Investigating the Proteome Reactivity and Selectivity of Aryl Halides

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 (SNAr) 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.