2. Academic Validation
  3. Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors

  • Bioorg Chem. 2024 May:146:107263. doi: 10.1016/j.bioorg.2024.107263.
Chao Huang 1,  Jinyu Liu 1,  Yuxin Chen 1,  Simin Sun 1,  Tongtong Kang 1,  Yuqi Jiang 2,  Xiaoyang Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China. Electronic address: jiangyuqi@ouc.edu.cn.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, China. Electronic address: lixiaoyang@ouc.edu.cn.
PMID: 38492493 DOI: 10.1016/j.bioorg.2024.107263
Abstract

The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 μM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 μM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.

Keywords

Anti-inflammatory; Biphenyl-sulfonamide; NLRP3 inflammasome; NLRP3 inhibitor.

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