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

• Published in: Nature communications Vol. 13; no. 1; p. 2079
• Main Authors: Zhao, Jianyuan, Wang, Jing, Pang, Xu, Liu, Zhenlong, Li, Quanjie, Yi, Dongrong, Zhang, Yongxin, Fang, Xiaomei, Zhang, Tao, Zhou, Rui, Guo, Zhe, Liu, Wancang, Li, Xiaoyu, Liang, Chen, Deng, Tao, Guo, Fei, Yu, Liyan, Cen, Shan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.04.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 14; 38/70; 38/89; 631/154/555; 631/326/22/1295; 631/326/596/1578; 631/337/458; 64; 64/60; 82/58; 82/80; 9/10; Animals; Antiviral agents; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Aspergillus; Biodegradation; Degradation; Drug development; Drug resistance; Endonuclease; Endonucleases - metabolism; Endophytes; Fungi; Humanities and Social Sciences; Humans; Infections; Influenza; Influenza A; Influenza A virus - metabolism; Influenza, Human - metabolism; Metabolites; Mice; Microorganisms; Mode of action; multidisciplinary; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Proteolysis; Science; Science (multidisciplinary); Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Viral Proteins - metabolism; Virus Replication; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29690-x

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. Here, Zhao et al. characterize the anti-viral effect of the compound APL-16-5, which is originally derived from the plant endophytic fungus Aspergillus, on Influenza A virus infection in vitro and in vivo. They find that APL-16-5 binds to the E3 ligase TRIM25 and viral polymerase subunit PA and therewith mediates ubiquitination of PA and subsequent proteasome-mediated degradation.’