Document 0637
 DOCN  M9460637
 TI    Human immunodeficiency virus type 1 protease inhibitors: evaluation of
       resistance engendered by amino acid substitutions in the enzyme's
       substrate binding site.
 DT    9404
 AU    Sardana VV; Schlabach AJ; Graham P; Bush BL; Condra JH; Culberson JC;
       Gotlib L; Graham DJ; Kohl NE; LaFemina RL; et al; Department of Virus
       and Cell Biology, Merck Research; Laboratories, West Point, Pennsylvania
       19486.
 SO    Biochemistry. 1994 Mar 1;33(8):2004-10. Unique Identifier : AIDSLINE
       MED/94162203
 AB    The human immunodeficiency virus type 1 (HIV-1) protease is a
       homodimeric aspartyl endopeptidase that is required for virus
       replication. A number of specific, active-site inhibitors for this
       enzyme have been described. Many of the inhibitors exhibit significant
       differences in activity against the HIV-1 and HIV type 2 (HIV-2)
       enzymes. An initial study was conducted to ascertain the HIV-1
       protease's potential to lose sensitivity to several test inhibitors
       while retaining full enzymatic activity. The substrate binding sites of
       the HIV-1 and HIV-2 enzymes are almost fully conserved, except for four
       amino acid residues at positions 32, 47, 76, and 82. Accordingly,
       recombinant mutant type 1 proteases were constructed that contained the
       cognate type 2 residue at each of these four positions. The substitution
       at position 32 resulted in a significant adverse effect on inhibitor
       potency. However, this substitution also mediated a noted increase in
       the Km of the substrate. Individual substitutions at the remaining three
       positions, as well as a combination of all four substitutions, had very
       little effect on enzyme activity or inhibitor susceptibility. Hence, the
       four studied active site residues are insufficient to be responsible for
       differences in inhibitor sensitivity between the HIV-1 and HIV-2
       proteases and are unlikely to contribute to the generation of
       inhibitor-resistant mutant HIV-1 protease.
 DE    Amino Acids/*GENETICS  Benzopyrans/PHARMACOLOGY  Binding Sites/GENETICS
       Cloning, Molecular  Computer Graphics  Drug Resistance, Microbial
       Escherichia coli/GENETICS  HIV Protease/*GENETICS/METABOLISM  HIV
       Protease Inhibitors/CHEMISTRY/*PHARMACOLOGY  Isoquinolines/PHARMACOLOGY
       Kinetics  Models, Molecular  Morpholines/PHARMACOLOGY
       Peptides/PHARMACOLOGY  Quinolines/PHARMACOLOGY  Recombinant
       Proteins/GENETICS/METABOLISM  Valine/ANALOGS & DERIVATIVES/PHARMACOLOGY
       JOURNAL ARTICLE

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