Abstract
Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These molecules function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, most notably at reactive cysteines. More specifically, electrophiles target critical cysteines in redox regulatory proteins to activate protective pathways such as the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) antioxidant signaling pathway while also inhibiting Nuclear Factor κB (NF-κB). During inflammatory states, reactive species broadly alter cell signaling through the oxidation of lipids, amino acids, and nucleic acids, effectively propagating the inflammatory sequence. Subsequent changes in metabolic signaling inform immune cell maturation and effector function. Therapeutic strategies targeting inflammatory pathologies leverage electrophilic drug compounds, in part, because of their documented effect on the redox balance of the cell. With mounting evidence demonstrating the link between redox signaling and metabolism, electrophiles represent ideal therapeutic candidates for the treatment of inflammatory conditions. Through their pleiotropic signaling activity, electrophiles may be used strategically to both directly and indirectly target immune cell metabolism.
Highlights
Inflammation is essential to the management of both sterile and infectious insults
It has been posited that succinate accumulation in LPS-activated macrophages is the result of itaconate production and subsequent inhibition of succinate dehydrogenase (SDH)) two anaplerotic pathways are utilized by activated macrophage as a fuel source: the glutamine shunt and the arginosuccinate shunt
The Reactive species (RS) produced during both acute and chronic inflammatory conditions are sufficient to alter cell signaling through the oxidation of lipids, amino acids, and even nucleic acids
Summary
Inflammation is essential to the management of both sterile and infectious insults. The cellular processes regulating the resolution of these inflammatory responses are required to prevent unnecessary host damage [1]. Protein functional groups containing nucleophilic moieties are subject to adduction by these electrophilic species As soft electrophiles, this reaction is reversible, but capable of creating PTM at active cysteine, lysine, and histidine residues, thereby altering enzyme activity or signaling functionality in the cell. While these PTM most commonly occur on cysteine thiols during redox signaling, a Schiff base may form with amine groups found on lysine and histidine residues. In addition to increasing the expression of genes directly involved in redox homeostasis, electrophiles can alter the redox signaling indirectly through the inhibition of the pro-inflammatory transcription factor, nuclear factor kappa light chain enhancer of activated B cells (NF-κB) [38,39]. Reversible adduct that can alter the cell signaling activity or enzymatic activity of the effected protein
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