病毒
可药性
甲型流感病毒
核苷
病毒学
化学
法维皮拉维
体内
体外
抗病毒药物
聚合酶
正粘病毒科
合理设计
药理学
生物
酶
生物化学
医学
基因
遗传学
生物技术
疾病
2019年冠状病毒病(COVID-19)
病理
传染病(医学专业)
作者
Xinjin Liu,Zhichao Xu,Jinsen Liang,Tao Xu,Wenting Zou,Lijun Zhu,Yonglin Wu,Chune Dong,Ke Lan,Shuwen Wu,Hai-Bing Zhou
标识
DOI:10.1016/j.ejmech.2023.115678
摘要
Evidence suggests that rapidly evolving virus subvariants risk rendering current vaccines and anti-influenza drugs ineffective. Hence, exploring novel scaffolds or new targets of anti-influenza drugs is of great urgency. Herein, we report the discovery of a series of acylthiourea derivatives produced via a scaffold-hopping strategy as potent antiviral agents against influenza A and B subtypes. The most effective compound 10m displayed subnanomolar activity against H1N1 proliferation (EC50 = 0.8 nM) and exhibited inhibitory activity toward other influenza strains, including influenza B virus and H1N1 variant (H1N1, H274Y). Additionally, druggability evaluation revealed that 10m exhibited favorable pharmacokinetic properties and was metabolically stable in liver microsome preparations from three different species as well as in human plasma. In vitro and in vivo toxicity studies confirmed that 10m demonstrated a high safety profile. Furthermore, 10m exhibited satisfactory antiviral activity in a lethal influenza virus mouse model. Moreover, mechanistic studies indicated that these acylthiourea derivatives inhibited influenza virus proliferation by targeting influenza virus RNA-dependent RNA polymerase. Thus, 10m is a potential lead compound for the further exploration of treatment options for influenza.
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