16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

CONTRACEPTIVE AND NON-CONTRACEPTIVE THIOUREA NON-NUCLEOSIDE INHIBITOR-BASED ANTI-HIV MICROBICIDES

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. WeAa0502

D'Cruz O.¹, Uckun F.^2
1 Paradigm Pharmaceuticals, LLC, Drug Discovery Program, St. Paul, MN, United States, ² Parker Hughes Institute, Virology, St. Paul, MN, United States

BACKGROUND: Since sexual transmission of HIV-1 is the most common mode of infection globally, the development of both contraceptive and non-contraceptive microbicides is of paramount importance in the fight against the spread of sexually transmitted AIDS. Membrane-permeable tight-binding non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) have emerged as a new class of microbicides because of their ability to block cell-free and cell-associated HIV-1 infection in semen without metabolic activation.

METHODS: A novel composite NNRTI binding pocket constructed from 9 RT/NNRTI crystal structures led to the rational design of new phenethylthiazolylthiourea derivatives. Several phenyl, cyclohexenyl, and alicyclic ring-substituted thiourea NNRTIs were synthesized based on how drug-resistance RT mutations would change the enzyme-inhibitor binding pocket shape, volume, and chemical make-up, and how these changes could affect inhibitor binding. Compounds that better fit the composite binding pocket were identified based on low inhibition constant (Ludi Ki), rRT IC₅₀ and p24 IC₅₀ values. Lead thiourea NNRTIs were evaluated for structure-activity relationships against wild-type and drug escape mutants, pharmacokinetics, efficacy, toxicity, formulation, stability as well as bioavailability.

RESULTS: Phenyl, cyclohexenyl or alicyclic ring-substituted thourea NNRTIs displayed high-binding affinity for HIV-1 RT and robust anti-HIV-1 activity against the wild-type and drug-resistant strains carrying clinically relevant mutations (Y181C and K103N + Y181C). Notably, thiourea NNRTIs displayed nanomolar anti-HIV-1 activity against genotypic and/or phenotypically drug-resistant primary clinical non-subtype B isolates originating from South America, Asia, and sub-Saharan Africa. Both spermicidal and non-spermicidal thiourea NNRTIs were identified with high selectivity indices, lack of mucosal toxicity and systemic absorption and displayed potent in vivo microbicidal activity in the humanized PBL-SCID mouse model of vaginally transmitted HIV-1.

CONCLUSIONS: Membrane-permeable tight-binding thiourea NNRTIs have particular clinical utility as spermicidal or non-spermicidal broad-spectrum anti-HIV-1 microbicides as well as prophylactic antiviral agents.

Supported by: NIH grants AI052594, AI052633, AI054352 and HD043683.

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2006-08-13
WeAa0502

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