人APOBEC3G（hA3G）是人自身编码的HIV-1限制因子，可以高效抑制HIV-1的复制。HIV-1的Vif蛋白特异性地结合hA3G并诱导其降解，使病毒得以生存。鉴于HIV-1天然靶细胞中均表达hA3G，如能有效阻断Vif降解hA3G，宿主细胞就可以利用自身编码的hA3G抑制HIV-1的复制。因此，Vif降解hA3G成为极具发展潜力的抗HIV-1药物的新靶点。本申请课题组应用针对该靶点的虚拟筛选方法，获得了活性小分子化合物IMB-301和IMB-945，二者可以有效抑制Vif降解hA3G和HIV-1的复制。本申请课题拟进一步开展IMB-301和IMB-945抗HIV-1机制的研究，确定其直接作用靶点及其阻断Vif降解hA3G的分子机制，探索活性化合物的构效关系，建立活性小分子化合物和药物靶点相互作用的分子模型，推动以Vif降解hA3G为靶点的新型抗HIV-1药物的研发。

Human APOBEC3G (hA3G) is a restriction factor that inhibits human immunodeficiency 1 virus (HIV-1) replication. The virally encoded protein Vif binds to hA3G and induces its degradation, thereby counteracting the antiviral activity of hA3G. Vif-mediated hA3G degradation clearly represents a potential target for anti-HIV drug development. Our preliminary works have performed virtual screening to discover small molecule inhibitors that target the binding interface of the Vif/hA3G complex. Subsequent biochemical studies have led to the identification of small molecule inhibitors. IMB-301 and IMB-945 inhibited Vif-mediated degradation of hA3G, strongly inhibits HIV-1 replication in a hA3G-dependent manner. In this proposal, we will investigate the mechanism of the two molecules anti-HIV-1. Our findings provide a potential host-cell target for improved anti-HIV-1 therapies.