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

胰淀素由胰岛β细胞分泌，对胃排空和食物摄入有重要影响。Pramlintide是一种非淀粉样样的人类amylin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，胰淀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，当与其他减肥药（如GLP-1）共同使用时，已观察到协同效应。因此，人们对开发新的胰淀素类似物来治疗肥胖和合并症非常感兴趣。Amylin对饱腹感的影响局限于脑后区域的Amylin受体，涉及AMY3R，一种降钙素受体（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项目先前已经确定了新的激动剂肽，这些激动剂肽既具有amylin肽样（对AMY3R （RAMP3+CTR）的功效明显高于CTR），又具有平衡的双重激动剂特性。这些都是通过测量肽诱导的cAMP积累而确定的（AMY3R和CTR都是gs偶联的gpcr，其激活导致细胞内cAMP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，我们将采用多学科方法，结合自由能计算和分子动力学模拟等计算机方法，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异构体选择性测定），并在急性食物摄入和肥胖模型中支持肽合成和体内翻译。我们的数据将为胰淀素受体药物的发现提供新的依据。

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.