Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
J Am Chem Soc. 2015 Jan 21;137(2):715-21. doi: 10.1021/ja508766b. Epub 2015 Jan 8.
Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side-chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds toward development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.
药物设计工作正在转向新一代治疗靶点，如蛋白质-蛋白质相互作用（PPIs），这些靶点以前被认为是典型小分子“不可成药”的。有一种新的观点认为，要实现这些靶点，需要的分子比典型的小分子药物更大、更复杂。在这里，我们提出了一种基于组合文库的合成和渗透性筛选来发现具有不同几何形状和膜渗透性的环状肽支架的方法，然后对膜渗透性支架进行去卷积，以鉴定具有良好至优异的被动细胞渗透性的环状肽。我们使用实验和计算相结合的方法来研究其中一种支架中的结构-渗透性关系，并揭示了控制一组相关环状肽非对映异构体中被动膜扩散的结构和构象因素。此外，我们通过单点多样化来研究其中一种支架的渗透性对侧链身份的依赖性，以证明这些支架在开发适合生物活性筛选的渗透性偏向文库方面的适应性。总的来说，我们的结果表明，除了在现有天然产物中发现的那些以外，还有许多新型的、可穿透细胞的支架存在，并且可以使用合成和去卷积的组合来快速识别这些支架，原则上可以将其应用于任何类型的大环模板。
