Electrophile Modulation of Inflammation: A Two-Hit Approach

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.

Electrophilic Compounds in the Human Diet and Their Role in the Induction of the Transcription Factor NRF2

“…In recent decades, ECs have attracted much attention in the field of drugs that are able to interact covalently. Electrophiles have long been recognized as mediators in inflammatory processes and can even modulate the immune response by regulating metabolic networks, as they function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, especially reactive cysteines [ 282 ].…”

Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease

“…MG covalently modifies nucleic acids and protein, leading to long-term changes that can exacerbate disease onset and progression (Figure ). These modifications can contribute to a “two-hit” approach, meaning that they induce secondary effects beyond those induced by changes in metabolic flux . MG was present in the plasma of lean individuals at 132 ± 63 nM, was increased to 181 ± 61 nM in overweight individuals, and further increased to 245 ± 123 nM in obese subjects. , Glucose is a significant source of MG both from its nonenzymatic breakdown (autoxidation) and from glycolysis. − Approximately 0.1% of glycolytic flux gives rise to MG .…”

Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine

“…Although, there are currently no active clinical trials investigating itaconate or its derivatives in any inflammatory conditions, this is most probably since research into its therapeutic use is in early stages ( Table 1 ). However, there are several other electrophilic compounds approved for therapeutic use including: dimethyl fumarate (DMF) for plaque psoriasis and multiple sclerosis, bardoxolone for chronic kidney disease and sulforaphane for prostate cancer and asthma [ 62 ]. To note, similarly to itaconate, DMF is thought to activate the NRF2-Keap1 signalling pathways as well as an adduct to GAPDH resulting in inhibition of glycolysis and hence immune cell activation.…”