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Peer-reviewedCC BYActa pharmaceutica Sinica. B

Identification of FDA-approved IMPDH inhibitors boosting the broad-spectrum antiviral potential of ribavirin through depleting cellular GTP pool.

  • Qiangyun Ai1,2
  • Huina Hu2,3,4
  • Kaixiong Ma1,2
  • Qingxing Wang1,2
  • Shenglin Huang2
  • Yongzhi Lu1,2
  • Nan Qi1,2
  • Jinsai Shang1,2
  • Ruikun Du5
  • Shaobo Wang1,2
5 affiliations
  1. 1State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou National Laboratory Clinical Base, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  2. 2Guangzhou National Laboratory, Department of Basic Research, Guangzhou 510005, China.
  3. 3Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
  4. 4University of the Chinese Academy of Sciences, Beijing 100049, China.
  5. 5Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China.
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Abstract

Nucleoside analogues are among the most promising broad-spectrum antiviral agents. We developed a high-throughput synergistic screening system to identify US Food and Drug Administration-approved drugs that enhance the effectiveness of nucleoside analogues. Unlike conventional combination approaches, this strategy does not require boost agents to have direct antiviral activity; instead, they can enhance antiviral agent's effect through novel synergistic mechanisms. We identified mycophenolate mofetil (MMF), which significantly boosts ribavirin's (RBV) antiviral efficacy against influenza A virus, even at concentrations where MMF alone shows minimal activity. MMF enhances RBV by inhibiting IMPDH (inosine-5'-monophosphate dehydrogenase) and reducing cellular GTP levels, potentially increasing RBV incorporation and its antiviral potency. This mechanism was confirmed by adding exogenous GTP, which reversed the synergy. In a mouse model, MMF also enhanced RBV's effectiveness against PR8 in vivo. Moreover, MMF showed synergistic effects against other influenza subtypes and RNA viruses including ZIKV and HCoV-OC43, demonstrating the potential wide applicability of this strategy. Our study introduces a new screening system and identifies novel RBV combinations, offering a promising approach for developing effective broad-spectrum antiviral combinations against emerging viral threats.

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Cite

BibTeXRIS
BibTeX
@article{ai2026identification,
  title = {{Identification of FDA-approved IMPDH inhibitors boosting the broad-spectrum antiviral potential of ribavirin through depleting cellular GTP pool.}},
  author = {Qiangyun Ai and Huina Hu and Kaixiong Ma and Qingxing Wang and Shenglin Huang and Yongzhi Lu and Nan Qi and Jinsai Shang and Ruikun Du and Shaobo Wang},
  journal = {Acta pharmaceutica Sinica. B},
  year = {2026},
  month = may,
  doi = {10.1016/j.apsb.2026.05.017},
  url = {https://europepmc.org/article/MED/42948370},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Identification of FDA-approved IMPDH inhibitors boosting the broad-spectrum antiviral potential of ribavirin through depleting cellular GTP pool.
AU  - Qiangyun Ai
AU  - Huina Hu
AU  - Kaixiong Ma
AU  - Qingxing Wang
AU  - Shenglin Huang
AU  - Yongzhi Lu
AU  - Nan Qi
AU  - Jinsai Shang
AU  - Ruikun Du
AU  - Shaobo Wang
PY  - 2026
DA  - 2026/05/20
JO  - Acta pharmaceutica Sinica. B
DO  - 10.1016/j.apsb.2026.05.017
UR  - https://europepmc.org/article/MED/42948370
AB  - Nucleoside analogues are among the most promising broad-spectrum antiviral agents. We developed a high-throughput synergistic screening system to identify US Food and Drug Administration-approved drugs that enhance the effectiveness of nucleoside analogues. Unlike conventional combination approaches, this strategy does not require boost agents to have direct antiviral activity; instead, they can enhance antiviral agent's effect through novel synergistic mechanisms. We identified mycophenolate mofetil (MMF), which significantly boosts ribavirin's (RBV) antiviral efficacy against influenza A virus, even at concentrations where MMF alone shows minimal activity. MMF enhances RBV by inhibiting IMPDH (inosine-5'-monophosphate dehydrogenase) and reducing cellular GTP levels, potentially increasing RBV incorporation and its antiviral potency. This mechanism was confirmed by adding exogenous GTP, which reversed the synergy. In a mouse model, MMF also enhanced RBV's effectiveness against PR8 in vivo. Moreover, MMF showed synergistic effects against other influenza subtypes and RNA viruses including ZIKV and HCoV-OC43, demonstrating the potential wide applicability of this strategy. Our study introduces a new screening system and identifies novel RBV combinations, offering a promising approach for developing effective broad-spectrum antiviral combinations against emerging viral threats.
SN  - 2211-3835
SN  - 2211-3843
ER  -