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Electrophile Modulation of Inflammation: A Two-Hit Approach

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 net...

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Detalles Bibliográficos
Autores principales: O’Brien, James, Wendell, Stacy G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696920/
https://www.ncbi.nlm.nih.gov/pubmed/33182676
http://dx.doi.org/10.3390/metabo10110453
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author O’Brien, James
Wendell, Stacy G.
author_facet O’Brien, James
Wendell, Stacy G.
author_sort O’Brien, James
collection PubMed
description 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.
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spelling pubmed-76969202020-11-29 Electrophile Modulation of Inflammation: A Two-Hit Approach O’Brien, James Wendell, Stacy G. Metabolites Review 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. MDPI 2020-11-10 /pmc/articles/PMC7696920/ /pubmed/33182676 http://dx.doi.org/10.3390/metabo10110453 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
O’Brien, James
Wendell, Stacy G.
Electrophile Modulation of Inflammation: A Two-Hit Approach
title Electrophile Modulation of Inflammation: A Two-Hit Approach
title_full Electrophile Modulation of Inflammation: A Two-Hit Approach
title_fullStr Electrophile Modulation of Inflammation: A Two-Hit Approach
title_full_unstemmed Electrophile Modulation of Inflammation: A Two-Hit Approach
title_short Electrophile Modulation of Inflammation: A Two-Hit Approach
title_sort electrophile modulation of inflammation: a two-hit approach
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696920/
https://www.ncbi.nlm.nih.gov/pubmed/33182676
http://dx.doi.org/10.3390/metabo10110453
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