Journal
MOLECULAR HUMAN REPRODUCTION
Volume 11, Issue 10, Pages 767-777Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molehr/gah236
Keywords
AIDS or HIV; drug resistance; intravaginal; microbicide; non-nucleoside inhibitor; reverse transcriptase; sperm; thymidine analogue mutations
Funding
- NIAID NIH HHS [AI 54352] Funding Source: Medline
- NICHD NIH HHS [HD43683] Funding Source: Medline
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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 K-i = 0.07 mu M) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50 = < 0.001 mu M) as well as primary clinical isolates (IC50 = 0.009-0.04 mu M) 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.
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