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

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

Lihong Huang (Co-first Author)
, Lele Liu (Co-first Author)
, Junhai Zhu (Co-first Author)
, Nanjun Chen
, Jie Chen
, Chuen-Fuk Chan
, Fei Gao
, Youqin Yin
, Jiufeng Sun
, Rongxin Zhang
, Kehui Zhang^*
, Wenbao Qi^*
, Jianbo Yue^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

22 Citations (Scopus)

148 Downloads (CityUHK Scholars)

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. © 2024 The Authors.

Original language	English
Pages (from-to)	892-908
Number of pages	17
Journal	Virologica Sinica
Volume	39
Issue number	6
Online published	7 Sept 2024
DOIs	https://doi.org/10.1016/j.virs.2024.09.001
Publication status	Published - Dec 2024

Funding

This work was supported by the National Key Research and Development Program of China (2022YFD1800100), the National Natural Science Foundation of China (32302843, 32070702, and 82161128014), GuangDong Basic and Applied Basic Research Foundation (2023A1515010748), Innovation and Technology Fund of Hong Kong (MRP/064/21, GHP/097/20GD, and MHP/072/21), Hong Kong Research Grant Council (RGC) grant (11103620 and 11104422), and research grants from Shenzhen Science and Technology Innovation Committee (SGDX20201103093201010 and JCYJ20210324134007020), Kunshan Shuang Chuang Grant (kssc202302073), and the Kunshan Municipal Government research funding.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

Autophagy
Bis-benzylisoquinoline alkaloids (BBAs)
Endolysosomes
Flavivirus
TRPML channels
Zika virus (ZIKV)

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

RGC Funding Information

RGC-funded

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10.1016/j.virs.2024.09.001

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Cite this

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title = "Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy",

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. {\textcopyright} 2024 The Authors.",

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

year = "2024",

month = dec,

doi = "10.1016/j.virs.2024.09.001",

language = "English",

volume = "39",

pages = "892--908",

journal = "Virologica Sinica",

issn = "1674-0769",

publisher = "KeAi Communications",

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Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy. / Huang, Lihong (Co-first Author); Liu, Lele (Co-first Author); Zhu, Junhai (Co-first Author) et al.
In: Virologica Sinica, Vol. 39, No. 6, 12.2024, p. 892-908.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy

AU - Huang, Lihong

AU - Liu, Lele

AU - Zhu, Junhai

AU - Chen, Nanjun

AU - Chen, Jie

AU - Chan, Chuen-Fuk

AU - Gao, Fei

AU - Yin, Youqin

AU - Sun, Jiufeng

AU - Zhang, Rongxin

AU - Zhang, Kehui

AU - Qi, Wenbao

AU - Yue, Jianbo

PY - 2024/12

Y1 - 2024/12

N2 - 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. © 2024 The Authors.

AB - 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. © 2024 The Authors.

KW - Autophagy

KW - Bis-benzylisoquinoline alkaloids (BBAs)

KW - Endolysosomes

KW - Flavivirus

KW - TRPML channels

KW - Zika virus (ZIKV)

UR - https://www.scopus.com/pages/publications/85206673745

UR - https://www.scopus.com/pages/publications/85206673745#tab=impact

U2 - 10.1016/j.virs.2024.09.001

DO - 10.1016/j.virs.2024.09.001

M3 - RGC 21 - Publication in refereed journal

C2 - 39251138

SN - 1674-0769

VL - 39

SP - 892

EP - 908

JO - Virologica Sinica

JF - Virologica Sinica

IS - 6

ER -

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

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

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Permanent Link

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GRF: Functional and Mechanistic Studies of FAM129B Signaling in Endosomal Trafficking

ITF: Autologous-Allogeneic Human Peripheral CAK-NK Cells Construction and Combination with Immune Checkpoint Inhibitors on Treatment of Genitourinary Tumors: Key Technology Innovation, Efficacy and Mechanistic Study

ITF: Development of Bisbenzylisoquinoline Alkaloid-Berbamine and Its Analogs to Prevent and Treat COVID-19 by Compromising the Endosome-lysosome Transport of ACE2

Cite this

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

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

GRF: Functional and Mechanistic Studies of FAM129B Signaling in Endosomal Trafficking

ITF: Autologous-Allogeneic Human Peripheral CAK-NK Cells Construction and Combination with Immune Checkpoint Inhibitors on Treatment of Genitourinary Tumors: Key Technology Innovation, Efficacy and Mechanistic Study

ITF: Development of Bisbenzylisoquinoline Alkaloid-Berbamine and Its Analogs to Prevent and Treat COVID-19 by Compromising the Endosome-lysosome Transport of ACE2

Cite this