Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
J Med Chem. 2021 Jan 14;64(1):768-781. doi: 10.1021/acs.jmedchem.0c01743. Epub 2020 Dec 1.
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 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-1β release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays 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.
小檗碱（BBR）是一种传统中药，对多种炎症相关疾病具有治疗作用，但它的直接蛋白质组靶标仍不清楚。我们首次使用基于活性的蛋白质谱分析方法证明，BBR 直接靶向 NEK7 蛋白，该蛋白的 2,3-亚甲二氧基和 121-精氨酸（R121）残基之间存在氢键。事实上，R121 精确地位于 NEK7-NLRP3 相互作用的关键结构域内，这使得 BBR 能够特异性地阻断 NEK7-NLRP3 相互作用，并相继抑制 IL-1β 的释放，而不依赖 NF-κB 和 TLR4 信号通路。此外，BBR 以 NEK7 依赖性方式发挥抗炎作用。因此，我们认为 NEK7 是 BBR 治疗 NLRP3 相关炎症性疾病的关键靶标，并且使用 NEK7 作为靶标可能很容易开发出新型的 NEK7-NLRP3 相互作用抑制剂。
