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

IF 5.5 3区医学 Q1 Medicine

Virologica Sinica Pub Date : 2024-09-07 DOI:10.1016/j.virs.2024.09.001

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

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引用次数: 0

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.

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双苄基异喹啉生物碱通过影响内溶酶体转运和自噬抑制黄病毒的进入和复制。

登革病毒（DENV）、寨卡病毒（ZIKV）和日本脑炎病毒（JEV）等黄病毒是公共卫生面临的重大挑战，因为目前还没有获得批准的治疗方法。在这里，我们研究了双苄基异喹啉生物碱（BBAs）对黄病毒感染的抗病毒作用。我们评估了五种特定的 BBA--小檗胺、四氢喹啉、异四氢喹啉、芳喹啉和头花苋碱--发现它们通过阻断黄病毒生命周期中病毒进入和基因组复制阶段，有效抑制了 ZIKV、DENV 或 JEV 的感染。此外，我们还合成了一种含荧光团的 BBA，结果表明 BBA 可靶向内溶酶体，使溶酶体 pH 碱化。对 BBAs 抑制 ZIKV 感染的机理研究发现，这些化合物阻断了 TRPML 通道，导致溶酶体功能紊乱，减少了 ZIKV 进入细胞的关键受体 NCAM1 的表达，从而降低了细胞对 ZIKV 感染的易感性。此外，BBAs 还能抑制自噬体和溶酶体的融合，从而显著减少病毒 RNA 的复制。总之，我们的研究结果表明，BBAs 可分别通过损害溶酶体内转运和自噬作用来抑制黄病毒的进入和复制，突出了 BBAs 作为黄病毒感染治疗剂的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Virologica Sinica Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

7.70

自引率

1.80%

发文量

3149

期刊介绍： Virologica Sinica is an international journal which aims at presenting the cutting-edge research on viruses all over the world. The journal publishes peer-reviewed original research articles, reviews, and letters to the editor, to encompass the latest developments in all branches of virology, including research on animal, plant and microbe viruses. The journal welcomes articles on virus discovery and characterization, viral epidemiology, viral pathogenesis, virus-host interaction, vaccine development, antiviral agents and therapies, and virus related bio-techniques. Virologica Sinica, the official journal of Chinese Society for Microbiology, will serve as a platform for the communication and exchange of academic information and ideas in an international context. Electronic ISSN: 1995-820X; Print ISSN: 1674-0769