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Stability and Cell Permeability of Sulfonyl Fluorides in the Design of Lys‐Covalent Antagonists of Protein‐Protein Interactions
Author(s) -
Gambini Luca,
Udompholkul Parima,
Salem Ahmed F.,
Baggio Carlo,
Pellecchia Maurizio
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000355
Subject(s) - sulfonyl , covalent bond , chemistry , protein stability , permeability (electromagnetism) , cell permeability , combinatorial chemistry , stereochemistry , biophysics , pharmacology , biochemistry , organic chemistry , medicine , biology , membrane , alkyl
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.