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Drug–protein adducts: past, present, and future

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Abstract

Research over the past half-century has demonstrated that the metabolism of drugs and other foreign compounds to chemically reactive intermediates that bind covalently to endogenous proteins can, in certain cases, lead to organ damage or to immune-mediated adverse reactions. While the chemistry of metabolic activation is now relatively well understood, the molecular events that link exposure to reactive metabolites to toxic sequalae remain ill-defined. In particular, the role of covalent protein binding in drug-induced toxicities is unclear, and has been a controversial issue in drug discovery efforts. In this article, the covalent binding of drugs and other xenobiotics to proteins is reviewed from a historical perspective, and the evolution of the field is traced from an early dependence on radiolabeled tracers that provided limited information on adduct structure to contemporary label-free approaches based on powerful chemical proteomics and mass spectrometry methodology that provide a global perspective on proteome reactivity. Currently evolving databases of the proteins targeted by safe and toxic xenobiotics likely will lead in the future to predictive algorithms that can be exploited by medicinal chemists to assist in the design of safe therapeutic agents.

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  1. Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, 98195-7610, USA

    Thomas A. Baillie

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This article is dedicated to Professor Robert P Hanzlik on the occasion of his retirement after 49 years of research, teaching and service at the University of Kansas

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Baillie, T.A. Drug–protein adducts: past, present, and future. Med Chem Res 29, 1093–1104 (2020). https://doi.org/10.1007/s00044-020-02567-8

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