Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/85928
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dc.contributor.authorVerma, Chandra Shekharen
dc.contributor.authorLane, David P.en
dc.contributor.authorMortellaro, Alessandraen
dc.contributor.authorPal, Arumayen
dc.contributor.authorNeo, Kurten
dc.contributor.authorRajamani, Lakshminarayananen
dc.contributor.authorFerrer, Fernando Joseen
dc.date.accessioned2019-05-17T08:55:22Zen
dc.date.accessioned2019-12-06T16:12:55Z-
dc.date.available2019-05-17T08:55:22Zen
dc.date.available2019-12-06T16:12:55Z-
dc.date.issued2019en
dc.identifier.citationPal, A., Neo, K., Rajamani, L., Ferrer, F. J., Lane, D. P., Verma, C. S., & Mortellaro, A. (2019). Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides. Scientific Reports, 9, 4913-. doi:10.1038/s41598-019-41211-3en
dc.identifier.urihttps://hdl.handle.net/10356/85928-
dc.description.abstractInterleukin-1β (IL-1β) is a major cytokine that initiates and enhances inflammatory responses. Excessive IL-1β production is a characteristic of most chronic inflammatory diseases, including atherosclerosis, type 2 diabetes, and obesity, which affect a large proportion of the global population. The production of bioactive IL-1β is mediated by a caspase-1-activating complex known as an ‘inflammasome’. The NLRP3 inflammasome has been associated with several human inflammatory and autoimmune diseases and represents a potential therapeutic target for disrupting IL-1β production. We used molecular modeling guided by molecular dynamics simulations to design α-helical stapled peptides targeting the pyrin domain of the adaptor protein ASC to interrupt the development of its filament, which is crucial for NLRP3 inflammasome formation. The peptides were effectively internalized by human monocytic cells and efficiently suppressed the release of the inflammasome-regulated cytokines IL-1β and IL-18, following exogenous activation of the NLRP3 inflammasome. The peptides reduced ASC speck formation and caspase-1 processing thereby suppressing pro-IL-1β processing and release of active IL-1β. This is the first demonstration of the successful use of stapled peptides designed to target the adaptor protein ASC, and can be extended to other inflammatory pathways to disrupt excessive IL-1β production.en
dc.description.sponsorshipASTAR (Agency for Sci., Tech. and Research, S’pore)en
dc.format.extent15 p.en
dc.language.isoenen
dc.relation.ispartofseriesScientific Reportsen
dc.rights© 2019 The Author(s) (Nature Publishing Group). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.subjectDRNTU::Science::Biological sciencesen
dc.subjectMolecular Modellingen
dc.subjectInflammasomeen
dc.titleInhibition of NLRP3 inflammasome activation by cell-permeable stapled peptidesen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.identifier.doi10.1038/s41598-019-41211-3en
dc.description.versionPublished versionen
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