The Experts below are selected from a list of 948 Experts worldwide ranked by ideXlab platform
Lieselotte Vande Walle - One of the best experts on this subject based on the ideXlab platform.
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Correction: MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimír ŠubrAbstract:[This corrects the article DOI: 10.1371/journal.pbio.3000354.].
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MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract: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.
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mcc950 crid3 potently targets the NACHT Domain of wild type nlrp3 but not disease associated mutants for inflammasome inhibition
PLOS Biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract: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.
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MCC950/CRID3 potently targets the NACHT Domain of wildtype NLRP3 but not disease-associated mutants for inflammasome inhibition
2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
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mcc950 crid3 potently targets the NACHT Domain of wildtype nlrp3 but not disease associated mutants for inflammasome inhibition
bioRxiv, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
Wei Jiang - One of the best experts on this subject based on the ideXlab platform.
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Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity.
Nature communications, 2018Co-Authors: Hua Jiang, Yun Chen, Aoli Wang, Chao Wang, Qingsong Liu, Gaolin Liang, Xianming Deng, Wei JiangAbstract:Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT Domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori’s anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.
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Tranilast directly targets NLRP3 to treat inflammasome-driven diseases.
EMBO molecular medicine, 2018Co-Authors: Yi Huang, Hua Jiang, Yun Chen, Gaolin Liang, Xianming Deng, Xiaqiong Wang, Yanqing Yang, Jinhui Tao, Huafeng Zhang, Wei JiangAbstract:Abstract The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT Domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases.
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Tranilast directly targets NLRP3 to treat inflammasome‐driven diseases
Wiley, 2018Co-Authors: Yi Huang, Hua Jiang, Yun Chen, Gaolin Liang, Xianming Deng, Xiaqiong Wang, Yanqing Yang, Jinhui Tao, Huafeng Zhang, Wei JiangAbstract:Abstract The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT Domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases
Pedro Henrique Viana Saavedra - One of the best experts on this subject based on the ideXlab platform.
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Correction: MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimír ŠubrAbstract:[This corrects the article DOI: 10.1371/journal.pbio.3000354.].
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MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract: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.
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mcc950 crid3 potently targets the NACHT Domain of wild type nlrp3 but not disease associated mutants for inflammasome inhibition
PLOS Biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract: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.
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MCC950/CRID3 potently targets the NACHT Domain of wildtype NLRP3 but not disease-associated mutants for inflammasome inhibition
2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
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mcc950 crid3 potently targets the NACHT Domain of wildtype nlrp3 but not disease associated mutants for inflammasome inhibition
bioRxiv, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
Filip Van Hauwermeiren - One of the best experts on this subject based on the ideXlab platform.
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Correction: MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimír ŠubrAbstract:[This corrects the article DOI: 10.1371/journal.pbio.3000354.].
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MCC950/CRID3 potently targets the NACHT Domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition
PLoS biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract: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.
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mcc950 crid3 potently targets the NACHT Domain of wild type nlrp3 but not disease associated mutants for inflammasome inhibition
PLOS Biology, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract: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.
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MCC950/CRID3 potently targets the NACHT Domain of wildtype NLRP3 but not disease-associated mutants for inflammasome inhibition
2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana Saavedra, Petr Šimon, Vladimir SubrtAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
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mcc950 crid3 potently targets the NACHT Domain of wildtype nlrp3 but not disease associated mutants for inflammasome inhibition
bioRxiv, 2019Co-Authors: Lieselotte Vande Walle, Irma B. Stowe, Pavel Šácha, Bettina L. Lee, Dieter Demon, Amelie Fossoul, Filip Van Hauwermeiren, Pedro Henrique Viana SaavedraAbstract:Summary The 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 syndromes (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, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight in the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome. Here, we show that the NACHT Domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labelling of the NACHT Domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance, 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 LPS-challenged wildtype mice but not in Nlrp3L351P knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wildtype 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 wildtype NLRP3, but not CAPS-associated mutants.
Mrinal Samanta - One of the best experts on this subject based on the ideXlab platform.
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molecular characterization of nucleotide binding and oligomerization Domain nod 2 analysis of its inductive expression and down stream signaling following ligands exposure and bacterial infection in rohu labeo rohita
Developmental and Comparative Immunology, 2012Co-Authors: Banikalyan Swain, Bikash R Sahoo, Madhubanti Basu, N K Maiti, P Routray, A E Eknath, Mrinal SamantaAbstract:Abstract Nucleotide-binding and oligomerization Domain (NOD)-2 is a cytoplasmic pattern recognition receptor (PRR) and is a member of NOD like receptor (NLR) family. It senses a wide range of bacteria and viruses or their products and is involved in innate immune responses. In this report, NOD-2 gene was cloned and characterized from rohu ( Labeo rohita ) which is highly commercially important fish species in the Indian subcontinent. The full length rohu NOD-2 (rNOD-2) cDNA comprised of 3176 bp with a single open reading frame (ORF) of 2949 bp encoding a polypeptide of 982 amino acids (aa) with an estimated molecular mass of 109.65 kDa. The rNOD-2 comprised two N-terminal CARD Domains (at 4–91 aa and 111–200 aa), one NACHT Domain (at 271–441 aa) and seven C-terminal leucine rich repeat (LRR) regions. Phylogenetically, rNOD-2 was closely related to grass carp NOD-2 (gcNOD2) and exhibited significant similarity (94.2%) and identity (88.6%) in their amino acids. Ontogeny analysis of rNOD-2 showed its constitutive expression across the developmental stages, and highlighted the embryonic innate defense system in fish. Tissue specific analysis of rNOD-2 by quantitative real-time PCR (qRT-PCR) revealed its wide distribution; highest expression was in liver followed by blood. In response to PGN and LTA stimulation, Aeromonas hydrophila and Edwardsiella tarda infection, and poly I:C treatment, expression of rNOD-2 and its associated downstream molecules RICK and IFN-γ were significantly enhanced in the treated fish compared to control. These findings suggested the key role of NOD-2 in augmenting innate immunity in fish in response to bacterial and viral infection. This study may be helpful for the development of preventive measures against infectious diseases in fish.
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Molecular cloning and characterization of nucleotide binding and oligomerization Domain-1 (NOD1) receptor in the Indian Major Carp, rohu (Labeo rohita), and analysis of its inductive expression and down-stream signalling molecules following ligands e
Fish & shellfish immunology, 2012Co-Authors: Banikalyan Swain, Madhubanti Basu, Mrinal SamantaAbstract:Abstract Nucleotide binding and oligomerization Domain-1 (NOD1) is a cytoplasmic pattern recognition receptor (PRR), and is a member of the NOD-like receptor (NLR) family. It senses a wide range of bacteria and viruses or their products, and plays a key role in inducing innate immunity. In this report, NOD1 gene was cloned and characterized in rohu (Labeo rohita), a fish species of highest commercial importance in the Indian subcontinent. The full-length rohu NOD1 (rNOD1) cDNA comprised of 3168 bp with a single open reading frame (ORF) of 2814 bp, encoding a polypeptide of 937 amino acids (aa) with an estimated molecular mass of 106.13 kDa. Structurally, it comprised of one caspase recruitment Domain (CARD) at N-terminal, seven leucine rich repeat (LRR) regions at C-terminal and one NACHT Domain in between N and C-terminals. Phylogenetically, rNOD1 was closely related to grass carp NOD1 (gcNOD1), and exhibited significant similarity (95.8%) and identity (91.0%) in their amino acids. Ontogenic expression analysis of rNOD1 and its associated down-stream signaling molecule RICK (receptor interacting serine–threonine kinase) by quantitative real-time PCR (qRT-PCR) revealed their constitutive expression in all embryonic developmental stages. Basal expression analysis of rNOD1 showed its wide range of expression in all examined tissues, highest was in spleen and the lowest was in blood. Inductive expression of rNOD1 was observed following LPS and poly I:C exposure, and Aeromonas hydrophila, Edwardsiella tarda and Shigella flexneri infections. Expression of RICK in various organs was significantly enhanced by ligands exposure and bacterial infections, and was correlated with the inductive expression of rNOD1. Together, these findings highlighted the important role of NOD1 in fish in response to pathogenic invasion.
