Valentine Jacob, Tavassoli Ali
School of Chemistry, University of Southampton, Southampton, United Kingdom.
School of Chemistry, University of Southampton, Southampton, United Kingdom.
Methods Enzymol. 2018;610:117-134. doi: 10.1016/bs.mie.2018.09.020. Epub 2018 Oct 24.
With the increasing utilization of high-throughput screening for lead identification in drug discovery, the need for easily constructed and diverse libraries which cover significant chemical space is greater than ever. Cyclic peptides address this need; they combine the advantageous properties of peptides (ease of production, high diversity, high potential specificity) with increased resistance to proteolysis and often increased biological activity (due to conformational locking). There are a number of techniques for the generation and screening of cyclic peptide libraries. As drug discovery moves toward tackling challenging targets, such as protein-protein interactions, cyclic peptide libraries are expected to continue producing hits where small molecule libraries may be stymied. However, it is important to design robust systems for the generation and screening of these large libraries, and to be able to make sense of structure-activity relationships in these highly variable scaffolds. There are a plethora of possible modifications that can be made to cyclic peptides, which is both a weakness and a strength of these scaffolds; high variability will allow more precise tuning of leads to targets, but exploring the whole range of modifications may become an overwhelming challenge.
随着高通量筛选在药物发现中用于先导化合物识别的应用日益增加，对易于构建且能覆盖重要化学空间的多样化文库的需求比以往任何时候都更为迫切。环肽满足了这一需求；它们将肽的有利特性（易于生产、高度多样性、高潜在特异性）与增强的抗蛋白水解能力以及通常增强的生物活性（由于构象锁定）相结合。有多种用于生成和筛选环肽文库的技术。随着药物发现朝着攻克诸如蛋白质 - 蛋白质相互作用等具有挑战性的靶点发展，预计环肽文库将继续产生小分子文库可能受阻之处的活性分子。然而，设计用于生成和筛选这些大型文库的稳健系统，并能够理解这些高度可变支架中的构效关系非常重要。环肽有大量可能的修饰，这既是这些支架的弱点也是优点；高变异性将允许对先导化合物进行更精确的靶点调整，但探索整个修饰范围可能会成为一项艰巨的挑战。
