Coevolutionary analysis of resistance-evading peptidomimetic inhibitors ofHIV-1 protease

We have developed a coevolutionary method for the computational design of H IV-1 protease inhibitors selected for their ability to retain efficacy in t he face of protease mutation. For HIV-1 protease, typical drug design techn iques are shown to be ineffective for the design of resistance-evading inhi bitors: An inhibitor that is a direct analogue of one of the natural substr ates will be susceptible to resistance mutation, as will inhibitors designe d to fill the active site of the wild-type or a mutant enzyme. Two design p rinciples are demonstrated: (i) For enzymes with broad substrate specificit y, such as HIV-1 protease, resistance evading inhibitors are best designed against the immutable properties of the active site-the properties that mus t be conserved in any mutant protease to retain the ability to bind and cle ave all of the native substrates. (ii) Robust resistance-evading inhibitors can be designed by optimizing activity simultaneously against a large set of mutant enzymes, incorporating as much of the mutational space as possibl e.