Tong Lan, Cheng Peng, Xiyuan Yao, Rachel Shu Ting Chan, Tongyao Wei, Anuchit Rupanya, Aleksandar Radakovic, Sijie Wang, Shiyu Chen, Scott Lovell, Scott A Snyder, Matthew Bogyo, Bryan C Dickinson
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引用次数: 0
摘要
大环肽是发现共价配体的前景广阔的支架。然而，能以高通量方式直接鉴定共价大环配体的平台却很有限。在这项研究中，我们提出了一种 mRNA 展示平台，该平台允许使用 1,3-二溴丙酮-乙烯基砜（DBA-VS）选择共价大环抑制剂。在对 TEV 蛋白酶进行试验选择后，产生了具有不同环状结构的强效共价抑制剂，其中 cTEV6-2 是一种具有独特 C 端环化结构的大环肽，是迄今为止描述的最强效的 TEV 蛋白酶共价抑制剂。本研究概述了将化学功能化--共价弹头的安装--与 mRNA 展示相结合的工作流程，并展示了其在靶向共价配体发现中的应用。
Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display.
Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalization─installation of a covalent warhead─with mRNA display and showcases its application in targeted covalent ligand discovery.
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The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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