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Abstract
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.
Highlights
The NLRP3 inflammasome is a multimeric protein complex consisted of innate immune sensor NLRP3 (NLR family, Pyrin domain containing 3), adaptor protein ASC and effector cysteine protease caspase-1, it plays a pivotal role in host defense against microbial infection and inflammation (Schroder and Tschopp, 2010; Davis et al, 2011)
We identify compound 149-01, an RRx-001 analogue, as a potent, specific and covalent NLRP3 inhibitor, which can effectively inhibit the NLRP3 inflammasome activation both in vitro and in vivo
Our study suggests that 149-01 may be a useful small molecule tool to investigate the mechanism of NLRP3 inflammasome activation and a potential lead for
Summary
The NLRP3 inflammasome is a multimeric protein complex consisted of innate immune sensor NLRP3 (NLR family, Pyrin domain containing 3), adaptor protein ASC and effector cysteine protease caspase-1, it plays a pivotal role in host defense against microbial infection and inflammation (Schroder and Tschopp, 2010; Davis et al, 2011). Biologic agents targeting IL-1β are clinically used to treat NLRP3-driven diseases, including canakinumab (a neutralizing IL-1β monoclonal antibody), anakinra (a recombinant non-glycosylated IL-1 receptor antagonist), and rilonacept (a soluble decoy IL-1β receptor) (Dinarello et al, 2012). These agents have been proven to be effective in the treatment of Cryopyrin-associated periodic syndromes (CAPS) caused by NLRP3 gene mutations and have been applied in clinical trials for other NLRP3-associated disorders (Dinarello et al, 2012; Dinarello and van der Meer, 2013). Our findings demonstrate that 149-01 is active both in vitro and in vivo, suggesting that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related human inflammatory diseases
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