Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical School, 100050, Beijing, PR China.
Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, H3T 1E2, Canada.
Nat Commun. 2022 Apr 19;13(1):2079. 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.
新的高致病性和耐药性流感株的出现促使人们开发新型流感 A 病毒（IAV）治疗药物。在这里，我们报告了一种抗 IAV 的微生物代谢产物 APL-16-5 的发现，它最初是从植物内生真菌 Aspergillus sp. CPCC 400735 中分离出来的。APL-16-5 结合到 E3 连接酶 TRIM25 和 IAV 聚合酶亚单位 PA 上，导致 TRIM25 泛素化 PA，并随后在蛋白酶体中降解 PA。这种作用模式符合蛋白酶体靶向嵌合体（proteolysis targeting chimera）的作用模式，它利用细胞内的泛素-蛋白酶体机制，通过化学诱导来降解靶蛋白。重要的是，APL-16-5 能有效抑制 IAV，并能保护小鼠免受致命性 IAV 感染。因此，我们已经鉴定出一种具有强大体内抗 IAV 活性的天然微生物代谢产物，并有潜力成为一种新的 IAV 治疗药物。APL-16-5 的抗病毒机制为通过药物化学调整其对 TRIM25 和病毒 PA 蛋白的亲和力来提高其抗 IAV 效力和特异性提供了可能。
