2. Academic Validation
  3. The combinatorial activities of oseltamivir and molnupiravir against influenza virus infections in vitro and in vivo

The combinatorial activities of oseltamivir and molnupiravir against influenza virus infections in vitro and in vivo

  • Virology. 2025 Oct:611:110642. doi: 10.1016/j.virol.2025.110642.
Xili Feng 1,  Xuanye Yang 1,  Xinyan Hu 1,  Qianyun Liu 1,  Yulin Ding 2,  Xiaoan Cao 3,  Zhongren Ma 1,  Xiaoxia Ma 4
Affiliations

Affiliations

  • 1 Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, 730030, China; College of Life Science and Engineering, Northwest Minzu University, Lanzhou, Gansu, 730010, China.
  • 2 College of Veterinary Medicine, Key Laboratory of Clinical Diagnosis and Treatment Technology in Animal Disease, Inner Mongolia Agricultural University, Hohhot, 010018, China.
  • 3 State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, 730046, China.
  • 4 Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, Gansu, 730030, China; College of Life Science and Engineering, Northwest Minzu University, Lanzhou, Gansu, 730010, China. Electronic address: maxiaoxia956@163.com.
PMID: 40730007 DOI: 10.1016/j.virol.2025.110642
Abstract

Oseltamivir, a neuraminidase inhibitor, is widely used in the clinic for treating Influenza Virus infections. However, suboptimal efficacy and risk of drug resistance development remain major challenges. Molnupiravir, a ribonucleoside analog, was originally developed to treat influenza, but was repurposed and first approved for treating COVID-19 in 2021. Considering their complementary mode-of-actions, this study aimed to investigate the combinatorial activities of oseltamivir and molnupiravir against Influenza Virus infections. In Cell Culture models, we found that β-d-N4-hydroxycytidine (NHC), the active form of molnupiravir, exerted more potent Antiviral activities against influenza A and B viruses, when compared to oseltamivir treatment. Combination of NHC with oseltamivir exhibited a synergistic Antiviral effect against the influenza A/Puerto Rico/8/34 H1N1 strain, but not the influenza B/Washington/02/2019 strain. In a mouse model infected with the PR/8 virus strain, treatment with molnupiravir alone or in combination with oseltamivir effectively attenuated lung injury and reduced viral load in the tissue. Taken together, molnupiravir can be explored in combination with oseltamivir to treat influenza, especially for patients infected with the oseltamivir-resistant strains, whereas further research is warranted.

Keywords

Antiviral; Drug-combination; Influenza virus; Molnupiravir; Oseltamivir.

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