Recent advances in antiviral research: identification of inhibitors of the herpesvirus proteases.
Major advances have been reported in the last two years regarding the molecular biology and structural properties of the herpesvirus proteases. X-ray diffraction studies have enabled several groups to solve the structure of the human cytomegalovirus protease. Fluorescence-based substrate assays have also been recently reported. These substrates exhibit sufficient kinetic and sensitivity properties to enable high-throughput screening efforts dedicated toward the discovery of protease inhibitors. Three classes of inhibitors have been reported recently: nonpeptidic aryl trifluoromethylketones; alternate substrate inhibitors (benzoxazinones/azalactones); and thiol-modifying inhibitors. The thiol-modifying class offers a unique opportunity to discover inhibitors specific to the human cytomegalovirus protease, as this protease requires reduced cysteine residues for its enzymatic activity.
Searle Research and Development, Department of Medicinal Chemistry, 800 N Lindbergh Blvd, St Louis, MO 63167, USA. dlflyn@monsanto.com
D L
DL
Flynn
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Abood
B C
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Holwerda
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000627:therapeutic use*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors