Targeting of G-protein coupled receptors in sepsis

The Third International Consensus Definitions (Sepsis-3) define sepsis as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection. Sepsis can progress to septic shock—an even more lethal condition associated with profound circulatory, cellular and metabolic abnor...

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Published in:Pharmacology & therapeutics (Oxford) 2020-07, Vol.211, p.107529-107529, Article 107529
Main Authors: Rehman, Abdul, Baloch, Noor Ul-Ain, Morrow, John P., Pacher, Pál, Haskó, György
Format: Article
Language:English
Subjects:
Animals
Aptamers
Drug Development
G-protein coupled receptors
Humans
Intrabodies
Ligands
Molecular Targeted Therapy
Pepducins
Receptors, G-Protein-Coupled - metabolism
Sepsis
Sepsis - drug therapy
Sepsis - physiopathology
Septic shock
Shock, Septic - drug therapy
Shock, Septic - physiopathology
Signal Transduction - drug effects
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Summary:The Third International Consensus Definitions (Sepsis-3) define sepsis as life-threatening multi-organ dysfunction caused by a dysregulated host response to infection. Sepsis can progress to septic shock—an even more lethal condition associated with profound circulatory, cellular and metabolic abnormalities. Septic shock remains a leading cause of death in intensive care units and carries a mortality of almost 25%. Despite significant advances in our understanding of the pathobiology of sepsis, therapeutic interventions have not translated into tangible differences in the overall outcome for patients. Clinical trials of antagonists of various pro-inflammatory mediators in sepsis have been largely unsuccessful in the past. Given the diverse physiologic roles played by G-protein coupled receptors (GPCR), modulation of GPCR signaling for the treatment of sepsis has also been explored. Traditional pharmacologic approaches have mainly focused on ligands targeting the extracellular domains of GPCR. However, novel techniques aimed at modulating GPCR intracellularly through aptamers, pepducins and intrabodies have opened a fresh avenue of therapeutic possibilities. In this review, we summarize the diverse roles played by various subfamilies of GPCR in the pathogenesis of sepsis and identify potential targets for pharmacotherapy through these novel approaches.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2020.107529