Reactive electrophiles (RES)

Reactive electrophiles are electron-deficient chemical species that possess a high affinity for nucleophilic centers, such as the sulfhydryl groups of cysteine residues in proteins or nitrogenous bases in DNA (LoPachin & Gavin, 2014). These species can be generated endogenously through lipid peroxidation and metabolic processes, or they can be exogenous, arising from environmental toxins or the bioactivation of certain pharmaceuticals (Liebler, 2008). While they play roles in physiological signaling—most notably through the Keap1-Nrf2 pathway which triggers antioxidant defenses—an imbalance or excess of reactive electrophiles leads to electrophilic stress (Jacob et al., 2011). This stress results in irreversible covalent modifications of proteins and nucleic acids, contributing to the pathogenesis of cancer, neurodegeneration, and organ-specific toxicities like drug-induced liver injury (Farmer & Davoine, 2007). In pharmacology, reactive electrophiles are typically viewed as toxic intermediates to be scavenged by agents like N-acetylcysteine, although they are also intentionally incorporated as reactive warheads in covalent drugs to achieve prolonged target inhibition (Parvez et al., 2018).

Other names

Reactive electrophilic speciesElectrophilic metabolitesElectrophilesElectrophilic stress agents

Neutralization of electron-deficient species via nucleophilic scavenging or enzymatic conjugation (e.g., by glutathione S-transferases) to prevent irreversible covalent damage to cellular DNA and proteins.