Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows

Franco F. Faucher, Daniel Abegg, Phillip Ipock, Alexander Adibekian, Scott Lovell, Matthew Bogyo

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)

Abstract

Macrocyclic peptides are attractive for chemoproteomic applications due to their modular synthesis and potential for high target selectivity. We describe a solid phase synthesis method for the efficient generation of libraries of small macrocycles that contain an electrophile and alkyne handle. The modular synthesis produces libraries that can be directly screened using simple SDS-PAGE readouts and then optimal lead molecules applied to proteomic analysis. We generated a library of 480 macrocyclic peptides containing the weakly reactive fluorosulfate (OSF) electrophile. Initial screening of a subset of the library containing each of the various diversity elements identified initial molecules of interest. The corresponding positional and confirmational isomers were then screened to select molecules that showed specific protein labeling patterns that were dependent on the probe structure. The most promising hits were applied to standard chemoproteomic workflows to identify protein targets. Our results demonstrate the feasibility of rapid, on-resin synthesis of diverse macrocyclic electrophiles to generate new classes of covalent ligands.

Original languageEnglish
Article numbere202300020
Number of pages11
JournalIsrael Journal of Chemistry
Volume63
Issue number3-4
Early online date1 Mar 2023
DOIs
Publication statusPublished - 1 Mar 2023

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article. The raw proteomics data is available on the PRIDE database with dataset identifier PXD039931.

Keywords

  • chemoproteomics
  • electrophile
  • Fluorosulfate
  • macrocycles
  • SuFEx

ASJC Scopus subject areas

  • Chemistry(all)

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