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：通过生物科学全面了解健康胰淀素由胰岛 Betha 细胞分泌，对胃排空和食物摄入具有强大影响。普兰林肽是人胰淀素的一种非淀粉样蛋白类似物，被批准与胰岛素联合治疗 1 型和 2 型糖尿病。然而，胰淀素类似物已被证明可以促进饱腹感，从而导致体重显着减轻。此外，当与其他减肥剂（例如 GLP-1）共同施用时，已观察到协同效应。因此，人们对开发新的胰岛淀粉样多肽类似物来治疗肥胖和合并症非常感兴趣。胰淀素对饱腹感的影响局限于后区的胰淀素受体，并涉及 AMY3R，降钙素受体 (CTR) 和受体活性修饰蛋白 3 (RAMP3) 的异聚体。制药公司的药物发现计划先前已鉴定出新型激动肽，这些肽显示出胰淀素肽样（对 AMY3R (RAMP3+CTR) 的功效显着更高） 超过 CTR）和平衡的双重激动剂特性。这些已被鉴定用于测量肽诱导的 cAMP 积累（AMY3R 和 CTR 都是 Gs 偶联的 GPCR，其激活会导致细胞内 cAMP 增加）。该学生奖学金将确定控制 AMY3R 激动剂选择性的分子决定因素。为了实现这一目标，我们将采用多学科方法，结合计算机方法，如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蛋白选择性测定和受体亚型选择性测定），并由肽合成和急性食物摄入和肥胖模型中的体内翻译支持。我们的数据将为胰岛淀粉样多肽受体药物的发现提供新的理论依据。