Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

摘要: ABSTRACT Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages are not targeted by currently use. Host-targeting drugs particular interest because they can offer a high barrier to resistance. Here we report identification two related small molecules inhibit HIV-1 late events, stage life cycle which potent and specific inhibitors lacking. This chemotype was discovered using cell-free protein synthesis assembly systems recapitulate intracellular host-catalyzed viral capsid pathways. These compounds replication human T cell lines PBMCs effective against primary isolate. They reduce production, likely inhibiting post-translational step Gag assembly. Notably, compound colocalizes with situ; however, unexpectedly, selection experiments failed identify compound-specific resistance mutations gag or pol, even though known developed parallel nelfinavir selection. Thus, hypothesized instead binding directly, these might localize intermediates, multiprotein complexes containing host factors formed during immature Indeed, imaging infected cells showed colocalization enzymes found ABCE1 DDX6. While exact target mechanism action this remain be determined, findings suggest represent first-in-class, host-targeting events IMPORTANCE The success antiretroviral treatment at risk being undermined growing problem drug use, such as To address gap, screen recapitulates assembly, including viral-host interactions promote effort led new inhibits nanomolar concentrations production. colocalized facilitate but did result gag, suggesting does directly Gag. We hypothesize may first-in-class inhibitor production acts targeting complex important