Dataset Information

Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides.

ABSTRACT: Interleukin-1? (IL-1?) is a major cytokine that initiates and enhances inflammatory responses. Excessive IL-1? 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-1? 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-1? production. We used molecular modeling guided by molecular dynamics simulations to design ?-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-1? and IL-18, following exogenous activation of the NLRP3 inflammasome. The peptides reduced ASC speck formation and caspase-1 processing thereby suppressing pro-IL-1? processing and release of active IL-1?. 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-1? production.

SUBMITTER: Pal A

PROVIDER: S-EPMC6426897 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides.

Pal Arumay A Neo Kurt K Rajamani Lakshminarayanan L Ferrer Fernando Jose FJ Lane David P DP Verma Chandra S CS Mortellaro Alessandra A

Scientific reports 20190320 1

Interleukin-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 diseas ...[more]

PMID: 30894604

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Project description:The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures, and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. SIGNIFICANCE STATEMENT: The NLRP3 inflammasome plays central role in innate immune sensing and control of inflammation. Pharmacological inhibition of NLRP3 demonstrated promising efficacy in a range of diseases in animal models. Recent elucidation of the structure and inhibitor binding of NLRP3 generated new insights into its mode of action and inhibitor-NLRP3 interaction at molecular levels, providing new framework for developing small chemical inhibitors of NLRP3 with improved efficacy and specificity against chronic disease that has become major health concerns worldwide.

Dataset Information

Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides.

Publications

Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides.

Similar Datasets

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