The development of anti-HIV agents targeting APOBEC3G/Vif axis.

The human host restriction factor APOBEC3G (Apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G, A3G) potently inhibits the replication of human immunodeficiency virus type 1 (HIV-1). To counteract this restriction, HIV-1 encodes the viral infectivity factor (Vif), which mediates the degradation of A3G and thereby abrogates A3G's antiviral activity. Previously, we identified IMB-301 via virtual screening coupled with biological validation, which protects A3G from Vif-induced degradation through binding specifically to A3G, thereby preserving A3G's deaminase activity to suppress HIV-1 replication. Herein, we performed structural optimization of IMB-301, yielding a library of 64 analogs. Most of these analogs retained HIV-1 inhibitory activity, with several exhibiting significantly enhanced potency relative to IMB-301. Further investigations demonstrated that these active analogs block the Vif-A3G interaction, restore intracellular A3G levels, and ultimately inhibit HIV-1 proliferation in an A3G-dependent manner. Collectively, this work highlights a promising avenue for the development of novel anti-HIV-1 therapeutic strategies and candidate molecules.