Identification of γ-Fagarine as a novel antiviral agent against respiratory virus (hMPV) infection

作者全名："Li, Jinhua; Zhao, Yao; Dai, Ying; Zhao, Junning"

作者地址："[Li, Jinhua; Zhao, Junning] Sichuan Univ, West China Sch Pharm, Dept Pharmacognosy, Chengdu 610041, Peoples R China; [Zhao, Junning] Natl Med Prod Adm NMPA, Natl Key Lab Drug Regulatory Sci, Beijing 100038, Peoples R China; [Zhao, Yao] Chongqing Med Univ, Childrens Hosp, Chongqing Key Lab Child Infect & Immun, Chongqing 400014, Peoples R China; [Dai, Ying] Sichuan Acad Chinese Med Sci, Sichuan Inst Translat Chinese Med, Translat Chinese Med Key Lab Sichuan Prov, Chengdu 610041, Sichuan, Peoples R China"

通信作者："Zhao, JN (通讯作者)，Sichuan Univ, West China Sch Pharm, Dept Pharmacognosy, Chengdu 610041, Peoples R China."

来源：VIRUS RESEARCH

ESI学科分类：MICROBIOLOGY

WOS号：WOS:001085041700001

JCR分区：Q3

影响因子：2.5

年份：2023

卷号：336

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：gamma-Fagarine; hMPV; Antiviral activity; Lysosome; HSPG

摘要："Human metapneumovirus (hMPV) causes significant upper and lower respiratory disease in all age groups worldwide. However, there is no licensed drugs or vaccine available against hMPV. gamma-Fagarine, an alkaloid isolated from the root of zanthoxylum, has been reported to be effective in the treatment of cancer, inflammatory diseases and antivirals. However, little is known about the inhibitory effect of gamma-Fagarine against respiratory virus infection and the mechanism. In this study, we aim to investigate the effect of gamma-Fagarine on hMPV infection and explore its underlying molecular mechanisms. Vero-E6 and 16HBE cells were used as cell models. Virus replication and microcosm character were explored in Vero-E6 cells. Then, the antiviral activities were investigated by quantitative real-time PCR (RT-qPCR), western blotting (WB), and indirect immunofluorescence assays (IFAs) in Vero-E6 and 16HBE. Potential mechanisms of gamma-Fagarine related to HSPG and lysosome pH were assessed in 16HBE cells. Lastly, a virus-infected mouse model was established and antiviral assay in vivo was conducted. gamma-Fagarine showed no toxicity toward Vero-E6 cells and 16HBE cells but demonstrated anti-hMPV activity. Virus titers of gamma-Fagarine group were reduced to 33% and 45% of the hMPV groups, respectively. Besides, mechanistic studies revealed that gamma-Fagarine could inhibit hMPV by dual mechanisms of direct restraining virus binding with HSPG and influencing lysosome pH. Furthermore, oral delivery of gamma-Fagarine to hMPVinfected mice at a dosage of 25 mg/kg reduced the hMPV load in lung tissues. After gamma-Fagarine treatment, pathological damage caused by viral infection was also ameliorated. These findings suggest that gamma-Fagarine has antiviral effects in vitro and in vivo, which are associated with its ability to restrain virus binding with HSPG and influence lysosome pH, thus indicating that gamma-Fagarine has the potential to serve as a candidate to fight against hMPV infection and other respiratory viruses such as influenza viruses and SARS-CoV-2."

基金机构：Project of Sichuan Provincial Administration of Traditional Chinese Medicine [2020YSHB01]; Major Scientific and Technological Projects of Sichuan Provincial Administration of Traditional Chinese Medicine [2021XYCZ001]

基金资助正文：The study was supported by grants from The Project of Sichuan Provincial Administration of Traditional Chinese Medicine (2020YSHB01) and Major Scientific and Technological Projects of Sichuan Provincial Administration of Traditional Chinese Medicine (2021XYCZ001) .