基于非肽类小分子激动剂Boc5的GLP-1R别构调节剂的功能和应用研究

胰高血糖素样肽-1受体（GLP-1R）是当今公认的、最重要的抗糖尿病药物作用靶点之一。内源分泌的肽类配体GLP-1通过激活GLP-1R在胰岛素分泌和β细胞功能中具有重要作用。我们在前期研究中发现了GLP-1R的非肽类小分子激动剂Boc5，具有可以口服，半衰期较长等优势。然而，由于Boc5活性较低，且易过度激活受体，其应用受到限制。别构调节因其具有高选择性、模拟生理性调控和不易过度激活受体等特点而备受业界关注。本课题拟在前期Boc5研究以及基于Boc5筛选到的85个GLP-1R别构调节剂基础上，开展基于GLP-1的别构调节剂功能研究，确定其别构调节类型，并探讨后者与Boc5及GLP-1联合用药在2型糖尿病治疗中的应用。以期发现新的GLP-1R的别构调节剂作为潜在治疗药物及研究用工具化合物。

Glucagon-like peptide 1 receptor (GLP-1R) is one of the most important drug targets in diabetes treatment. GLP-1 plays a key role in insulin secretion and β cell function. The non-peptidic GLP-1R agonist Boc5 discovered in our laborarry is orally available and has a long half-life.?However, its application is limited by low activity and receptor over-activation. Allosteric modulation has attracted much attention due to it can provide high selectivity, mimicry of physiological control and less over activation. The present study have identified 85 positive allosteric modulator (PAM) based on Boc5 and the abandunt compounds resources at the Chinese National Compound Library. In this project, we will futher to discover the allosteric regulation of 85 hits on GLP-1 agonist and to study its potential in treat type 2 diabetes as well as the molecular mechanism of PAM.