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<p>Covalent inhibitors that do not rely on hijacking enzymatic activity have mainly been limited to those targeting cysteine residues. The development of such cysteine-directed covalent inhibitors has greatly profited from the use of competitive residue-specific proteomics to determine their proteome-wide selectivity. Several probes have been developed to monitor other amino acids using this technology, and many more electrophiles exist to modify proteins. Nevertheless, there has been a lack of direct, proteome-wide comparisons of the selectivity of diverse electrophiles. Here we developed an unbiased workflow to analyse electrophile selectivity proteome-wide and used it to directly compare 56 alkyne probes containing diverse reactive groups. In this way, we verified and identified probes to monitor a total of nine different amino acids, as well as the protein amino terminus, across the proteome.</p><p></p>

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Profiling the proteome-wide selectivity of diverse electrophiles

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月30日

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  • Patrick R. A. Zanon,
  • Fengchao Yu,
  • Patricia Z. Musacchio,
  • Lisa Lewald,
  • Michael Zollo,
  • Kristina Krauskopf,
  • Dario Mrdović,
  • Patrick Raunft,
  • Thomas E. Maher,
  • Marko Cigler,
  • Christopher J. Chang,
  • Kathrin Lang,
  • F. Dean Toste,
  • Alexey I. Nesvizhskii,
  • Stephan M. Hacker

摘要

Covalent inhibitors that do not rely on hijacking enzymatic activity have mainly been limited to those targeting cysteine residues. The development of such cysteine-directed covalent inhibitors has greatly profited from the use of competitive residue-specific proteomics to determine their proteome-wide selectivity. Several probes have been developed to monitor other amino acids using this technology, and many more electrophiles exist to modify proteins. Nevertheless, there has been a lack of direct, proteome-wide comparisons of the selectivity of diverse electrophiles. Here we developed an unbiased workflow to analyse electrophile selectivity proteome-wide and used it to directly compare 56 alkyne probes containing diverse reactive groups. In this way, we verified and identified probes to monitor a total of nine different amino acids, as well as the protein amino terminus, across the proteome.