Document 0341
 DOCN  M94A0341
 TI    A C2 symmetry-based HIV protease inhibitor, A77003, irreversibly
       inhibits infectivity of HIV-1 in vitro.
 DT    9412
 AU    Kageyama S; Hoekzema DT; Murakawa Y; Kojima E; Shirasaka T; Kempf DJ;
       Norbeck DW; Erickson J; Mitsuya H; Experimental Retrovirology Section,
       National Cancer Institute,; Bethesda, Maryland.
 SO    AIDS Res Hum Retroviruses. 1994 Jun;10(6):735-43. Unique Identifier :
       AIDSLINE MED/94355120
 AB    A C2 symmetry-based HIV protease inhibitor, A77003, exerts potent
       antiviral activity against a wide spectrum of HIV isolates in vitro. In
       this study, we asked whether A77003 could cause irreversible
       conformational changes to HIV-1, whether the amounts of viral RNA and
       p24 capsid protein per virion were altered, and how the infectivity of
       the virus produced in the presence of the drug was affected. We found
       that the number of viral particles and per-virion viral RNA content of
       the virus produced in the presence of A77003 did not significantly
       differ from those of the virus produced in the absence of the drug,
       whereas significant morphological changes were observed as assessed by
       transmission electron microscopy. However, the virus produced in the
       presence of A77003 contained substantially less p24gag protein per
       virion particle as compared to those produced in the absence of the drug
       or in the presence of AZT. Virions produced in the presence of A77003
       showed up to 50-fold less infectious capability in subsequent tissue
       culture than control virions produced in the absence of drug or in the
       presence of AZT. This reduction in infectivity was maintained for at
       least 10 days in culture. The present data suggest that A77003 impairs
       HIV-1 protease-mediated Gag processing, interferes with the assembly and
       maturation of the virus, and leads to an irreversible loss of the
       infectivity of the virus, although a low but positive level of reversion
       to infectivity during the 10-day assay occurs. These features of A77003
       (and perhaps similar HIV protease inhibitors as well) anti-HIV activity
       should represent desirable properties for antiviral therapy of AIDS and
       related diseases.
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence  Cell Line  Comparative
       Study  Gene Products, gag/ANALYSIS  HIV Infections/DRUG
       THERAPY/*PREVENTION & CONTROL  HIV Protease Inhibitors/*PHARMACOLOGY
       HIV-1/*DRUG EFFECTS/PATHOGENICITY/ULTRASTRUCTURE  Molecular Sequence
       Data  RNA, Viral/ANALYSIS  Virion/DRUG EFFECTS  Zidovudine/PHARMACOLOGY
       JOURNAL ARTICLE

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