دورية أكاديمية
أعرض في EDS

MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.

التفاصيل البيبلوغرافية
العنوان: MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
المؤلفون: Vande Walle L; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.; Discovery Sciences, Janssen Research & Development, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium., Stowe IB; Department of Physiological Chemistry, Genentech, South San Francisco, California, United States of America., Šácha P; Institute of Organic Chemistry and Biochemistry of The Czech Academy of Sciences, Prague, Czech Republic., Lee BL; Department of Physiological Chemistry, Genentech, South San Francisco, California, United States of America., Demon D; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Fossoul A; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Van Hauwermeiren F; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.; Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium., Saavedra PHV; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium., Šimon P; Institute of Organic Chemistry and Biochemistry of The Czech Academy of Sciences, Prague, Czech Republic., Šubrt V; Institute of Macromolecular Chemistry, Academy of Science of the Czech Republic, Prague, Czech Republic., Kostka L; Institute of Macromolecular Chemistry, Academy of Science of the Czech Republic, Prague, Czech Republic., Stivala CE; Department of Discovery Chemistry, Genentech, South San Francisco, California, United States of America., Pham VC; Department of Discovery Chemistry, Genentech, South San Francisco, California, United States of America., Staben ST; Department of Discovery Chemistry, Genentech, South San Francisco, California, United States of America., Yamazoe S; Department of Discovery Chemistry, Genentech, South San Francisco, California, United States of America., Konvalinka J; Institute of Organic Chemistry and Biochemistry of The Czech Academy of Sciences, Prague, Czech Republic., Kayagaki N; Department of Physiological Chemistry, Genentech, South San Francisco, California, United States of America., Lamkanfi M; Inflammation Research Center, VIB, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.; Janssen Immunosciences, World Without Disease Accelerator, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
المصدر: PLoS biology [PLoS Biol] 2019 Sep 16; Vol. 17 (9), pp. e3000354. Date of Electronic Publication: 2019 Sep 16 (Print Publication: 2019).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, [2003]-
مواضيع طبية MeSH: Cryopyrin-Associated Periodic Syndromes/*genetics , Furans/*pharmacology , Inflammasomes/*antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists & inhibitors , Sulfonamides/*pharmacology, Animals ; Cytokines/antagonists & inhibitors ; Disease Models, Animal ; Drug Evaluation, Preclinical ; HEK293 Cells ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Indenes ; Lipopolysaccharides ; Macrophages/drug effects ; Mice ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Protein Domains ; Sulfones
مستخلص: The nucleotide-binding-domain (NBD)-and leucine-rich repeat (LRR)-containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant, and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndrome (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome pathway, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight into the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome pathway. Here, we show that the NAIP, CIITA, HET-E, and TP1 (NACHT) domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labeling (PAL) of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance with this finding, MCC950/CRID3 failed to inhibit NLRP3-driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1β and IL-18 in lipopolysaccharide (LPS)-challenged wild-type mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wild-type NLRP3 as the molecular target of MCC950/CRID3 and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wild-type NLRP3 but not CAPS-associated mutants.
Competing Interests: LVW, FVH, and ML are employees of Janssen Pharmaceutica. IBS, BLL, CES, VCP, STS, SY, and NK are employees of Genentech. The authors declare no competing financial interests.
التعليقات: Erratum in: PLoS Biol. 2019 Oct 16;17(10):e3000529. (PMID: 31618263)
References: J Immunol. 2012 Sep 15;189(6):2707-11. (PMID: 22904305)
ACS Chem Biol. 2018 Dec 21;13(12):3333-3342. (PMID: 30489064)
Nature. 2007 Feb 8;445(7128):661-5. (PMID: 17251932)
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8041-6. (PMID: 17483456)
J Immunol. 2013 Jan 1;190(1):334-9. (PMID: 23225887)
Nature. 2014 Oct 9;514(7521):187-92. (PMID: 25119034)
Science. 2013 Sep 13;341(6151):1246-9. (PMID: 23887873)
Future Med Chem. 2015;7(2):159-83. (PMID: 25686004)
Clin Immunol. 2018 Jun;191:100-109. (PMID: 29183866)
Nat Med. 2015 Mar;21(3):248-55. (PMID: 25686105)
Nature. 2006 Mar 9;440(7081):228-32. (PMID: 16407890)
Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1541-6. (PMID: 25605939)
Immunity. 2013 Jun 27;38(6):1142-53. (PMID: 23809161)
Immunity. 2009 Jun 19;30(6):875-87. (PMID: 19501000)
J Immunol. 2016 Sep 15;197(6):2421-33. (PMID: 27521339)
EMBO Mol Med. 2019 Jun;11(6):null. (PMID: 31015277)
J Cell Biol. 2009 Oct 5;187(1):61-70. (PMID: 19805629)
Nat Chem Biol. 2019 Jun;15(6):560-564. (PMID: 31086329)
N Engl J Med. 2017 Sep 21;377(12):1119-1131. (PMID: 28845751)
Curr Protoc Chem Biol. 2009 Dec;1:55-73. (PMID: 23667793)
Nature. 2015 Oct 29;526(7575):666-71. (PMID: 26375259)
Nature. 2012 Oct 25;490(7421):539-42. (PMID: 22885697)
J Immunol. 2009 Jul 15;183(2):787-91. (PMID: 19570822)
Cell. 2014 May 22;157(5):1013-22. (PMID: 24855941)
Nature. 2011 Oct 16;479(7371):117-21. (PMID: 22002608)
Nature. 2015 Oct 29;526(7575):660-5. (PMID: 26375003)
Nat Rev Drug Discov. 2018 Sep;17(9):688. (PMID: 30116046)
Science. 2013 Sep 13;341(6151):1250-3. (PMID: 24031018)
Cold Spring Harb Perspect Biol. 2019 Jan 2;11(1):null. (PMID: 29038114)
J Biol Chem. 2003 May 9;278(19):16567-78. (PMID: 12624100)
Nat Rev Immunol. 2016 Jul;16(7):407-20. (PMID: 27291964)
Nat Chem Biol. 2019 Jun;15(6):556-559. (PMID: 31086327)
Nat Methods. 2006 Apr;3(4):287-93. (PMID: 16554834)
المشرفين على المادة: 0 (Cytokines)
0 (Furans)
0 (Heterocyclic Compounds, 4 or More Rings)
0 (Indenes)
0 (Inflammasomes)
0 (Lipopolysaccharides)
0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (NLRP3 protein, human)
0 (Nlrp3 protein, mouse)
0 (Sulfonamides)
0 (Sulfones)
6RS86E2BWQ (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide)
تواريخ الأحداث: Date Created: 20190917 Date Completed: 20200205 Latest Revision: 20211214
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6762198
DOI: 10.1371/journal.pbio.3000354
PMID: 31525186
قاعدة البيانات: MEDLINE
الوصف
تدمد:1545-7885
DOI:10.1371/journal.pbio.3000354