Discovery of a selective NLRP3-targeting compound with therapeutic activity in MSU-induced peritonitis and DSS-induced acute intestinal inflammation

• Published in: Cellular and molecular life sciences : CMLS 2023-08, Vol.80 (8), p.230-230, Article 230
• Main Authors: Zhou, Yinghua, Yang, Zhongjin, Ou, Yitao, Cai, Haowei, Liu, Zhuorong, Lin, Geng, Liang, Shuli, Hua, Lei, Yan, Yuyun, Zhang, Xiuxiu, Wu, Ruiwen, Qin, Aiping, Hu, Wenhui, Sun, Ping
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Dextran; Dextran sulfate; Dextrans; domain; drugs; family; Humans; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - metabolism; Inflammatory diseases; Interleukin-1beta - metabolism; Intestine; intestines; Lead compounds; Life Sciences; Macrophages; Macrophages - metabolism; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nucleotides; Oligomerization; Original; Original Article; Pathogenesis; Peritonitis; Peritonitis - chemically induced; Peritonitis - drug therapy; Peritonitis - metabolism; Pharmacology; Pyrin protein; Stability analysis; Surface plasmon resonance; therapeutics; Uric acid
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-04881-x

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is known to contribute to the pathogenesis of various human inflammation-related diseases. However, to date, no small-molecule NLRP3 inhibitor has been used in clinical settings. In this study, we have identified SB-222200 as a novel direct NLRP3 inhibitor through the use of drug affinity responsive target stability assay, cellular thermal shift assay, and surface plasmon resonance analysis. SB-222200 effectively inhibits the activation of the NLRP3 inflammasome in macrophages, while having no impact on the activation of NLRC4 or AIM2 inflammasome. Furthermore, SB-222200 directly binds to the NLRP3 protein, inhibiting NLRP3 inflammasome assembly by blocking the NEK7 − NLRP3 interaction and NLRP3 oligomerization. Importantly, treatment with SB-222200 demonstrates alleviation of NLRP3-dependent inflammatory diseases in mouse models, such as monosodium urate crystal-induced peritonitis and dextran sulfate sodium-induced acute intestinal inflammation. Therefore, SB-222200 holds promise as a lead compound for the development of NLRP3 inhibitors to combat NLRP3-driven disease and serves as a versatile tool for pharmacologically investigating NLRP3 biology.