Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy

Lihong Huang; Lele Liu; Junhai Zhu; Nanjun Chen; Jie Chen; Chuen-Fuk Chan; Fei Gao; Youqin Yin; Jiufeng Sun; Rongxin Zhang; Kehui Zhang; Wenbao Qi; Jianbo Yue

doi:10.1016/j.virs.2024.09.001

December 2024

. doi: 10.1016/j.virs.2024.09.001

Citation: Lihong Huang, Lele Liu, Junhai Zhu, Nanjun Chen, Jie Chen, Chuen-Fuk Chan, Fei Gao, Youqin Yin, Jiufeng Sun, Rongxin Zhang, Kehui Zhang, Wenbao Qi, Jianbo Yue. Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy .VIROLOGICA SINICA, 2024, 39(6) : 892-908. http://dx.doi.org/10.1016/j.virs.2024.09.001

双苄基异喹啉生物碱通过影响内体溶酶体转运和自噬来抑制黄病毒的进入和复制

黄丽红 ^a,b,c,d ,
刘乐乐 ^a,b,c,d ,
朱君海 ^a,b,c,d ,
陈南峻 ^e ,
陈杰 ^a,b ,
陈全福 ^f ,
高飞 ^a,b,c,d ,
尹有勤 ^a,b,c,d ,
孙九峰 ^g ,
张荣信 ^h ,
张可辉 ^i,j,, ,
亓文宝 ^a,b,c,d,, ,
岳剑波 ^k,l,m,,

cstr: 32224.14.j.virs.2024.09.001

a. 动物疫病防控全国重点实验室, 华南农业大学兽医学院, 广州 510642;
b. 农业农村部人畜共患病重点实验室, 华南农业大学兽医学院, 广州 510642;
c. 人兽共患病防控制剂国家地方联合工程实验室, 华南农业大学兽医学院, 广州 510642;
d. 广东省动物源性人兽共患病预防与控制重点实验室, 广州 510642;
e. 香港城市大学电脑科学系, 香港 999077;
f. 香港城市大学生物医学系, 香港 999077;
g. 广东省疾病预防控制中心, 广州 511430;
h. 广东药科大学生命科学与生物制药学院, 广州 510006;
i. 天然药物活性物质与功能国家重点实验室, 中国医学科学院药物研究所, 北京 100730;
j. 活性物质发现与适药化研究北京重点实验室, 中国医学科学院药物研究所, 北京 100730;
k. 香港城市大学深圳研究院, 深圳 518057;
l. 昆山杜克大学, 昆山 215316;
m. 武汉大学生命科学学院, 武汉 430072

通讯作者： 张可辉, kehuizhang@imm.ac.cn; 亓文宝, qiwenbao@scau.edu.cn; 岳剑波, jianbo.yue@duke.edu
收稿日期： 2024-05-26
录用日期： 2024-08-29

摘要

黄病毒，如登革热病毒(DENV)、寨卡病毒(ZIKV)和日本脑炎病毒(JEV)，因目前仍没有批准的治疗方法，给公共卫生带来了极大的挑战。本文研究了双苄基异喹啉生物碱抗黄病毒感染的能力。我们发现5种特异的双苄基异喹啉生物碱（盐酸小檗胺、粉防己碱、异粉防己碱、防己诺林碱、千金藤素）通过阻断病毒进入和基因组复制阶段从而有效抑制ZIKV、DENV以及JEV的感染。此外，我们合成了一种荧光基团偶联的双苄基异喹啉生物碱，并发现其可靶向并碱化内体溶酶体。机制研究表明，这些化合物通过阻断TRPML通道，导致溶酶体功能障碍，从而降低NCAM1（NCAM1是ZIKV进入细胞的关键受体）的表达，从而降低细胞对ZIKV的易感性。此外，双苄基异喹啉生物碱还通过抑制自噬小体与溶酶体的融合从而降低病毒RNA的复制。总之，我们的研究结果表明，双苄基异喹啉生物碱分别通过影响内体溶酶体转运和自噬来抑制黄病毒的进入和复制。这一结果突出了双苄基异喹啉生物碱作为抗黄病毒感染治疗剂的潜力。
- 双苄基异喹啉类生物碱
- , 黄病毒
- , 寨卡病毒
- , 内体溶酶体
- , TRPML通道
- , 自噬

Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy

Lihong Huang ^a,b,c,d ,
Lele Liu ^a,b,c,d ,
Junhai Zhu ^a,b,c,d ,
Nanjun Chen ^e ,
Jie Chen ^a,b ,
Chuen-Fuk Chan ^f ,
Fei Gao ^a,b,c,d ,
Youqin Yin ^a,b,c,d ,
Jiufeng Sun ^g ,
Rongxin Zhang ^h ,
Kehui Zhang ^i,j,, ,
Wenbao Qi ^a,b,c,d,, ,
Jianbo Yue ^k,l,m,,

a. State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China;
b. Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China;
c. National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China;
d. Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China;
e. Department of Computer Science, City University of Hong Kong, Hong Kong, 999077, China;
f. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China;
g. Guangdong Workstation for Emerging Infectious Disease Control and Prevention, Guangdong Provincial Key Laboratory of Pathogen Detection for Emerging Infectious Disease Response, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China;
h. Laboratory of Immunology and Inflammation, Institute of Basic Medical Sciences and Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China;
i. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China;
j. Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China;
k. City University of Hong Kong Shenzhen Research Institute, Shenzhen, 518057, China;
l. Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Global Health Research Center, Duke Kunshan University, Kunshan, 215316, China;
m. College of Life Sciences, Wuhan University, Wuhan, 430072, China

Corresponding author: Kehui Zhang, kehuizhang@imm.ac.cn Wenbao Qi, qiwenbao@scau.edu.cn Jianbo Yue, jianbo.yue@duke.edu
Received Date: 26 May 2024
Accepted Date: 29 August 2024

Abstract

Flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV), represent a substantial public health challenge as there are currently no approved treatments available. Here, we investigated the antiviral effects of bis-benzylisoquinoline alkaloids (BBAs) on flavivirus infections. We evaluated five specific BBAs—berbamine, tetrandrine, iso-tetrandrine, fangchinoline, and cepharanthine—and found that they effectively inhibited infections by ZIKV, DENV, or JEV by blocking virus entry and genome replication stages in the flavivirus life cycle. Furthermore, we synthesized a fluorophore-conjugated BBA and showed that BBAs targeted endolysosomes, causing lysosomal pH alkalization. Mechanistic studies on inhibiting ZIKV infection by BBAs revealed that these compounds blocked TRPML channels, leading to lysosomal dysfunction and reducing the expression of NCAM1, a key receptor for the entry of ZIKV into cells, thereby decreasing cells susceptibility to ZIKV infection. Additionally, BBAs inhibited the fusion of autophagosomes and lysosomes, significantly reducing viral RNA replication. Collectively, our results suggest that BBAs inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy, respectively, underscoring the potential of BBAs as therapeutic agents against flavivirus infections.
- Bis-benzylisoquinoline alkaloids (BBAs)
- , Flavivirus
- , Zika virus (ZIKV)
- , Endolysosomes
- , TRPML channels
- , Autophagy

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