药学学报, 2021, 56(6): 1663-1669
引用本文:
范田运, 吴佳静, 李迎红, 黄维金, 郭茜茜, 赵丽萍, 汪燕翔, 王佑春, 宋丹青. N-环化小檗碱衍生物合成及抗SARS-CoV-2假病毒活性研究[J]. 药学学报, 2021, 56(6): 1663-1669.
FAN Tian-yun, WU Jia-jing, LI Ying-hong, HUANG Wei-jin, GUO Xi-xi, ZHAO Li-ping, WANG Yan-xiang, WANG You-chun, SONG Dan-qing. Synthesis and evaluation of N-cycloberberine derivatives as a novel class of anti-SARS-CoV-2 pseudovirus agents[J]. Acta Pharmaceutica Sinica, 2021, 56(6): 1663-1669.

N-环化小檗碱衍生物合成及抗SARS-CoV-2假病毒活性研究
范田运1, 吴佳静2, 李迎红1, 黄维金2, 郭茜茜1, 赵丽萍1, 汪燕翔1, 王佑春2, 宋丹青1*
1. 中国医学科学院、北京协和医学院医药生物技术研究所, 北京市抗感染重点实验室, 北京 100050;
2. 中国食品药品检定研究院, 北京 102629
摘要:
目前临床尚无治疗COVID-19的特效药物。传统天然药物小檗碱(BBR)具有中度抗SARS-CoV-2假病毒活性。本研究以BBR为先导物,设计合成了18个全新骨架N-环化BBR衍生物,评价了它们体外抗SARS-CoV-2假病毒活性。构效关系表明9-位引入适当的杂环利于活性提高。其中,化合物3m的EC50为1.61 μmol·L-1,SI为22.2,明显优于BBR。时间添加(time-of-addition)实验结果显示,化合物3m作用于病毒入侵宿主细胞的多个阶段,包括进入、吸附及膜融合过程,提示此类化合物通过多靶点的协同作用抑制SARS-CoV-2。研究结果为寻找抗SARS-CoV-2候选物提供了一类全新的先导物。
关键词:    N-环化小檗碱      SARS-CoV-2      构效关系      时间添加实验     
Synthesis and evaluation of N-cycloberberine derivatives as a novel class of anti-SARS-CoV-2 pseudovirus agents
FAN Tian-yun1, WU Jia-jing2, LI Ying-hong1, HUANG Wei-jin2, GUO Xi-xi1, ZHAO Li-ping1, WANG Yan-xiang1, WANG You-chun2, SONG Dan-qing1*
1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
2. National Institute for Food and Drug Control, Beijing 102629, China
Abstract:
There is no specific drug against COVID-19, but berberine (BBR) has moderate anti-SARS-CoV-2 pseudovirus activity. Taking BBR as the lead, 18 novel N-cycloberberine derivatives were synthesized and evaluated for their anti-SARS-CoV-2 pseudovirus activities in vitro. Structure-activity relationship analysis revealed that introducing an appropriate heterocyclic group at position 9 might be beneficial for potency. Among the tested compounds, compound 3m showed the most potent activity against SARS-CoV-2, with EC50 value of 1.61 μmol·L-1 and SI value of 22.2, much better than that of BBR. Additional experiment indicated that 3m had inhibitory activity on multiple processes in viral invasion, including adsorption and membrane fusion, suggesting a multi-target synergistic mechanism of action. These results provide a novel family of lead compounds for the discovery of anti-SARS-CoV-2 candidates.
Key words:    N-cycloberberine    SARS-CoV-2    structure-activity relationship    time-of-addition   
收稿日期: 2021-02-05
DOI: 10.16438/j.0513-4870.2021-0203
基金项目: 中国医学科学院医学与健康科技创新工程重大协同创新项目(2020-I2M-2-010);中国医学科学院医学与健康科技创新工程(2019-I2M-1-005).
通讯作者: 宋丹青,Tel/Fax:86-10-63165268,E-mail:songdanqingsdq@hotmail.com
Email: songdanqingsdq@hotmail.com
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