Journal
FRONTIERS IN PHARMACOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.822833
Keywords
RRx-001 analogues; NLRP3 inflammasome; anti-inflammation; NLRP3-related inflammatory diseases; NLRP3 inhibitor
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Funding
- National Key research and development program of China [2018YFA0507403, 2019YFA0508503]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB29030102]
- National Natural Science Foundation of China [82003765, 81821001, 31770991, 82130107]
- Fundamental Research Funds for the Central Universities
- University Synergy Innovation Program of Anhui Province [GXXT-2019-026]
- Natural Science Foundation of Anhui Province [1908085QC99]
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NLRP3 inflammasome is implicated in multiple inflammatory diseases, and compound 149-01 is identified as a potent and specific inhibitor of NLRP3. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to prevent its interaction with NEK7, thereby inhibiting NLRP3 inflammasome activation. Treatment with 149-01 effectively alleviates the severity of various inflammatory diseases in mice.
NLRP3 inflammasome is involved in the pathology of multiple human inflammatory diseases but there are still no clinically available medications targeting the NLRP3 inflammasome. We have previously identified RRx-001 as a highly selective and potent NLRP3 inhibitor, however, it contains high-energy nitro functional groups and may cause potential processing problems and generates highly toxic oxidants. Here, we show that compound 149-01, an RRx-001 analogue without high-energy nitro functional groups, is a potent, specific and covalent NLRP3 inhibitor. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to block the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome complex assembly and activation. Furthermore, treatment with 149-01 effectively alleviate the severity of several inflammatory diseases in mice, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate crystals (MSU)-induced peritonitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results indicate that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related inflammatory diseases.
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