Journal
CHEMMEDCHEM
Volume 15, Issue 22, Pages 2176-2184Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000355
Keywords
covalent drugs; Lys-covalent; Tyr-covalent; protein-protein interactions; sulfonyl fluorides; PPIs
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Funding
- NIH [CA168517, CA242620, NS107479]
- City of Hope - UC Riverside Biomedical Research Initiative (CUBRI)
- Division of Biomedical Sciences, School of Medicine at UCR
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Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein-protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys-targeting moieties, incorporating these electrophiles in XIAP (X-linked inhibitor of apoptosis protein) targeting agents. We evaluated stability in buffer and reactivity with Lys311 of XIAP of various aryl-sulfonyl fluorides using biochemical and biophysical approaches, including displacement assays, mass spectrometry, SDS gel electrophoresis, and denaturation thermal shift measurements. To assess whether these modified electrophilic warheads can also react with Tyr, we repeated these evaluations with a Lys311Tyr XIAP mutant. Using a direct cellular assay, we could demonstrate that selected agents are cell permeable and interact covalently with their intended target in cell. These results suggest that certain substituted aryl-sulfonyl fluorides can be useful Lys- or Tyr-targeting electrophiles for the design of covalent pharmacological tools or even future therapeutics targeting protein-protein interactions.
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