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

Nature Communications

Article

Wancang Liu¹  Liyan Yu¹  Quanjie Li¹  Tao Zhang¹  Zhe Guo¹  Jing Wang¹  Xu Pang¹  Xiaoyu Li¹  Dongrong Yi¹  Yongxin Zhang¹  Xiaomei Fang¹  Shan Cen¹  Jianyuan Zhao¹  Rui Zhou¹  Tao Deng²  Fei Guo³  Chen Liang⁴  Zhenlong Liu⁴ 

[1] Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, 100050, Beijing, PR China;Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China;Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical School, 100730, Beijing, PR China;Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, H3T 1E2, Montreal, Canada;

关键词: ;   

DOI  :  10.1038/s41467-022-29690-x

 received in 2021-10-08, accepted in 2022-03-16,  发布年份 2022

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2023

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