uc-781 and HIV-Infections

We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

Topics: Adenine; Anilides; Anti-HIV Agents; Anti-Infective Agents, Local; Colon; Drug Resistance, Viral; Furans; HIV Infections; HIV-1; Humans; Leukocytes, Mononuclear; Organophosphonates; Pyrimidines; Rectum; Reverse Transcriptase Inhibitors; Tenofovir; Thioamides; Tissue Culture Techniques; Virus Replication

Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30 microM lead has been optimized rapidly to the 10 nM level.

Topics: Computer-Aided Design; Drug Resistance, Multiple, Viral; HIV Infections; HIV Reverse Transcriptase; Models, Molecular; Molecular Structure; Monte Carlo Method; Mutation; Reverse Transcriptase Inhibitors

Following computational analyses, potential non-nucleoside inhibitors of HIV-1 reverse transcriptase have been pursued through synthesis and assaying for anti-viral activity. The general class Het-NH-Ph-U has been considered, where Het is an aromatic heterocycle and U is an unsaturated, hydrophobic group. Results for compounds with Het=2-thiazoyl and 2-pyrimidinyl are the focus of this report.

Topics: Amines; Drug Resistance, Multiple, Viral; Heterocyclic Compounds; HIV Infections; HIV Reverse Transcriptase; Hydrophobic and Hydrophilic Interactions; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thiazoles