北京中医药大学徐安龙研究组报道了植物化学生物碱协调免疫代谢对抗病毒感染。这一研究成果发表在2025年6月16日出版的国际学术期刊《国家科学评论》上。

课题组首先通过对所有可能的胆固醇转运体的系统分析，证明NPC1是通过改变胆固醇代谢和触发先天免疫反应来抑制病毒复制的关键胆固醇转运体。然后，课题组研究人员利用连接图（CMap）筛选NPC1抑制剂，这是一种系统的方法，用于识别遗传扰动和药物作用之间的功能联系，并发现双苄基异喹啉生物碱（BBAs）在抑制病毒感染方面表现出很高的功效。在该研究团队测试的所有有效的BBAs中，粉防己碱（Tet）是最有效的，它通过直接与NPC1结合并诱导溶酶体胆固醇积累来抵抗病毒的侵入。通过NPC1-STING界面机制，Tet进一步阻断STING溶酶体降解，从而增强体外和体内针对多种病毒的干扰素抗病毒应答。因此，BBAs是一种非常有前途的药物化合物，它通过胆固醇介导的免疫代谢靶向NPC1-STING界面，从而破坏病毒生命周期，增强抗病毒免疫。

据悉，胆固醇代谢在抗病毒免疫中的作用已经确定，但是这种胆固醇介导的免疫代谢是否以及如何被特定的小分子调节，对于寻找新的抗病毒治疗方法特别感兴趣。

附：英文原文

Title: The phytochemical alkaloids orchestrate immunometabolism against viral infections

Author: Cheng, Cuiqin, Wang, Yao, Wang, Han, Zhang, Meiqi, Li, Qiqi, Xu, Bing, Kong, Lingdong, Liu, Xia, Yu, Yanli, He, Yuting, Chu, Yingjie, Liu, Zhe, Qiao, Yuanyuan, Yuan, Xinxin, Jia, Xin, Xu, Anlong

Issue&Volume: 2025-06-16

Abstract: The role of cholesterol metabolism in antiviral immunity is established, but if and how this cholesterol-mediated immunometabolism can be regulated by specific small molecules is of particular interest to the quest for novel antiviral therapeutics. Here, we first demonstrate that NPC1 is the key cholesterol transporter for suppressing viral replication by changing cholesterol metabolism and triggering the innate immune response via systemic analyses of all possible cholesterol transporters. We then use the Connectivity Map (CMap), a systematic methodology for identifying functional connections between genetic perturbations and drug actions, to screen NPC1 inhibitors, and found that bis-benzylisoquinoline alkaloids (BBAs) exhibit high efficacy in the inhibition of viral infections. Among all potent BBAs that we tested, Tetrandrine (Tet) is the most effective, by directly binding to NPC1 and inducing lysosomal cholesterol accumulation to resist viral entries. Through NPC1-STING interface mechanism, Tet further blocks the STING lysosomal degradation leading to boosting interferon-based antiviral response against multiple viruses in vitro and in vivo. Therefore, BBAs represent very promising drug compounds for this newly discovered antiviral mechanism by targeting the NPC1-STING interface via cholesterol-mediated immunometabolism, which in turn disrupts the virus life cycle and boosts antiviral immunity.

DOI: 10.1093/nsr/nwaf190

Source: https://dx.doi.org/10.1093/nsr/nwaf190