Identification of small molecule compounds targeting the interaction of HIV-1 Vif and human APOBEC3G by virtual screening and biological evaluation

• Published in: Scientific reports Vol. 8; no. 1; pp. 8067 - 12
• Main Authors: Ma, Ling, Zhang, Zhixin, Liu, Zhenlong, Pan, Qinghua, Wang, Jing, Li, Xiaoyu, Guo, Fei, Liang, Chen, Hu, Laixing, Zhou, Jinming, Cen, Shan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-05-2018; Nature Publishing Group
• Subjects: 101/47; 119/118; 45/77; 631/326/596/1787; 631/326/596/2557; 82/1; Amino acids; Antiviral activity; Binding sites; Drug development; Feasibility studies; HIV; Human immunodeficiency virus; Humanities and Social Sciences; multidisciplinary; Mutation; Proteins; Replication; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-26318-3

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. Herein, we 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 a small molecule inhibitor, IMB-301 that binds to hA3G, interrupts the hA3G-Vif interaction and inhibits Vif-mediated degradation of hA3G. As a result, IMB-301 strongly inhibits HIV-1 replication in a hA3G-dependent manner. Our study further demonstrates the feasibility of inhibiting HIV replication by abrogating the Vif-hA3G interaction with small molecules.