Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.

ABSTRACT: We have developed a coevolutionary method for the computational design of HIV-1 protease inhibitors selected for their ability to retain efficacy in the face of protease mutation. For HIV-1 protease, typical drug design techniques are shown to be ineffective for the design of resistance-evading inhibitors: An inhibitor that is a direct analogue of one of the natural substrates will be susceptible to resistance mutation, as will inhibitors designed to fill the active site of the wild-type or a mutant enzyme. Two design principles are demonstrated: (i) For enzymes with broad substrate specificity, such as HIV-1 protease, resistance-evading inhibitors are best designed against the immutable properties of the active site-the properties that must be conserved in any mutant protease to retain th

SUBMITTER: Rosin CD 

PROVIDER: S-EPMC15469 | biostudies-literature | 1999 Feb

REPOSITORIES: biostudies-literature