Reactive electrophiles, oxidants, and disulfide bonds

Reactive electrophiles, oxidants, and disulfide bonds represent a broad category of chemical entities and modifications central to cellular redox homeostasis and signaling. Electrophiles and oxidants, such as reactive oxygen species (ROS), are produced endogenously during metabolism or introduced via exogenous stressors, where they can cause oxidative damage to DNA, lipids, and proteins (Sies et al., 2017, Nature Reviews Molecular Cell Biology). However, they also serve as critical signaling molecules by reacting with specific "sensor" cysteine thiols on proteins, often leading to the formation of disulfide bonds or covalent adducts that alter protein function. A primary example is the Keap1-Nrf2 pathway, where electrophilic modification of Keap1 triggers the nuclear translocation of Nrf2 to induce the expression of antioxidant genes (Yamamoto et al., 2018, Physiological Reviews). While not a single therapeutic target, this collective group is the focus of drug development aimed at either neutralizing harmful oxidants with antioxidants or utilizing "soft" electrophiles to pharmacologically activate protective cellular defenses. Drugs like dimethyl fumarate utilize electrophilic properties to modulate the immune system in multiple sclerosis by targeting these redox-sensitive pathways (Linker et al., 2011, Brain). Consequently, understanding the reactivity of these species is vital for designing covalent inhibitors and redox-modulating therapies for inflammation and neurodegeneration.

Other names

Reactive oxygen species (ROS)Electrophilic stressorsThiol-reactive speciesOxidative stressorsReactive nitrogen species (RNS)Thiol-disulfide exchange

Activation of the Nrf2-mediated antioxidant response via covalent modification of Keap1 cysteine residues and neutralization of reactive species (Yamamoto et al., 2018, Physiological Reviews; Sies et al., 2017, Nature Reviews Molecular Cell Biology).