An RRx-001 Analogue With Potent Anti-NLRP3 Inflammasome Activity but Without High-Energy Nitro Functional Groups

Hualong Lin; Mingyang Yang; Cong Li; Bolong Lin; Xianming Deng; Hongbin He; Rongbin Zhou

doi:10.3389/fphar.2022.822833

An RRx-001 Analogue With Potent Anti-NLRP3 Inflammasome Activity but Without High-Energy Nitro Functional Groups

Front Pharmacol. 2022 Feb 17:13:822833. doi: 10.3389/fphar.2022.822833. eCollection 2022.

Authors

Hualong Lin^{1

2

3}, Mingyang Yang⁴, Cong Li^{1

2

3}, Bolong Lin^{1

2

3}, Xianming Deng⁴, Hongbin He^{1

2

3}, Rongbin Zhou^{1

2

3}

Affiliations

¹ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
² CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Chinese Academy of Sciences Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China.
⁴ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.

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.

Keywords: NLRP3 inflammasome; NLRP3 inhibitor; NLRP3-related inflammatory diseases; RRx-001 analogues; anti-inflammation.