An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA

Jianyuan Zhao, Jing Wang, Xu Pang, Zhenlong Liu, Quanjie Li, Dongrong Yi, Yongxin Zhang, Xiaomei Fang, Tao Zhang, Rui Zhou, Tao Zhang, Zhe Guo, Wancang Liu, Xiaoyu Li, Chen Liang, Tao Deng, Fei Guo (), Liyan Yu () and Shan Cen ()
Additional contact information
Jianyuan Zhao: Chinese Academy of Medical Sciences and Peking Union Medical School
Jing Wang: Chinese Academy of Medical Sciences and Peking Union Medical School
Xu Pang: Chinese Academy of Medical Sciences and Peking Union Medical School
Zhenlong Liu: McGill University
Quanjie Li: Chinese Academy of Medical Sciences and Peking Union Medical School
Dongrong Yi: Chinese Academy of Medical Sciences and Peking Union Medical School
Yongxin Zhang: Chinese Academy of Medical Sciences and Peking Union Medical School
Xiaomei Fang: Chinese Academy of Medical Sciences and Peking Union Medical School
Tao Zhang: Chinese Academy of Medical Sciences and Peking Union Medical School
Rui Zhou: Chinese Academy of Medical Sciences and Peking Union Medical School
Tao Zhang: Chinese Academy of Medical Sciences and Peking Union Medical School
Zhe Guo: Chinese Academy of Medical Sciences and Peking Union Medical School
Wancang Liu: Chinese Academy of Medical Sciences and Peking Union Medical School
Xiaoyu Li: Chinese Academy of Medical Sciences and Peking Union Medical School
Chen Liang: McGill University
Tao Deng: Chinese Academy of Sciences
Fei Guo: Chinese Academy of Medical Sciences and Peking Union Medical School
Liyan Yu: Chinese Academy of Medical Sciences and Peking Union Medical School
Shan Cen: Chinese Academy of Medical Sciences and Peking Union Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.

Date: 2022
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DOI: 10.1038/s41467-022-29690-x

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