Dawn of non-nucleoside inhibitor-based anti-HIV microbicides

Abstract

The emergence of HIV/AIDS as a disease spread through sexual intercourse has prompted the search for safe and effective vaginal and rectal microbicides for curbing mucosal viral transmission via semen. Since endogenous reverse transcription is implicated in augmenting the sexual transmission of HIV-1 infection, potential microbicides should have the inherent ability to optimally inhibit both wild-type and drug-escape mutants. The non-nucleoside reverse transcriptase inhibitors (NNRTIs), which bind to an allosteric site on RT, are an important arsenal of drugs against HIV-1. The clinical success of NNRTI-based HIV/AIDS therapies has led to extensive structural and molecular modelling studies of enzyme complexes and chemical synthesis of second- and third-generation NNRTIs. Rationally designed NNRTIs deduced from changes in binding pocket size, shape and residue character that result from clinically observed NNRTI resistance-associated mutations exhibit high binding affinity for HIV-1 RT and robust anti-HIV activity against the wild-type and drug-escape mutants without cytotoxicity. Notably, membrane permeable tight binding NNRTIs have the ability to inactivate cell-free as well as cell-associated HIV-1 in semen without metabolic activation. Consequently, NNRTIs currently under development as experimental microbicides include thiourea-PETT (where PETT stands for phenethylthiazolylthiourea) derivatives (PHI-236, PHI-346 and PHI-443), urea-PETT derivatives (MIV-150), oxypyrimidines (S-DABOs), thiocarboxanilides (UC-781) and diarylpyrimidines (TMC-120). Mucoadhesive formulations of these NNRTIs have been studied for safety and efficacy in animal models and some have entered Phase I safety testing in humans. This review focuses on the structural, biological and preclinical studies relevant to the clinical development of these NNRTIs as molecular virucides intended to prevent the sexual transmission of HIV-1.

The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics

“…This will be closely followed by a microbicide containing dapivirine, which belongs to the nonnucleoside reverse transcriptase inhibitor (NNRTI) class of ARVs (6); trial results will be available in 2010. Three other ARV-based microbicides, containing NNRTIs, are in earlier-phase trials (3,5,(7)(8)(9)(10). ARV-based microbicides are anticipated to be highly effective; however, there is concern that, if used by HIV-positive women, class-specific drug resistance may emerge.…”

The Future of HIV Prevention: Prospects for an Effective Anti-HIV Microbicide

“…For this to be achieved, it is believed that the product should attack the virus at a point before integration (ie, before insertion of the proviral DNA into the host cell's DNA) [24]. Classes of microbicide drugs now under development are generally divided into four categories: (1) membrane disruptive agents [25], (2) entry inhibitors [26], (3) reverse transcriptase inhibitors [27], and (4) dendritic cell uptake inhibitors ( Fig. 1) [24].…”

“…These compounds inhibit viral replication by binding to the HIV-1 reverse transcriptase, which is the enzyme responsible for the transcription of viral RNA to proviral DNA [27]. Within this class is a subgroup of tightbinding NNRTIs that bind irreversibly to reverse transcriptase, and consequently they are highly potent with long half-lives.…”

“…However, the mechanism of this cell-free inhibition has yet to be determined, and its relevance in vivo is unknown [41]. NNRTI compounds currently in development as microbicides include dapivirine (TMC120), MIV-150, UC 781, and S-DABO [27,42,43].…”

Influence of long-term stability conditions on microbicidal nucleoside prodrug (WHI-07)-loaded gel-microemulsion

“…[3][4][5][6] Consequently, the development of safe, efficacious vaginal microbicides capable preventing the transmission of HIV-1 from infected leukocytes via semen is of paramount importance in the fight against the spread of sexually transmitted AIDS. [7][8][9] WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxyalaninyl phosphate), a novel aryl phosphate derivative of zidovudine (ZDV) is an anti-HIV-1 prodrug with in vivo microbicidal and contraceptive properties. [10][11][12][13][14] WHI-07 was rationally designed to bypass the kinase activation step, especially in thymidine kinase deficient or lacking monocytes/macrophages, the main carriers of HIV-1 in semen and female genital tract secretions.…”