Peptide therapeutics: Targeting the undruggable space
Peptide therapeutics: Targeting the undruggable space
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DOI：
10.1016/j.ejmech.2015.01.014
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发表时间：
2015-04-13
影响因子：
6.7
通讯作者：
Tsomaia, Natia
中科院分区：
文献类型：
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作者：
Tsomaia, Natia
基因组学的快速发展使人们对各种疾病的分子机制有了更好的了解，并确定了一些极具吸引力的靶类。其中一些靶点包括细胞内蛋白质相互作用(PPI)，它控制着许多基本的生物途径。它们的表面是一个多样化和未被探索的生物空间的一部分，在那里传统的小分子支架并不总是成功的。虽然大的生物制品可以有效地调节细胞外区域的PPI，但它们在穿过细胞膜方面的局限性使细胞内的蛋白质靶标无法到达。在制药领域，人们越来越需要突破传统药物设计的界限，发现能够通过抑制细胞内PPI来调节关键生物学途径的创新分子。多肽是在不久的将来可以提供这种疗法的最有希望的一类分子之一。在这篇综述中，我们描述了稳定活性多肽构象的技术进展和新出现的化学方法，包括装订、氢键替代、β-发夹模拟、稳定支架上的接枝和大环化。这些设计策略有望为多肽疗法打开大门，使其进入目前“无法用药”的领域。(C)2015年爱思唯尔·马森公司。版权所有。
Rapid advancements in genomics have brought a better understanding of molecular mechanisms for various pathologies and identified a number of highly attractive target classes. Some of these targets include intracellular protein protein interactions (PPIs), which control many essential biological pathways. Their surfaces are part of a diverse and unexplored biological space, where traditional small molecule scaffolds are not always successful. While large biologics can effectively modulate PPIs in the extracellular region, their limitation in crossing the cellular membrane leaves intracellular protein targets outside of their reach. There is a growing need in the pharmaceutical field to push the boundaries of traditional drug design and discover innovative molecules that are able to modulate key biological pathways by inhibiting intracellular PPIs. Peptides are one of the most promising classes of molecules that could deliver such therapeutics in the near future. In this review, we describe technological advancements and emerging chemical approaches for stabilizing active peptide conformations, including stapling, hydrogen bond surrogates, beta-hairpin mimetics, grafting on stable scaffolds, and macrocyclization. These design strategies carry the promise of opening the doors for peptide therapeutics to reach the currently "undruggable" space. (C) 2015 Elsevier Masson SAS. All rights reserved.