Document 0184
 DOCN  M9440184
 TI    Characterization of human immunodeficiency virus type 1 variants with
       increased resistance to a C2-symmetric protease inhibitor.
 DT    9404
 AU    Ho DD; Toyoshima T; Mo H; Kempf DJ; Norbeck D; Chen CM; Wideburg NE;
       Burt SK; Erickson JW; Singh MK; Aaron Diamond AIDS Research Center, New
       York University School of; Medicine, New York 10016.
 SO    J Virol. 1994 Mar;68(3):2016-20. Unique Identifier : AIDSLINE
       MED/94149902
 AB    Inhibitors of the human immunodeficiency virus type 1 protease represent
       a promising class of antiviral drugs for the treatment of AIDS, and
       several are now in clinical trials. Here, we report the in vitro
       selection of viral variants with decreased sensitivity to a C2-symmetric
       protease inhibitor (A-77003). We show that a single amino acid
       substitution (Arg to Gln or Lys) at position 8 of the protease results
       in a substantial decrease in the inhibitory activity of the drug on the
       enzyme and a comparable increase in viral resistance. These findings,
       when analyzed by using the three-dimensional structure of the
       protease-drug complex, provide a strategic guide for the future
       development of inhibitors of the human immunodeficiency virus type 1
       protease.
 DE    Amino Acid Sequence  Antiviral Agents/*PHARMACOLOGY  Base Sequence
       Comparative Study  Dose-Response Relationship, Drug  Drug Design  Drug
       Resistance, Microbial  HIV Protease/*DRUG EFFECTS/*GENETICS  HIV
       Protease Inhibitors/*PHARMACOLOGY  HIV-1/*ENZYMOLOGY  Models, Molecular
       Molecular Sequence Data  Selection (Genetics)  Sequence Homology, Amino
       Acid  Structure-Activity Relationship  Support, Non-U.S. Gov't  Support,
       U.S. Gov't, P.H.S.  Variation (Genetics)  JOURNAL ARTICLE

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