苏拉明与HIV-1衣壳蛋白六聚体中NTD/CTD界面互作调节CA蛋白装配  

Suramin modulates CA protein assembly by interacting with the NTD/CTD interface in the HIV-1 capsid hexamer

作　　者：许晓双 张大为 XU Xiao-shuang;ZHANG Da-wei(Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou 213001,China)

机构地区：[1]江苏理工学院电气信息工程学院生物信息与医药工程研究所,江苏常州213001

出　　处：《药学学报》2025年第3期817-824,共8页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(31700297)。

摘　　要：HIV-1衣壳蛋白(HIV-1 capsid protein,CA)是寻找抗病毒药物的有效靶点。靶向HIV-1 CA C端结构域(C-terminal domain of HIV-1 CA,CA CTD)中的CAI(capsid assembly inhibitor peptide)结合口袋可用来筛选CA蛋白抑制剂。本研究基于均相时间分辨荧光技术发现小分子化合物苏拉明(suramin)通过结合到该口袋靶向HIV-1CA,其抑制CA CTD-CAI相互作用的半数抑制浓度(IC_(50))值为2.1μmol·L^(-1)。生物膜干涉法(bio-layer interferometry,BLI)实验表明,苏拉明直接与CA蛋白结合,且与CA蛋白六聚体的结合亲和力(K_(D)=248 nmol·L^(-1))高于与CA单体的结合亲和力(K_(D)=227μmol·L^(-1))。此外,CA蛋白体外组装实验表明苏拉明促进了CA蛋白的无序多聚化。分子模拟结合模式分析结果显示,苏拉明通过N57、Q63、Q67和Y169残基结合到CA六聚体中相邻CA单体之间的界面上,起到增强CA蛋白多聚化的作用。综上所述,苏拉明是一种靶向CA六聚体的CA蛋白抑制剂,可作为发现新型CA抑制剂的起点。The HIV-1 capsid protein(CA)is an effective target for antiviral drug discovery.Targeting the capsid assembly inhibitor peptide(CAI)binding pocket in the C-terminal domain of HIV-1 CA(CA CTD)can be used to screen for CA protein inhibitors.In this study,we found that the small molecule suramin targets HIV-1 CA by binding to this pocket,with an IC_(50)value of 2.1μmol·L^(-1)for inhibiting the CA CTD-CAI interaction,based on homogeneous time-resolved fluorescence(HTRF)technology.Bio-layer interferometry(BLI)experiments demonstrated that suramin binds directly to CA,with a binding affinity to CA hexamer(K_(D)=248 nmol·L^(-1))higher than to CA monomer(K_(D)=227μmol·L^(-1)).In addition,in vitro CA protein assembly assays showed that suramin promotes disordered multimerization of CA protein.Binding model analysis revealed that suramin binds to the interface between adjacent CA monomers in the CA hexamer through the N57,Q63,Q67 and Y169 residues,thereby enhancing CA multimerization.In summary,suramin is a CA protein inhibitor that targets the CA hexamer and can serve as a starting point for the discovery of new CA inhibitors.

关 键 词：苏拉明 衣壳装配 生物膜干涉 人类免疫缺陷病毒1型 均相时间分辨荧光技术 

分 类 号：R943[医药卫生—药剂学]