       Document 0355
 DOCN  M9620355
 TI    Characteristics of a group of nonnucleoside reverse transcriptase
       inhibitors with structural diversity and potent anti-human
       immunodeficiency virus activity.
 DT    9602
 AU    Yang SS; Fliakas-Boltz V; Bader JP; Buckheit RW Jr; Antiviral Evaluation
       Branch, National Cancer Institute, Bethesda,; MD 20892, USA.
 SO    Leukemia. 1995 Oct;9 Suppl 1:S75-85. Unique Identifier : AIDSLINE
       MED/96022226
 AB    Current thrust in controlling the Acquired Immune Deficiency Syndrome
       (AIDS) focuses on antiviral drug development targeting the infection and
       replication of the human immunodeficiency virus (HIV), the causative
       agent of AIDS. To date, treatment of AIDS has relied on nucleoside
       reverse transcriptase inhibitors such as AZT, ddI, and ddC, which
       eventually become ineffective upon the emergence of resistant mutants
       bearing specific nucleotide substitutions. The Anti-AIDS Drug Screening
       Program of the NCI conducts and coordinates a high-capacity semi-robotic
       in vitro screening of synthetic or natural compounds submitted by
       academic, research and pharmaceutical institutions world-wide. About
       10,000 synthetic compounds are screened annually for anti-HIV activity.
       Confirmed active agents are subjected to in-depth studies on range and
       mechanism of action. Emerging from this intense screening activity were
       a number of potentially promising categories of nonnucleoside reverse
       transcriptase inhibitors (NNRTI) with structural diversity but strong
       and reproducible anti-HIV activity. Over 2500 active compounds were
       evaluated for their inhibitory activity against a panel of both
       laboratory 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 categories with an additional 16 unique compounds that share the
       characteristics of NNRTI. These NNRTIs were shown to inhibit reverse
       transcriptase enzymatically using homopolymeric or ribosomal RNA as
       templates. NNRTIs demonstrated similarity in their inhibitory pattern
       against the HIV-1 laboratory strains IIIB and RF, and an AZT-resistant
       strain; all were inactive against HIV-2. These compounds were further
       tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1
       isolates were selected and characterized with respect to the change(s)
       in the viral reverse transcriptase nucleotide sequence. Also,
       differential cross-resistance 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, suggesting that combination antiviral therapy of
       NNRTIs with AZT may be therapeutically promising for AIDS treatment.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY  Antiviral
       Agents/*PHARMACOLOGY/THERAPEUTIC USE  Cell Line  Cell Survival/DRUG
       EFFECTS  Comparative Study  Drug Resistance, Microbial  Drug
       Screening/METHODS  Human  HIV-1/*DRUG EFFECTS/PHYSIOLOGY  National
       Institutes of Health (U.S.)  Reverse Transcriptase
       Inhibitors/*PHARMACOLOGY/THERAPEUTIC USE  RNA-Directed DNA
       Polymerase/*METABOLISM  Structure-Activity Relationship  Support, U.S.
       Gov't, P.H.S.  United States  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

