Mizuno Akira, Matsui Kouhei, Shuto Satoshi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
Chemistry. 2017 Oct 17;23(58):14394-14409. doi: 10.1002/chem.201702119. Epub 2017 Aug 22.
Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug molecules. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell-membrane permeability for targeting protein-protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomolecules. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chemistry is described.
肽模拟物是生物活性肽的非天然模拟物，是一类重要的药物分子。肽模拟物设计的本质是模拟生物活性肽与靶点结合时所呈现的关键构象。调节肽模拟物的构象不仅对于提高靶点结合亲和力和选择性很重要，而且对于赋予细胞膜通透性以靶向细胞内的蛋白质-蛋白质相互作用也很重要。然而，由于肽固有的灵活性及其与靶标生物分子结合时的动态构象变化，合理设计具有合适三维结构的肽模拟物具有挑战性。在这篇小型综述中，描述了一种基于环丙烷特征结构特征的三维结构多样性导向策略，以解决肽模拟化学中的这一具有挑战性的问题。
