2. Academic Validation
  3. Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy

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

  • Virol Sin. 2024 Sep 7:S1995-820X(24)00140-8. doi: 10.1016/j.virs.2024.09.001.
Lihong Huang 1,  Lele Liu 1,  Junhai Zhu 1,  Nanjun Chen 2,  Jie Chen 3,  Chuen-Fuk Chan 4,  Fei Gao 1,  Youqin Yin 1,  Jiufeng Sun 5,  Rongxin Zhang 6,  Kehui Zhang 7,  Wenbao Qi 8,  Jianbo Yue 9
Affiliations

Affiliations

  • 1 State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China.
  • 2 Department of Computer Science, City University of Hong Kong, Hong Kong, 999077, China.
  • 3 State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China.
  • 4 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 999077, China.
  • 5 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.
  • 6 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.
  • 7 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; 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. Electronic address: kehuizhang@imm.ac.cn.
  • 8 State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, 510642, China; Key Laboratory of Zoonoses, Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, 510642, China; National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control, Guangzhou, 510642, China; Key Laboratory of Zoonoses Prevention and Control of Guangdong Province, Guangzhou, China. Electronic address: qiwenbao@scau.edu.cn.
  • 9 City University of Hong Kong Shenzhen Research Institute, Shenzhen, 518057, China; Division of Natural and Applied Sciences, Synear Molecular Biology Lab, Global Health Research Center, Duke Kunshan University, Kunshan, 215316, China; College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: jianbo.yue@duke.edu.
PMID: 39251138 DOI: 10.1016/j.virs.2024.09.001
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.

Keywords

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

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