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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00509605" target="_blank" >RIV/61388963:_____/19:00509605 - isvavai.cz</a>

Alternative codes found

RIV/61389013:_____/19:00509605

Result on the web

<a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000354" target="_blank" >https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000354</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1371/journal.pbio.3000354" target="_blank" >10.1371/journal.pbio.3000354</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA16-02938S" target="_blank" >GA16-02938S: Macromolecular conjugates for targeted drug delivery, imaging and isolation of proteins based on hydrophilic polymers decorated by functional moieties</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

P L o S Biology

ISSN

1544-9173

e-ISSN

—

Volume of the periodical

17

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

24

Pages from-to

e3000354

UT code for WoS article

000496470000025

EID of the result in the Scopus database

2-s2.0-85072718262