2. Academic Validation
  3. Artesunate inhibits PDE4 leading to intracellular cAMP accumulation, reduced ERK/MAPK signaling, and blockade of influenza A virus vRNP nuclear export

Artesunate inhibits PDE4 leading to intracellular cAMP accumulation, reduced ERK/MAPK signaling, and blockade of influenza A virus vRNP nuclear export

  • Antiviral Res. 2023 May 14;105635. doi: 10.1016/j.antiviral.2023.105635.
Xia Yang 1,  Feixiang Long 1,  Weixin Jia 2,  Mingxin Zhang 1,  Guanming Su 1,  Ming Liao 2,  Zhenling Zeng 1,  Weisan Chen 3,  Jianxin Chen 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Guangzhou, 510642, China; College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
  • 2 College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
  • 3 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia. Electronic address: Weisan.Chen@latrobe.edu.au.
  • 4 Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, Guangzhou, 510642, China; College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong, 510642, China. Electronic address: jxchen@scau.edu.cn.
PMID: 37192683 DOI: 10.1016/j.antiviral.2023.105635
Abstract

Influenza A viruses (IAV) have been a major cause of mortality. Given the potential for future deadly pandemics, effective drugs are needed for the treatment of severe influenzas, such as those caused by H5N1 IAV. The anti-malaria drugs artemisinin and its derivates, including artesunate (AS), have been reported to have broad Antiviral activities. Here, we showed AS's Antiviral activity against H5N1, H1N1, H3N2 and oseltamivir-resistant influenza A(H1N1)virus in vitro. Moreover, we showed that AS treatment significantly protected mice from lethal challenges with H1N1 and H5N1 IAV. Strikingly, the combination of AS and peramivir treatment significantly improved survival outcomes compared to their monotherapy with either AS or peramivir. Furthermore, we demonstrated mechanistically that AS affected the later stages of IAV replication and limited nuclear export of viral ribonucleoprotein (vRNP) complexes. In A549 cells, we demonstrated for the first time that AS treatment induced cAMP accumulation via inhibiting PDE4, and consequently reduced ERK phosphorylation and blocked IAV vRNP export, and thus suppressed IAV replication. These AS's effects were reversed by the pre-treatment with a cAMP inhibitor SQ22536. Our findings suggest that AS could serve as a novel IAV inhibitor by interfering vRNP nuclear export to prevent and treat IAV Infection.

Keywords

Artesunate (AS); ERK/MAPK; Influenza A virus (IAV); PDE4; Viral ribonucleoprotein (vRNP); cAMP.

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