Berberine Directly Targets the NEK7 Protein to Block the NEK7–NLRP3 Interaction and Exert Anti-inflammatory Activity

• Published in: Journal of medicinal chemistry Vol. 64; no. 1; pp. 768 - 781
• Main Authors: Zeng, Qingxuan, Deng, Hongbin, Li, Yinghong, Fan, Tianyun, Liu, Yang, Tang, Sheng, Wei, Wei, Liu, Xiaojia, Guo, Xixi, Jiang, Jiandong, Wang, Yanxiang, Song, Danqing
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 14.01.2021
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Berberine - chemistry; Berberine - metabolism; Berberine - pharmacology; Binding Sites; Chemistry, Medicinal; Humans; Hydrogen Bonding; Interleukin-1beta - metabolism; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; NF-kappa B - metabolism; NIMA-Related Kinases - antagonists & inhibitors; NIMA-Related Kinases - genetics; NIMA-Related Kinases - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - chemistry; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pharmacology & Pharmacy; Protein Interaction Domains and Motifs - drug effects; RNA Interference; RNA, Small Interfering - metabolism; Science & Technology; Signal Transduction - drug effects; Structure-Activity Relationship; MIGRATION; MECHANISM; SPECIFICITY; PRODUCTS; INSULIN-RESISTANCE; MACROPHAGES; NLRP3 INFLAMMASOME ACTIVATION; KINASE; ALPHA; UP-REGULATION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01743

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1 beta release, independent of the NF-kappa B and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.