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：综合理解健康酰胺的生物科学是从胰岛betha-cells分泌的，对胃排空和食物摄入量有有效的影响。 pramlintide是人淀粉蛋白的一种非淀粉样蛋白类似物，用于与胰岛素结合治疗1型和2型糖尿病。但是，已证明淀粉蛋白类似物可以促进饱腹感，从而大大减轻体重。此外，已经观察到与其他重量失去的剂（例如GLP-1）共同管理协同作用。因此，对治疗肥胖和合并症的新木蛋白类似物的发展具有重大兴趣。淀粉蛋白对ATITIAT的影响定位于该区域的链淀粉受体，并涉及Amy3R，Amy3R是降钙素受体（CTR）的异构体和调节蛋白3（RAMP3）的受体活性的蛋白质。在CTR）和平衡的双激动剂特性上。这些已被鉴定出测量肽诱导的cAMP积累（AMY3R和CTR都是GS耦合的GPCR，其激活会导致细胞内cAMP增加）。该学生将确定分子确定控制AMY3R激动剂选择性的分子。 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.我们的数据将为淀粉蛋白酶受体药物发现提供新的理性。