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      A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases


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          Inflammasomes induce maturation of the inflammatory cytokines IL‐1β and IL‐18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small‐molecule inhibitors to target inflammasome activity and reduce disease‐associated inflammatory burden.


          We examined the therapeutic potential of a novel small‐molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome‐mediated inflammation in vivo. In vitro, we characterised ADS032 function, target engagement and specificity.


          We describe ADS032 as the first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL‐1β in human‐derived macrophages and bronchial epithelial cells in response to the activation of NLPR1 and NLRP3. ADS032 also reduced NLRP3‐induced ASC speck formation, indicative of targeting inflammasome formation. In vivo, ADS032 reduced IL‐1β and TNF‐α levels in the serum of mice challenged i.p. with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Critically, ADS032 protected mice from lethal influenza A virus challenge, displayed increased survival and reduced pulmonary inflammation.


          ADS032 is the first described dual inflammasome inhibitor and a potential therapeutic to treat both NLRP1‐ and NLRP3‐associated inflammatory diseases and also constitutes a novel tool that allows examination of the role of NLRP1 in human disease.


          ADS032 represents the first described dual NLRP1 and NLRP3 inflammasome inhibitor, effective in reducing human inflammasome‐mediated inflammation in vitro. ADS032 also effectively reduces both pulmonary and systemic inflammasome‐induced inflammation. Taken together, ADS032 may provide an effective therapeutic strategy to reduce inflammasome‐associated inflammatory diseases.

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          Most cited references62

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          The inflammasomes.

          Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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            Inflammasomes: mechanism of assembly, regulation and signalling.

            Inflammasomes are multiprotein signalling platforms that control the inflammatory response and coordinate antimicrobial host defences. They are assembled by pattern-recognition receptors following the detection of pathogenic microorganisms and danger signals in the cytosol of host cells, and they activate inflammatory caspases to produce cytokines and to induce pyroptotic cell death. The clinical importance of inflammasomes reaches beyond infectious disease, as dysregulated inflammasome activity is associated with numerous hereditary and acquired inflammatory disorders. In this Review, we discuss the recent developments in inflammasome research with a focus on the molecular mechanisms that govern inflammasome assembly, signalling and regulation.
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              Gout-associated uric acid crystals activate the NALP3 inflammasome.

              Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals were first identified as the aetiological agent of gout in the eighteenth century and more recently as a 'danger signal' released from dying cells, little is known about the molecular mechanisms underlying MSU- or CPPD-induced inflammation. Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1beta activation. Moreover, an impaired neutrophil influx is found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1beta receptor (IL-1R). These findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

                Author and article information

                Clin Transl Immunology
                Clin Transl Immunology
                Clinical & Translational Immunology
                John Wiley and Sons Inc. (Hoboken )
                22 June 2023
                : 12
                : 6 ( doiID: 10.1002/cti2.v12.6 )
                : e1455
                [ 1 ] Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research Clayton VIC Australia
                [ 2 ] Department of Molecular and Translational Sciences Monash University Clayton VIC Australia
                [ 3 ] University of Edinburgh Centre for Inflammation Research Queen's Medical Research Institute, Edinburgh BioQuarter Edinburgh UK
                [ 4 ] Department of Biochemistry and Molecular Biophysics Washington University School of Medicine St. Louis MO USA
                [ 5 ] Hub‐Bio Strategic Advising Lexington MA USA
                [ 6 ] Adiso Therapeutics Concord MA USA
                Author notes
                [*] [* ] Correspondence

                A Mansell, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27–31 Wright St, Clayton, VIC 3168, Australia.

                E‐mail: ashley.mansell@ 123456hudson.org.au


                Equal contributors.

                Author information
                CTI21455 CTI-23-OA-0004.R2
                © 2023 Adiso Therapeutics and The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 14 May 2023
                : 05 June 2023
                : 08 January 2023
                : 06 June 2023
                Page count
                Figures: 9, Tables: 0, Pages: 19, Words: 12074
                Funded by: National Health and Medical Research Council , doi 10.13039/501100000925;
                Award ID: 1098298
                Award ID: 1123319
                Award ID: 1181522
                Award ID: MRFF2006197
                Funded by: Victorian State Government Operational Infrastructure Scheme
                Original Article
                Original Articles
                Custom metadata
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.9 mode:remove_FC converted:23.06.2023

                drug targets,inflammasome,inflammation,nlrp1,nlrp3,pulmonary inflammation


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