UT配体的β-arrestin信号通路偏向性机制及药物发现

Urotensin II (UII) is a most potent mammalian vasoconstrictor identified so far. The urotensin II receptor (UT) is a G protein-coupled receptor (GPCR), which is a novel therapeutic target for the treatment of cardiovascular disease. At present, none drug target UT is in clinical usage, and only three are in phase I or II study. Studies show that a considerable portion of the candidates has limited efficacy and even toxicity. The discovery of receptor bias activity has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity, which provides new opportunity for UT drug discovery and study. The binding of ligand to GPCR induces signaling through G protein and/or β-arrestin-mediated pathways. GPCRs do not uniformly activate all cellular signaling pathways linked to a given receptor (a phenomenon termed ligand bias). Studies showed that the activation by UT was mediated by arrestin recruitment and conferred cardioprotection, which indicate that agonist that bias activate the β-arrestin pathway while block G protein pathway, which may be more efficient and low toxicity. Our subject intends to take advantage of our existing GPCR technical platform, to establish a β-arrestin biased UT ligand screening platform to study the mechanisms of β-arrestin biased UT ligand on the cell signaling and function. The platform includes β-arrestin recruitment assay, G protein signaling assays, binding assay and virtual screening assay. Through evaluation of β-arrestin and G protein pathway activation and to calculate the pathway bias ratio, to obtain the ligands that bias trigger UT β-arrestin pathway. We will investigate the effect of active compounds on the downstream signaling proteins in smooth muscle cells. And study the effect of β-arrestin biased UT ligands on the vascular systolic and diastolic function in rat aorta and mesenteric arteries. We also discuss how biased molecules may perform in cell, and what potential therapeutic advantages they may provide.

尾加压素在心血管疾病中发挥重要作用，是目前已知最强缩血管物质，其受体UT为G蛋白耦联受体，激动后经Gq和/或β-arrestin通路传导。当前因效能低和毒性问题，制约了靶向UT的药物研发。UT的信号传导具有偏向性，偏向β-arrestin通路有心血管保护作用。UT配体的β-arrestin信号偏向机制研究将有助于发现高效、低毒的靶向UT药物。我们在前期UT靶点、信号传导及筛选模型研究基础上，拟建立β-arrestin偏向的UT配体筛选平台进行小分子化合物筛选。通过β-arrestin信号偏向性UT配体，来研究UT配体的β-arrestin信号通路偏向性机制。以偏向性配体对平滑肌细胞转化、增殖、凋亡、分泌及迁移等作用为切入点，探讨UT偏向性激动对细胞功能及相关信号通路产生的影响。通过对大、小动脉血管舒缩及模型动物血压、心脏功能的影响，分析偏向性调控心血管功能的作用机制。

尾加压素II（UrotensinII，UII ）是迄今为止发现收缩血管活性最强的物质，其配体UII具有广泛的生物学效应。尾加压素受体（UT）是G蛋白耦联受体（GPCR），广泛分布于人体各组织器官。近年来，各国制药公司相继开展UII受体激动或者拮抗药物的开发，探索其用于高血压等心血管疾病的治疗，然而大部分临床效果并不显著。研究发现，尾加压素系统参与代谢性疾病病理生理进程，激动后经Gq和/或β-arrestin通路传导。我们在UT靶点、信号传导及筛选模型研究基础上，建立了β-arrestin偏向的UT配体筛选平台进行小分子化合物筛选，获得了UT配体，来研究UT配体的β-arrestin信号通路偏向性机制。虽然有关UT系统的研究较多，但目前仍未明确该靶点在疾病中的具体地位及作用。现有的靶向UT的先导化合物如Palosuran的临床试验是以抗糖尿病肾病目标，但最终还是因作用不确切及副作用而在临床研究方面驻足不前。因此本课题将为UT系统在心血管及抗糖尿病方面的地位及作用提供线索。本课题发现，UT系统对糖脂代谢具有调控作用，可调控相关基因的表达。另外，本课题还发现了作用于UT受体的新型小分子配体，为新型血管系统、代谢系统药物的开发提供了加契机。