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

Ling Ma,Jing Wang,Xiaoyu Li,Qinghua Pan,Zhixin Zhang,Zhenlong Liu,Jinming Zhou,Fei Guo,Chen Liang,Shan Cen,Laixing Hu

doi:10.1038/s41598-018-26318-3

Abstract

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.

Highlights

Human Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 G, which belongs to the APOBEC superfamily containing at least 10 members, is a restriction factor that inhibits the replication of HIV-11
Virtual screening of small molecule compounds that target the interface of Human APOBEC3G (hA3G)/Vif interaction
The results of sequence alignment showed that the template human APOBEC3F (hA3F) and the CD1 domain of hA3G have a high sequence identity of 41.5%, with a sequence similarity of 57.9%, which indicates that the template is suitable for homology model building

Summary

Introduction

Human Apolipoprotein B mRNA-editing catalytic polypeptide-like 3 G (hA3G), which belongs to the APOBEC superfamily containing at least 10 members, is a restriction factor that inhibits the replication of HIV-11. Further studies of the co-immunoprecipitation and molecular docking have indicated that ZBMA-1 inhibits the Vif-mediated hA3G degradation via affecting the binding of Elongin C with Vif protein[26]. Further molecular docking study suggests that IMB-26/35 binds to a putative site near the 124-YYFW-127 motif in the hA3G-CD1 model[27], which has been generated through homology modeling based on the template APO2 dimer structure (PDBID: 3IQS)[28]. This putative site provides a potential target for virtual screening. Further biochemical experiments have verified that IMB-301 binds to hA3G, restores hA3G expression in the presence of Vif, and inhibits the replication of HIV-1 in a hA3G-dependent manner

Methods

Results

Conclusion