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The Proteome-Wide Potential for Reversible Covalency at Cysteine
Kristine Senkane1, Ekaterina V Vinogradova1, Radu M Suciu1
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Angewandte Chemie (International Ed. in English)
|June 22, 2019
Summary
Reversible covalent chemistry offers sustained target engagement without permanent protein damage. This study reveals broad proteome potential for reversible cysteine engagement using a novel mass spectrometry platform, aiding chemical probe discovery.
Area of Science:
- Chemical Biology
- Proteomics
- Drug Discovery
Background:
- Reversible covalent interactions offer sustained target engagement without permanent protein modification.
- Previous studies focused on reversible covalency in individual kinases, leaving proteome-wide potential unexplored.
- Cysteine residues are key targets for reversible covalent modification.
Purpose of the Study:
- To develop and apply a mass spectrometry-based platform for assessing proteome-wide cysteine engagement.
- To evaluate both irreversible and reversible interactions of small-molecule electrophiles with cysteine residues.
- To explore the potential of reversible covalency for chemical probe discovery.
Main Methods:
- Integration of gel filtration with activity-based protein profiling (ABPP).
- Mass spectrometry-based analysis of cysteine residues across the human proteome.
- Assessment of interactions with small-molecule electrophiles, including cyanoacrylamide fragments.
Main Results:
- Identification of numerous cysteine residues from diverse protein classes.
- Demonstration of reversible engagement of these cysteines by cyanoacrylamide electrophiles.
- Validation of the platform for assessing reversible covalent interactions.
Conclusions:
- Reversible covalency is a broadly applicable strategy for engaging cysteine residues across the proteome.
- The developed platform enables comprehensive assessment of cysteine reactivity.
- This approach holds significant potential for discovering novel chemical probes.
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