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J Biol Chem, Vol. 274, Issue 34, 23699-23701, August 20, 1999
From the Department of Antiviral Research, Merck Research
Laboratories, West Point, Pennsylvania 19486
Three high level, cross-resistant variants of the
HIV-1 protease have been analyzed for their ability to bind four
protease inhibitors approved by the Food and Drug Administration
(saquinavir, ritonavir, indinavir, and nelfinavir) as AIDS
therapeutics. The loss in binding energy (
Gb)
going from the wild-type enzyme to mutant enzymes ranges from 2.5 to
4.4 kcal/mol, 40-65% of which is attributed to amino acid
substitutions away from the active site of the protease and not in
direct contact with the inhibitor. The data suggest that non-active
site changes are collectively a major contributor toward engendering
resistance against the protease inhibitor and cannot be ignored when
considering cross-resistance issues of drugs against the HIV-1 protease.
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