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Updated: May 2, 2026
Identification of Small Molecule-binding Proteins in a Native Cellular Environment by Live-cell Photoaffinity Labeling
Published on: September 20, 2016
Investigating the proteome reactivity and selectivity of aryl halides
D Alexander Shannon1, Ranjan Banerjee, Elizabeth R Webster
1Department of Chemistry, Merkert Chemistry Center , Boston College, Chestnut Hill, Massachusetts 02467, United States.
Abstract:
Protein-reactive electrophiles are critical to chemical proteomic applications including activity-based protein profiling, site-selective protein modification, and covalent inhibitor development. Here, we explore the protein reactivity of a panel of aryl halides that function through a nucleophilic aromatic substitution (S(N)Ar) mechanism. We show that the reactivity of these electrophiles can be finely tuned by varying the substituents on the aryl ring. We identify p-chloro- and fluoronitrobenzenes and dichlorotriazines as covalent protein modifiers at low micromolar concentrations. Interestingly, investigating the site of labeling of these electrophiles within complex proteomes identified p-chloronitrobenzene as highly cysteine selective, whereas the dichlorotriazine favored reactivity with lysines. These studies illustrate the diverse reactivity and amino-acid selectivity of aryl halides and enable the future application of this class of electrophiles in chemical proteomics.
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