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Berberine Directly Targets the NEK7 Protein to Block the NEK7–NLRP3 Interaction and Exert Anti-inflammatory Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-01 , DOI: 10.1021/acs.jmedchem.0c01743 Qingxuan Zeng 1 , Hongbin Deng 1 , Yinghong Li 1 , Tianyun Fan 1 , Yang Liu 1 , Sheng Tang 1 , Wei Wei 1 , Xiaojia Liu 1 , Xixi Guo 1 , Jiandong Jiang 1 , Yanxiang Wang 1 , Danqing Song 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-01 , DOI: 10.1021/acs.jmedchem.0c01743 Qingxuan Zeng 1 , Hongbin Deng 1 , Yinghong Li 1 , Tianyun Fan 1 , Yang Liu 1 , Sheng Tang 1 , Wei Wei 1 , Xiaojia Liu 1 , Xixi Guo 1 , Jiandong Jiang 1 , Yanxiang Wang 1 , Danqing Song 1
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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-1β release, independent of the NF-κB 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.
中文翻译：
小ber碱直接靶向NEK7蛋白以阻断NEK7-NLRP3相互作用并发挥抗炎活性
小ber碱（BBR）是一种传统中药，对多种炎症相关疾病具有治疗作用，但其直接蛋白质组学靶标尚不清楚。使用基于活动的蛋白质谱，我们首先证明BBR通过2，3-亚甲二氧基和121-精氨酸（R121）残基之间的氢键直接靶向NEK7蛋白。R121恰好位于NEK7-NLRP3相互作用所涉及的关键域之内的事实，使BBR能够特异性阻断NEK7-NLRP3相互作用并连续抑制IL-1β的释放，而与NF-κB和TLR4信号通路无关。此外，BBR可在体内显示NEK7依赖性的抗炎功效。因此，我们认为NEK7是BBR治疗NLRP3相关炎症性疾病的关键靶标，并且以NEK7为靶标可以轻松实现新型NEK7–NLRP3相互作用抑制剂的开发。
更新日期：2021-01-14
中文翻译：
小ber碱直接靶向NEK7蛋白以阻断NEK7-NLRP3相互作用并发挥抗炎活性
小ber碱（BBR）是一种传统中药，对多种炎症相关疾病具有治疗作用，但其直接蛋白质组学靶标尚不清楚。使用基于活动的蛋白质谱，我们首先证明BBR通过2，3-亚甲二氧基和121-精氨酸（R121）残基之间的氢键直接靶向NEK7蛋白。R121恰好位于NEK7-NLRP3相互作用所涉及的关键域之内的事实，使BBR能够特异性阻断NEK7-NLRP3相互作用并连续抑制IL-1β的释放，而与NF-κB和TLR4信号通路无关。此外，BBR可在体内显示NEK7依赖性的抗炎功效。因此，我们认为NEK7是BBR治疗NLRP3相关炎症性疾病的关键靶标，并且以NEK7为靶标可以轻松实现新型NEK7–NLRP3相互作用抑制剂的开发。
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