Cepharanthine inhibits influenza A virus replication by impairing viral polymerase activity and regulating influenza-induced immune response

Yinyan Li; Huiting Sang; Qinxian Mo; Linrui Jiang; Zhixuan Chen; Jinlong Liang; Chunyu Zhang; Zhengyin Zhang; Chenglai Xia; Jie Yang

Phytomedicine Plus (May 2024)

Cepharanthine inhibits influenza A virus replication by impairing viral polymerase activity and regulating influenza-induced immune response

Yinyan Li,
Huiting Sang,
Qinxian Mo,
Linrui Jiang,
Zhixuan Chen,
Jinlong Liang,
Chunyu Zhang,
Zhengyin Zhang,
Chenglai Xia,
Jie Yang

Affiliations

Yinyan Li: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Huiting Sang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Qinxian Mo: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Linrui Jiang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Zhixuan Chen: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Jinlong Liang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Chunyu Zhang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Zhengyin Zhang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
Chenglai Xia: Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, 528000, China
Jie Yang: NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Corresponding author.

Journal volume & issue: Vol. 4, no. 2
p. 100553

Abstract

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Background: Cepharanthine (CEP), a natural bis-benzylisoquinoline alkaloid extracted from the plant Stephania cephalantha Hayata, has been widely used to treat several acute and chronic diseases. However, its antiviral potential against influenza A virus (IAV) infection remains unknown. Purpose: The study aims to assess the antiviral and immunomodulatory effects of CEP in vivo and in vitro and investigate its underlying antiviral mechanisms. Methods: Antiviral and anti-inflammatory activities of CEP were assessed in MDCK, A549 and RAW264.7 cells infected with influenza virus. Proinflammatory cytokine levels were measured by qRT-PCR and ELISA. The anti-influenza effect and underlying antiviral mechanism of CEP were mainly determined by MTT assay, plaque reduction assay, time-of-addition and mini-replicon assay. The inhibition of CEP on IAV-induced activation of innate immune signaling was detected by western blotting. Furthermore, BALB/c mice were infected intranasally with A/PR/8/34 (H1N1) virus and treated with CEP (60, 30, 15 mg/kg/d) or oseltamivir (60 mg/kg/d). The changes in body weight, survival rates, viral titers, proinflammatory cytokine levels and pathological parameters were detected. Results: CEP exhibited antiviral effects against multiple IAV strains, while also demonstrating anti-inflammatory effects in influenza virus-infected RAW264.7 and A549 cells. The results of the mechanism study indicated that CEP effectively suppressed IAV replication by limiting viral polymerase activity. On the other hand, CEP could modulate pro-inflammatory responses via inhibition of janus kinase/signal transducer and activator of transcription/ nuclear factor kappa B (JAK/STAT/NF‑κB) signaling pathways involved in influenza virus pathogenesis. Treatment of mice with CEP improved the survival rate and body weight of influenza virus-infected mice, reduced viral titers and alleviated influenza virus-induced pathological damage and inflammation in mouse lung tissue. Conclusion: Collectively, the anti-influenza virus property of CEP was a result of inhibiting viral polymerase activity and preventing virus-induced excessive inflammation, highlighting it might be an oral medication for the treatment of IAV infection.

Published in Phytomedicine Plus

ISSN: 2667-0313 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Other systems of medicine
Website: https://www.journals.elsevier.com/phytomedicine-plus/

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