PHI-443 (N'-[2-(2-
thiophene)ethyl]-N'-[2-(5-bromopyridyl)]
thiourea) is a rationally designed novel
thiophene thiourea nonnucleoside
reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity against the wild-type and
drug-resistant primary clinical human immunodeficiency virus (HIV-1) isolates. This study examined the potential utility of
PHI-443 as a nonspermicidal
microbicide for prevention of sexual transmission of HIV. Our goal in this study was to test the effects of
PHI-443 on in vivo sperm functions under conditions shown to inactivate viruses in human cells.
PHI-443 completely prevented the vaginal transmission of a genotypically and phenotypically
drug-resistant HIV-1 isolate in the humanized severe combined immunodeficient (Hu-SCID) mouse model of sexually transmitted
AIDS. Exposure of human sperm to
PHI-443 at doses 30 000 times higher than those that yield effective concentrations against the AIDS virus had no adverse effect on sperm motility, kinematics, cervical mucus penetrability, or the viability of vaginal and cervical epithelial cells. Exposure of rabbit semen to
PHI-443 either ex vivo or in vivo had no adverse impact on in vivo fertilizing ability in the rabbit model. Reproductive indices (i.e., pregnancy rate, embryo implantation, and preimplantation losses) were not affected by pretreatment of rabbit semen with
PHI-443. Likewise, intravaginal application of 2%
PHI-443 via a self-emulsifying gel at the time of artificial insemination resulted in healthy offspring with no apparent peri- or postnatal repercussions. Repeated
intravaginal administration of 0.5%- 2%
PHI-443 gel was found to be safe in rabbits and lacked systemic absorption.
PHI-443 has clinical potential as a prophylactic broad-spectrum anti-HIV
microbicide without
contraceptive activity.