Targeting protein-protein interactions: Lessons from p53/MDM2

被引:152
作者
Murray, Justin K. [1 ]
Gellman, Samuel H. [1 ]
机构
[1] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA
关键词
protein-protein interaction; p53; MDM2; foldamer; proteomimetic;
D O I
10.1002/bip.20741
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:657 / 686
页数:30
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