Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

被引：2

作者：

Lan, Tong ^{[1
]}

Peng, Cheng ^{[1
]}

Yao, Xiyuan ^{[1
]}

Chan, Rachel Shu Ting ^{[1
]}

Wei, Tongyao ^{[1
]}

Rupanya, Anuchit ^{[1
]}

Radakovic, Aleksandar ^{[1
]}

Wang, Sijie ^{[2
]}

Chen, Shiyu ^{[2
,3
]}

Lovell, Scott ^{[2
,4
]}

Snyder, Scott A. ^{[1
]}

Bogyo, Matthew ^{[2
,5
]}

Dickinson, Bryan C. ^{[1
,6
]}

机构：

[1] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[2] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Biotech Drug Res Ctr, Shanghai 201203, Peoples R China

[4] Univ Bath, Dept Biol & Biochem, Claverton Down BA2 7AY, Bath, England

[5] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA

[6] Chan Zuckerberg Biohub, Chicago, IL 60642 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2024年 / 146卷 / 34期

基金：

美国国家卫生研究院;

关键词：

IN-VITRO SELECTION; PEPTIDES; FUSIONS;

D O I：

10.1021/jacs.4c07851

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 & horbar;installation of a covalent warhead & horbar;with mRNA display and showcases its application in targeted covalent ligand discovery.

引用

页码：24053 / 24060

页数：8

共 15 条

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BIOMEDICINES, 2018, 6 (04)
[2] Recent Advances in Non-Standard Macrocyclic Peptide Ligand Discovery using mRNA Display
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ISRAEL JOURNAL OF CHEMISTRY, 2024, 64 (8-9)
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ACS CHEMICAL BIOLOGY, 2017, 12 (03) : 795 - 804
[10] A mechanistic perspective, clinical applications, and phage-display-assisted discovery of TNFα inhibitors
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