病毒蛋白的核输入过程:抗HIV-1药物研究的新靶点

Nuclear import process:a novel anti-HIV-1 drug target

核输入是HIV-1生命周期中的关键步骤,主要指HIV-1的整合前复合体(PIC)及病毒辅助蛋白通过核孔蛋白复合物进入到细胞核的过程。HIV-1的PIC包含了病毒的基质蛋白、整合酶、病毒蛋白R、cDNA以及多种细胞辅助因子,如晶状体上皮细胞衍生生长因子(LEDGF/p75)、输入蛋白α和转运蛋白SR2。因此HIV-1核输入是一个多因子参与的复杂过程,依赖于PIC成分或单独HIV-1蛋白与细胞核输入因子之间的蛋白质-蛋白质相互作用。相对于传统的抗HIV治疗方法(如靶向于逆转录酶、整合酶、蛋白酶等),针对核输入过程的治疗有可能成为一种新的选择。目前,作用于核输入过程的抗HIV药物研发主要基于两种途径:将功能蛋白的关键区域直接衍生或经修饰而得到具有抑制活性的多肽;基于蛋白质-蛋白质相互作用的具体模式进行合理设计,或通过筛选发现小分子抑制剂。本文综述了关于HIV PIC核输入机制、核输入过程中的关键因子,以及有抑制作用的多肽和小分子化合物的研究进展。

Nuclear import including transportation of essential preintegration complex（PIC） and viral regulatory proteins into the nucleus is a critical step in the life cycle of HIV-1.The HIV-1 PIC consists of the matrix protein,integrase,viral protein R,cDNA flap and cellular cofactors such as LEDGF/p75,importin and TNPO3/TRN-SR2.Given that multiple factors involved in the process,HIV-1 nuclear import depends on intricate interactions between the PIC components or individual HIV-1 proteins and the cellular nuclear import factors.Being different from the classical approach to anti-HIV-1 drug development,this step presents a novel attractive target for therapeutic intervention.Up to now,there are two main methods to discover new potent compounds targeting this process：obtaining peptides derived from either protein binding partner directly,or after modifcation to improve affnity and physicochemical properties;designing small molecules based on protein-protein interaction in this process,or through random screening.In this review,we will describe the mechanisms of nuclear import of HIV-1 PIC,the viral and cellular factors involved in this process,as well as several classes of novel peptides and small molecules which target this step and effectively block viral replication.