Discovery of 2,5-dimethoxy-substituted 5-bromopyridyl thiourea (PHI-236) as a potent broad-spectrum anti-human immunodeficiency virus microbicide.

Abstract

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 microM) for HIV-1 RT and robust anti-HIV activity against the wild type (IC50 = <0.001 microM) as well as primary clinical isolates (IC50 = 0.009-0.04 microM) 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.

• Authors: Osmond J D'Cruz, Fatih M Uckun
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 11 Issue 10 Pg. 767-77 (Oct 2005) ISSN: 1360-9947 [Print] England
• PMID: 16254003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-HIV Agents
• HI 236
• Pyridines
• Reverse Transcriptase Inhibitors
• Thiourea

Topics

• Animals
• Anti-HIV Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Design
• Female
• HIV Infections (enzymology, prevention & control, transmission)
• HIV-1 (drug effects, genetics)
• Humans
• Mice
• Mice, SCID
• Microbial Sensitivity Tests
• Premedication
• Pyridines (chemistry, pharmacology, therapeutic use)
• Reverse Transcriptase Inhibitors (chemistry, pharmacology, therapeutic use)
• Semen (drug effects, virology)
• Thiourea (analogs & derivatives, chemistry, pharmacology, therapeutic use)