title: Investigating the proteome reactivity and selectivity of aryl halides.
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.
authors.affiliation: Department of Chemistry, Merkert Chemistry Center , Boston College, Chestnut Hill, Massachusetts 02467, United States.
authors.forename: D Alexander
authors.initials: DA
authors.lastname: Shannon
authors.forename: Ranjan
authors.initials: R
authors.lastname: Banerjee
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Webster
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bak
authors.forename: Chu
authors.initials: C
authors.lastname: Wang
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
mesh_terms: D000595:Amino Acid Sequence; D001554:Benzene / Q000737:chemistry*; D006219:Halogens / Q000737:chemistry*; D008969:Molecular Sequence Data; D020543:Proteome / Q000737:chemistry*
chemical_list: D006219:Halogens; D020543:Proteome; D001554:Benzene