Mapping proteome-wide interactions of reactive chemicals using chemoproteomic platforms

• Many pharmaceuticals and environmental chemicals act through covalent mechanisms.
• Deciphering direct targets of reactive chemicals is important in mitigating toxicity.
• Chemoproteomics enables selectivity assessment of irreversibly-acting chemicals.

A large number of pharmaceuticals, endogenous metabolites, and environmental chemicals act through covalent mechanisms with protein targets. Yet, their specific interactions with the proteome still remain poorly defined for most of these reactive chemicals. Deciphering direct protein targets of reactive small-molecules is critical in understanding their biological action, off-target effects, potential toxicological liabilities, and development of safer and more selective agents. Chemoproteomic technologies have arisen as a powerful strategy that enable the assessment of proteome-wide interactions of these irreversible agents directly in complex biological systems. We review here several chemoproteomic strategies that have facilitated our understanding of specific protein interactions of irreversibly-acting pharmaceuticals, endogenous metabolites, and environmental electrophiles to reveal novel pharmacological, biological, and toxicological mechanisms.