Journal
BIOPOLYMERS
Volume 88, Issue 5, Pages 657-686Publisher
WILEY
DOI: 10.1002/bip.20741
Keywords
protein-protein interaction; p53; MDM2; foldamer; proteomimetic
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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, beta-hairpins, poligobenzamides, beta-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. (c) 2007 Wiley Periodicals, Inc.
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