Targeting protein–protein interactions: Lessons from p53/MDM2

Abstract

The tremendous challenge of inhibiting therapeutically important protein–protein interactions has created the opportunity to extend traditional medicinal chemistry to a new class of targets and to explore nontraditional strategies. Here we review a widely studied system, the interaction between tumor suppressor p53 and its natural antagonist MDM2, for which both traditional and nontraditional approaches have been reported. This system has been a testing ground for novel proteomimetic scaffold-based strategies, i.e., for attempts to mimic the recognition surface displayed by a folded protein with unnatural oligomers. Retroinverso peptides, peptoids, terphenyls, β-hairpins, p-oligobenzamides, β-peptides, and miniproteins have all been explored as inhibitors of the p53/MDM2 interaction, and we focus on these oligomer-based efforts. Traditional approaches have been successful as well, and we briefly review small molecule inhibitors along with other strategies for reactivation of the p53 pathway, for comparison with oligomer- based approaches. We close with comments on an emerging dichotomy among protein–protein interaction targets. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 657–686, 2007.

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