物分子相关。问题之所以出现，是因为当药物与A1R相互作用时，无论是在中枢神经系统（CNS）还是在心肺系统中，都会在细胞内部激活许多途径。中枢神经系统的途径可能会导致疼痛缓解，但是心肺系统中的途径减慢了心脏，降低血压和呼吸。心肺系统中的这些途径会导致不可接受的副作用，因此导致A1R作为药物靶标的兴趣丧失。这些理想和不良的途径会出现，因为A1R是伴侣与多种G蛋白结合的GPCR。某些G蛋白会产生有利的结果，同时其他G蛋白可能会导致不利的结果。最近，我们偶然地发现了一种称为Bnocpa的激动剂分子（BNO代表氧苯甲酰，CPA是环戊酰腺苷），它以A1R作为药物靶标完全转化了景观。 （激动剂是一种激活受体的分子，而不是像咖啡因这样阻塞受体的拮抗剂。）Bnocpa激动剂完全改变了范式，因为它仅激活一个G蛋白（GOB），从而使Vivo中的疼痛救济在Vivo中呈现。它不会激活密切相关的G蛋白果阿，因此没有心血管副作用。 BNOCPA现在允许我们提出一种理性方法，用于设计仅激活一种G蛋白的A1R激动剂。在偶然发现Bnocpa之后，我们提出了一项旨在合理设计类似化合物的研究计划。我们提出了有关BnoCPA和类似分子如何与A1R相互作用的实验研究。我们提出了有关BNOCPA和相关分子如何与受体相互作用的计算研究。我们还提出了这些受体/分子组合如何与相关G蛋白相互作用或不相互作用的研究。这些研究将通过化学合成的结果来补充。 BNOCPA是一个相当大的分子，它延伸到主A1R结合位点超出所谓的变构结合位点，在该位点上，变构调节剂可以结合以帮助天然腺苷激动剂。因此，这些研究将由对变构调节剂存在的激动剂的研究来指导，因为理解的是，变构调节剂的一部分可能会影响Bnocpa的氧苯甲酰基群结合，因此激动剂/变构调节剂的组合可能显示出与BNOCPA的相似特性。收集的信息将用于设计只能与指定G蛋白相互作用的Bnocpa类似物。这些研究中所学的原则可能为除A1R以外的其他GPCR设计G蛋白选择性激动剂的设计打开了大门。