Efficient ligand discovery using sulfur(VI) fluoride reactive fragments

Arron Aatkar, Aini Vuorinen, Oliver E. Longfield, Katharine Gilbert, Rachel Peltier-Heap, Craig D. Wagner, Francesca Zappacosta,  Katrin Rittinger, Chun-wa Chung, David House, Nicholas C. O. Tomkinson, Jacob T. Bush

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of "beyond-cysteine" covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesized, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterized to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of "beyond-cysteine" covalent inhibitors.
Original languageEnglish
Pages (from-to)1926-1937
Number of pages12
JournalACS Chemical Biology
Issue number9
Early online date21 Apr 2023
Publication statusPublished - 15 Sept 2023


  • ligand discovery
  • sulfur (VI) fluoride reactive fragments
  • beyond-cysteine covalent inhibitors
  • ligands
  • liganded proteome
  • protein modifications


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