title: 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.affiliation: Department of Reproductive Biology, Drug Discovery Program, Parker Hughes Institute, St. Paul, MN 55113, USA. odcruz@ih.org
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D015658:HIV Infections / Q000201:enzymology / Q000517:prevention & control* / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008826:Microbial Sensitivity Tests; D011292:Premedication; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012661:Semen / Q000187:drug effects / Q000821:virology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; C121245:HI 236; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D013890:Thiourea