title: Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor.
abstract: 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.
authors.affiliation: Aaron Diamond AIDS Research Center, New York University School of Medicine, New York 10016.
authors.forename: D D
authors.initials: DD
authors.lastname: Ho
authors.forename: T
authors.initials: T
authors.lastname: Toyoshima
authors.forename: H
authors.initials: H
authors.lastname: Mo
authors.forename: D J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: D
authors.initials: D
authors.lastname: Norbeck
authors.forename: C M
authors.initials: CM
authors.lastname: Chen
authors.forename: N E
authors.initials: NE
authors.lastname: Wideburg
authors.forename: S K
authors.initials: SK
authors.lastname: Burt
authors.forename: J W
authors.initials: JW
authors.lastname: Erickson
authors.forename: M K
authors.initials: MK
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004352:Drug Resistance, Microbial; D014644:Genetic Variation; D016333:HIV Protease / Q000187:drug effects* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D008782:Methylurea Compounds; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011725:Pyridines; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D011725:Pyridines; C079555:Abbott 77003; D016333:HIV Protease; D014633:Valine