Targeting protein-protein interactions: Lessons from p53/MDM2
Targeting protein-protein interactions: Lessons from p53/MDM2
复制标题
DOI：
10.1002/bip.20741
复制
发表时间：
2007-01-01
期刊：
影响因子：
2.9
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Murray, Justin K.;Gellman, Samuel H.
抑制治疗上重要的蛋白质-蛋白质相互作用的巨大挑战创造了将传统药物化学扩展到一类新靶点和探索非传统策略的机会。在这里，我们回顾了一个广泛研究的系统，肿瘤抑制基因p53和它的天然拮抗剂MDM 2之间的相互作用，传统和非传统的方法都有报道。该系统已经成为基于新型蛋白质模拟支架的策略的试验场，即，用于尝试模拟具有非天然寡聚体的折叠蛋白质所展示的识别表面。逆转录酶肽，类肽，三联苯，β-发夹，poligobenzamides，β-肽，和miniproteins都已被探索作为抑制剂的p53/MDM 2相互作用，我们专注于这些寡聚体为基础的努力。传统的方法也取得了成功，我们简要回顾了小分子抑制剂沿着与其他策略的p53通路的再激活，与寡聚体为基础的方法进行比较。最后，我们对蛋白质-蛋白质相互作用靶点之间出现的二分法进行了评论。(c)2007 Wiley Periodicals，Inc.
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.