Mol. Hum. Reprod. Advance Access originally published online on October 27, 2005
Molecular Human Reproduction 2005 11(10):767-777; doi:10.1093/molehr/gah236
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Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide
1Department of Reproductive Biology, Drug Discovery Program, 2Department of Virology, Parker Hughes Institute and 3Paradigm Pharmaceuticals, LLC, St. Paul, MN, USA
4 To whom correspondence should be addressed at: Parker Hughes Institute, 2657 Patton Road, St. Paul, MN 55113, USA. E-mail: odcruz{at}ih.org
The increased risk of heterosexual transmission of human immunodeficiency virus-1 (HIV-1) has prompted the search for safe and effective female-controlled vaginal microbicides. Because endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-resistant mutant strains of HIV-1. N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-236) is a rationally designed non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) that was deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance mutations. PHI-236 displayed high-binding affinity (Ludi Ki = 0.07 µM) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50 = <0.001 µM) as well as primary clinical isolates (IC50 = 0.009–0.04 µM) carrying multiple RT gene mutations associated with NRTI and NNRTI resistance. PHI-236 displayed high-selectivity index against human vaginal and cervical epithelial cells and did not affect human sperm functions. In the humanized severe combined immunodeficient mouse model for HIV/acquired immune deficiency syndrome (AIDS), pretreatment of HIV-1 (BaL)-infected human monocytes and semen with PHI-236 prevented the systemic infection via the vaginal route. PHI-236 has particular clinical utility as a non-spermicidal microbicide as well as a prophylactic antiviral agent to inactivate cell-free and cell-associated HIV-1 in semen before assisted reproductive technology procedures.
Key words: AIDS or HIV/drug resistance/intravaginal/microbicide/non-nucleoside inhibitor/reverse transcriptase/sperm/thymidine analogue mutations