A novel vaginal microbicide containing the rationally designed anti-HIV compound HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]).

Introduction: A focal point in contemporary research aimed at preventing the heterosexual spread of AIDS has been the development of intravaginal anti-HIV microbicides to curb the mucosal human immunodeficiency virus type 1 (HIV-1) transmission.

Areas Covered: This article reviews the preclinical activity and safety profile of the thiophene thiourea PETT derivative, HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]). HI-443 is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with unprecedented activity against primary clinical HIV-1 isolates with NRTI or NNRTI resistance, multidrug resistance as well as non-B envelope subtypes of HIV-1. HI-443 exhibited a favorable toxicity and pharmacokinetics profile following oral, intraperitoneal or intravenous administration in rodents and a favorable safety profile after repeated intravaginal dosing via a gel formulation in rabbits and pigs. HI-443 did not induce the secretion of pro-inflammatory cytokines and chemokines by three-dimensional reconstituted human vaginal epithelia integrating Langerhans cells ex vivo or in the in vivo porcine model at therapeutic dose levels. Intravaginally administered HI-443 prevented vaginal transmission of a drug-resistant clinical HIV-1 isolate in the surrogate Hu-PBL-SCID mouse model of AIDS.

Expert Opinion: The discovery of HI-443 as a non-spermicidal broad-spectrum antiretroviral agent represents a significant step forward in the development of a prophylactic microbicide without contraceptive activity for curbing heterosexual HIV transmission.