The Human Immunodeficiency Virus protease (HIV PR) is essential for viral replication. The FDA has approved ten competitive HIV PR inhibitors for antiretroviral therapy, but all of them illicit the evolution of resistant protease variants. The development of non-competitive inhibitors (directed at the dimerization domain) would enable combination therapy directed against two different sites within HIV PR. We “randomized” the dimerization domain of HIV protease, and identified a dominant negative mutant by genetic selection in recombinant Escherichia coli. The selected amino acids are completely unrelated to the analogous wild-type sequence, but the mutant protein efficiently inhibits the wild-type enzyme activity in vitro and in vivo. The synthetic pentapeptide in isolation also inhibits the wild-type protease activity in vitro. This approach could be applied to identify novel pharmaceutical lead compounds against a variety of oligomeric targets.

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