CHARACTERISTICS OF A GROUP OF NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS WITH STRUCTURAL DIVERSITY AND POTENT ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS ACTIVITY

Current thrust in controlling the Acquired immune Deficiency Syndrome (AIDS) focuses on antiviral drug development targeting the infection a nd replication of the human immunodeficiency virus (HIV), the causativ e agent of AIDS. To date, treatment of AIDS has relied on nucleoside r everse transcriptase inhibitors such as AZT, ddl, and ddC, which event ually become ineffective upon the emergence of resistant mutants beari ng specific nucleotide substitutions. The Anti-AIDS Drug Screening pro gram of the NCI conducts and coordinates a high-capacity semi-robotic in vitro screening of synthetic or natural compounds submitted by acad emic, research and pharmaceutical institutions world-wide. About 10000 synthetic compounds are screened annually for anti-HIV activity. Conf irmed active agents are subjected to in-depth studies on range and mec hanism of action. Emerging from this intense screening activity were a number of potentially promising categories of nonnucleoside reverse t ranscriptase inhibitors (NNRTI) with structural diversity but strong a nd reproducible anti-HIV activity. Over 2500 active compounds were eva luated for their Inhibitory activity against a panel or both laborator y and clinical virus isolates in the appropriate established cell line or fresh human peripheral blood leukocyte and macrophage preparations . Out of these, 40 agents could be placed structurally in nine categor ies with an additional 16 unique compounds that share the characterist ics of NNRTI, These NNRTIs were shown to inhibit reverse transcriptase enzymatically using homopolymeric or ribosomal RNA as templates. NNRT Is demonstrated similarity in their inhibitory pattern against the HIV -1 laboratory strains III, and RF, and an AZT-resistant strain; all we re inactive against HIV-2. These compounds were further tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1 isolates were s elected and characterized with respect to the change(s) in the viral r everse transcriptase nucleotide sequence. Also, differential cross-res istance or sensitivity patterns to NNRTIs were studied in detail among NNRTI-resistant mutants. When tested in combination with AZT, all of the NNRTI's uniformly exhibited synergistic inhibition of HIV-1, sugge sting that combination antiviral therapy of NNRTIs with AZT may be the rapeutically promising for AIDS treatment.