Deciphering the molecular basis of amylin receptor-mediated satiation as an obesity treatment

破译胰淀素受体介导的饱腹感作为肥胖治疗方法的分子基础

• 批准号: 2888775
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2888775
• 关键词: Deciphering; molecular; basis; amylin; receptor

BBSRC strategic theme: Bioscience for an integrated understanding of healthAmylin is secreted from pancreatic islet Betha-cells and has potent effects on gastric emptying and food intake. Pramlintide, a nonamyloidogenic analogue of human amylin is approved for the treatment of type-1 and type-2 diabetes in combination with insulin. However, amylin analogues have been shown to promote satiation leading to significant weight loss. Moreover, when co-administered with other weight losing agents (e.g. GLP-1) synergistic effects have been observed. Accordingly, there is significant interest in the development of new amylin analogues to treat obesity and co-morbidities. Amylin effects on satiation are localized to amylin receptors in the area postrema and involve the AMY3R, a heteromer of the calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3).Pharmaceutical company drug discovery programmes have previously identified novel agonistic peptides that showed both amylin peptide-like (significantly higher efficacy towards the AMY3R (RAMP3+CTR) over the CTR) and balanced dual agonist properties. These have been identified measuring peptide-induced cAMP accumulation (the AMY3R and CTR are both Gs-coupled GPCRs whose activation leads to increased intracellular cAMP). This studentship will determine the molecular determinates that govern AMY3R agonist selectivity. To achieve this, we will use a multidisciplinary approach combining in silico approaches like free energy calculations and molecular dynamic simulations, molecular pharmacology techniques (including fluorescent ligand binding, and G protein selectivity assays, and receptor isoform selectivity assays) supported by peptide synthesis and in vivo translation in models of acute food intake and obesity. Our data will provide a new rational for amylin receptor drug discovery.

BBSRC战略主题：全面了解健康的生物科学胰淀素是由胰岛贝塔细胞分泌的，对胃排空和食物摄入有强大的影响。普拉林肽是一种人胰淀素的非淀粉样变性类似物，已被批准与胰岛素联合治疗1型和2型糖尿病。然而，淀粉素类似物已被证明可以促进饱腹感，从而显著减轻体重。此外，当与其他减肥剂(如GLP-1)联合使用时，也观察到了协同效应。因此，人们对开发新的胰淀素类似物来治疗肥胖症和合并症非常感兴趣。胰淀素对饱腹感的影响局限于最后一区的淀粉素受体，涉及降钙素受体(CTR)和受体活性修改蛋白3(RAMP3)的异构体AMY3R。制药公司的药物发现计划以前已经发现了新的激动肽，既表现出类胰淀素多肽(显著高于CTR对AMY3R(RAMP3+CTR)的疗效)，又具有平衡的双重激动剂特性。这些都是通过测量多肽诱导的cAMP积累来确定的(AMY3R和CTR都是Gs偶联的GPCRs，它们的激活导致细胞内cAMP的增加)。这项研究将确定控制AMY3R激动剂选择性的分子决定因素。为了实现这一目标，我们将使用多学科方法，结合自由能计算和分子动力学模拟、分子药理学技术(包括荧光配体结合、G蛋白选择性分析和受体异构体选择性分析)，并在急性食物摄入和肥胖模型中进行体内翻译。我们的研究结果将为胰淀素受体药物的开发提供新的理论依据。