Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display

J Am Chem Soc. 2024 Aug 28;146(34):24053-24060. doi: 10.1021/jacs.4c07851. Epub 2024 Aug 13.

Abstract

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.

MeSH terms

  • Cyclization
  • Drug Discovery
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology
  • Molecular Structure
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • RNA, Messenger* / antagonists & inhibitors
  • Sulfides / chemistry
  • Sulfides / pharmacology
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • RNA, Messenger
  • Sulfides
  • Peptides, Cyclic
  • Macrocyclic Compounds
  • Sulfones
  • Protease Inhibitors