Jin Yafei, Zhong Huailing, Omnaas John R, Neubig Richard R, Mosberg Henry I
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109, USA
Methods Enzymol. 2004;389:266-77. doi: 10.1016/S0076-6879(04)89016-5.
One of the principal roles of the multifunctional regulator of G-protein signaling (RGS) proteins is to terminate G-protein-coupled receptor (GPCR) signaling by binding to the G-protein Galpha subunit, thus acting as GTPase-activating proteins (GAPs). In principle, then, selective inhibitors of this GAP function would have potential as therapeutic agents, as they could be used to augment the effects of endogenous or exogenous GPCR agonists. Using the published RGS4-G(ialpha1) X-ray structure, we have designed and synthesized a series of cyclic peptides, modeled on the G(ialpha) switch I region, that inhibit RGS4 GAP activity, presumably by blocking the interaction between RGS4 and G(ialpha1). These compounds should prove useful for elucidating RGS-mediated activity and serve as a starting point for the development of a novel class of therapeutic agent.
G蛋白信号调节蛋白（RGS）的主要作用之一是通过与G蛋白α亚基结合来终止G蛋白偶联受体（GPCR）信号传导，从而作为GTP酶激活蛋白（GAP）发挥作用。那么原则上，这种GAP功能的选择性抑制剂具有作为治疗药物的潜力，因为它们可用于增强内源性或外源性GPCR激动剂的作用。利用已发表的RGS4-G（α1）X射线结构，我们设计并合成了一系列以G（α）开关I区域为模型的环肽，这些环肽抑制RGS4 GAP活性，可能是通过阻断RGS4与G（α1）之间的相互作用来实现的。这些化合物应有助于阐明RGS介导的活性，并作为开发新型治疗药物的起点。
