Synergistic binding of inhibitors to the protease from HIV type 1.
Inhibition of the protease in HIV is a potentially useful approach for the treatment of AIDS. In the course of evaluating inhibitors of the HIV-1 protease, we observed a strong synergism between certain inhibitors that might be expected to bind to different sites in this enzyme. The binding affinity of carbobenzyloxyisoleucinylphenylalaninol, for example, is increased 125-fold in the presence of carbobenzyloxyglutaminylisoamylamide. These synergistic effects between inhibitors have specific structural requirements that correlate well with the known substrate preference of the enzyme. The modular basis for this phenomenon remains to be elucidated but it could involve substrate-induced conformational change as part of the reaction mechanism. Similar effects have been reported previously for several zinc proteases. Thus this work extends the observation to a different class of enzymes and suggests that the phenomenon might be widespread.
Asante-Appiah
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Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Chan
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D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004357:Drug Synergism; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D010446:Peptide Fragments; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease