靶向AT1R偏向性信号通路多肽探针的作用机制研究

Angiotensin II type 1 receptor (AT1R) is the main regulator of blood pressure and an important target for anti-hypertensive drugs. AT1R peptide ligands exhibit variety of efficacies. The natural ligand AngII activates both G protein and β-arrestin signaling, [Sar1,Thr8]AngII blocks both signaling, TRV120055 activates G-protein biased signaling, and TRV120027 activates β-arrestin signaling of AT1R. Particularly, TRV120027 could not only lower the blood pressure but also protect the heart, which could be used for the treatment of acute heart failure. However, the mechanisms for AT1R regulation by peptide ligands are still elusive. The applicant previously solved the crystal structure of AT1R with the small molecule ligand, and here proposes to use the peptide ligands as the targeted probes, to study the interactions between AT1R and probes, the conformational changes of AT1R induced by probes, and the transmembrane signaling of AT1R mediated by probes, by determining the AT1R-probe structures. The results are expected to elucidate the mechanisms for AT1R biased signaling regulated by probes, and provide new insights into drug discovery for cardiovascular disease based on the chemical probes.

AT1R是人体内主要的血压调节蛋白和降血压药物的作用靶标。AT1R多肽配体具有多种不同的药理活性，天然配体AngII能激活AT1R介导的G蛋白和β阻遏蛋白信号通路，[Sar1,Thr8]AngII能完全抑制AT1R的活性，TRV120055能偏向性激活G蛋白信号通路，TRV120027能偏向性激活β阻遏蛋白信号通路。其中，TRV120027在降低血压的同时还能起到心肌保护的功能，具有治疗急性心脏衰竭的潜力。但是多肽配体调控AT1R的分子机理还有待进一步研究。申请人计划在前期成功解析AT1R与小分子配体复合物结构的基础上，以一系列AT1R多肽配体为靶向探针，进一步解析AT1R与探针的复合物结构，系统研究探针与AT1R的相互作用、探针诱导AT1R发生的构象变化、以及探针介导的AT1R跨膜信号转导，从而阐明探针调控AT1R偏向性信号转导的机理，为基于靶向化学探针的心血管药物发现提供重要依据。

AT1R是人体内主要的血压调节蛋白和降血压药物的作用靶标。AT1R多肽配体具有多种不同的药理活性，但是多肽配体调控AT1R的分子机理还有待进一步研究。以一系列AT1R多肽配体为化学探针，进一步解析AT1R与探针的复合物结构，系统研究探针与AT1R的相互作用、探针诱导AT1R发生的构象变化、以及探针介导的AT1R跨膜信号转导，从而阐明探针调控AT1R偏向性信号转导的机理，为基于靶向化学探针的心血管药物发现提供重要依据。