腺苷A1激动剂的受体保留时间和脂肪细胞脂解活性的相关性研究

Elevated circulating free fatty acid (FFA) level is closely linked to the pathogenesis of type 2 diabetes mellitus (T2DM). Adenosine A1 receptor agonists can inhibit the lipolysis process in adipocytes and modulate the level of FFA in plasma, hence representing a potential target for the development of anti-lipolytic agents. Recently, drug-target residence time (RT) is receiving increasing attention. Previous results from our lab and others indicated that an endured drug-target interaction might produce higher functional efficacy, while a transient drug-target interaction might induce lower efficacy. In this project we will set up a novel, whole-cell based assay, enabling fast and high-throughput kinetic measurements, to obtain physiologically relevant drug-target binding kinetics. After this, a correlation study will be performed regarding the RT of adenosine A1 receptor agonists and the lipolytic activity in adipocytes, the result of which may provide new rationales for the development of novel anti-lipolytic agents for the treatment of T2DM.

血清中游离脂肪酸（free fatty acid, FFA）水平的异常升高，与2型糖尿病(type 2 diabetes mellitus, T2DM)的发生、发展密切相关。腺苷A1受体激动剂可以对脂肪细胞中脂解过程产生抑制，从而调控血清中FFA水平。因此，可以将其作为潜在的脂解抑制剂展开深入研究。近期，药物-受体保留时间（Drug-target residence time，RT）逐渐受到关注。申请者及国内外同行的前期研究表明，药物与靶点长时间结合，可能产生较高的功效。相比之下，药物与靶点短时间结合，可能产生较低的功效。据此，申请者拟在全细胞上进一步建立快速、高通量的检测方法，以获得更加接近于生理条件下的RT，并在此基础上，验证A1受体激动剂的RT与脂解活性强度的相关性，为设计新型脂解抑制剂提供新的依据，为T2DM防治药物的研发提供的新思路。