The nonnucleoside reverse transcriptase (RT) inhibitors comprise a class of structurally diverse compounds that are functionally related and specific for the human An essential step in the replicative cycle of human immunodeficiency virus type 1 (HIV-1) is the synthesis, catalyzed by the virally encoded reverse transcriptase (RT), of a DNA copy of the viral RNA. Accordingly, the development of RT inhibitors has been the central focus of numerous anti-HIV-1 therapeutic research programs. Over the past several years, a chemically diverse class of RT inhibitors has been described. These compounds have been designated the nonnucleoside RT inhibitors to distinguish them from the nucleoside analogs. The class includes the pyridinone derivatives L-697,661 and L-696,229 as well as BI-RG-587 and the TIBO derivative R82913 (7,8,14,16,18,22). These compounds are potent inhibitors of HIV-1 infection in cell culture.

L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.

To evaluate the potential that multiply resistant human immunodeficiency virus type 1 variants may arise during combination nucleoside and nonnucleoside reverse transcriptase inhibitor therapy, we constructed a series of mutant reverse transcriptase enzymes and viruses that coexpressed various combinations of resistance-associated amino acid substitutions. Substitutions at residues 100 (Leu-->Ile) and 181 (Tyr-->Cys), which mediate resistance to the nonnucleosides, suppressed resistance to 3'-azido-3'-deoxythymidine (AZT) when coexpressed with AZT-specific substitutions. However, a number of viral variants that exhibited significantly reduced susceptibilities to both classes of inhibitors were constructed.

No abstract