Inhibiting the NLRP3 Inflammasome

Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicab...

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Main Authors: Lina Y. El-Sharkawy, David Brough, Sally Freeman
Format: Article
Language:English
Published: MDPI AG 2020-11-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/25/23/5533
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author Lina Y. El-Sharkawy
David Brough
Sally Freeman
author_facet Lina Y. El-Sharkawy
David Brough
Sally Freeman
author_sort Lina Y. El-Sharkawy
collection DOAJ
description Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches.
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spelling doaj.art-bf7776a190534112aacd8f410a98c85e2023-11-20T22:19:50ZengMDPI AGMolecules1420-30492020-11-012523553310.3390/molecules25235533Inhibiting the NLRP3 InflammasomeLina Y. El-Sharkawy0David Brough1Sally Freeman2Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UKDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKDivision of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UKInflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches.https://www.mdpi.com/1420-3049/25/23/5533inflammationNLRP3inflammasomecytokinecryo-EMdrug discovery
spellingShingle Lina Y. El-Sharkawy
David Brough
Sally Freeman
Inhibiting the NLRP3 Inflammasome
Molecules
inflammation
NLRP3
inflammasome
cytokine
cryo-EM
drug discovery
title Inhibiting the NLRP3 Inflammasome
title_full Inhibiting the NLRP3 Inflammasome
title_fullStr Inhibiting the NLRP3 Inflammasome
title_full_unstemmed Inhibiting the NLRP3 Inflammasome
title_short Inhibiting the NLRP3 Inflammasome
title_sort inhibiting the nlrp3 inflammasome
topic inflammation
NLRP3
inflammasome
cytokine
cryo-EM
drug discovery
url https://www.mdpi.com/1420-3049/25/23/5533
work_keys_str_mv AT linayelsharkawy inhibitingthenlrp3inflammasome
AT davidbrough inhibitingthenlrp3inflammasome
AT sallyfreeman inhibitingthenlrp3inflammasome