Applications of Reactive Cysteine Profiling

Curr Top Microbiol Immunol. 2019;420:375-417. doi: 10.1007/82_2018_120.


Cysteine thiols are involved in a diverse set of biological transformations, including nucleophilic and redox catalysis, metal coordination and formation of both dynamic and structural disulfides. Often posttranslationally modified, cysteines are also frequently alkylated by electrophilic compounds, including electrophilic metabolites, drugs, and natural products, and are attractive sites for covalent probe and drug development. Quantitative proteomics combined with activity-based protein profiling has been applied to annotate cysteine reactivity, susceptibility to posttranslational modifications, and accessibility to chemical probes, uncovering thousands of functional and small-molecule targetable cysteines across a diverse set of proteins, proteome-wide in an unbiased manner. Reactive cysteines have been targeted by high-throughput screening and fragment-based ligand discovery efforts. New cysteine-reactive electrophiles and compound libraries have been synthesized to enable inhibitor discovery broadly and to minimize nonspecific toxicity and off-target activity of compounds. With the recent blockbuster success of several covalent inhibitors, and the development of new chemical proteomic strategies to broadly identify reactive, ligandable and posttranslationally modified cysteines, cysteine profiling is poised to enable the development of new potent and selective chemical probes and even, in some cases, new drugs.

Publication types

  • Review

MeSH terms

  • Cysteine / chemistry*
  • Cysteine / metabolism*
  • Humans
  • Ligands
  • Protein Processing, Post-Translational
  • Proteome / analysis*
  • Proteome / chemistry
  • Proteome / metabolism*
  • Proteomics*


  • Ligands
  • Proteome
  • Cysteine