Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases

The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The form...

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Bibliographic Details
Published in:Cell death & disease 2021-12, Vol.12 (12), p.1155-1155, Article 1155
Main Authors: Soriano-Teruel, Paula M., García‑Laínez, Guillermo, Marco-Salvador, María, Pardo, Julián, Arias, Maykel, DeFord, Christian, Merfort, Irmgard, Vicent, María J., Pelegrín, Pablo, Sancho, Mónica, Orzáez, Mar
Format: Article
Language:English
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Alzheimer's disease
Animals
Antibodies
Apoptosis
Biochemistry
Biomedical and Life Sciences
CARD Signaling Adaptor Proteins - antagonists & inhibitors
CARD Signaling Adaptor Proteins - metabolism
Carrier Proteins - metabolism
Caspase
Caspase 1 - metabolism
Caspase-1
Cell Biology
Cell Culture
Cell death
Cell Line
Cell lines
Cytokines
Immune system
Immunology
Inflammasomes
Inflammasomes - metabolism
Inflammation
Inflammation - drug therapy
Inflammatory diseases
Innate immunity
Intracellular
Life Sciences
Mice
Oligomerization
Peritonitis
Proteins
Pyroptosis
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Summary:The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-021-04420-1