|
|
 |
Abstract
Contraceptive and non-contraceptive Thiourea non-nucleoside inhibitor-based anti-HIV microbicides
O. D'Cruz1, F. Uckun2
1Paradigm Pharmaceuticals, LLC, Drug Discovery Program, St. Paul, MN, United States, 2Parker 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.
Back
|