Design of a highly potent bifunctional HIV-1 entry inhibitor targeting both gp120 and gp41

Previous studies have demonstrated the essential role of the envelope glycoprotein (Env) gp120 and gp41 N-terminal heptad repeat (NHR) region in human immunodeficiency virus type 1 (HIV-1) life cycle steps. Based on the multitarget-directed ligand (MTDL) design strategy, we herein report a series of bifunctional entry inhibitors consisting of an aroyl indoleoxoacetyl piperazine-based attachment inhibitor, IAC, and a gp41 NHR-targeting peptide fusion inhibitor SP22. We found that one of these chimeras, named ISP, showed potent inhibitory potency against HIV-1, about 180- and 54-fold over that of its parent inhibitors, IAC and SP22, respectively. Our work provides a potent peptide-based bifunctional HIV-1 entry inhibitor and offers new insights into the design of therapies against infection of other enveloped viruses.