核蛋白
病毒学
生物
查尔酮
核糖核蛋白
甲型流感病毒
病毒
抗病毒药物
奥司他韦
药物发现
病毒复制
核出口信号
微生物学
化学
细胞质
医学
核糖核酸
基因
生物化学
细胞核
2019年冠状病毒病(COVID-19)
疾病
病理
传染病(医学专业)
立体化学
作者
Ping Li,Jiuqiang Han,Ying Zhang,Jazmin Galván Achi,Dongwei Kang,Jinmi Zou,Ruikun Du,Qinghua Cui,Xinyong Liu,Lijun Rong,Peng Zhan
摘要
Influenza viruses pose a significant threat to human health worldwide due to seasonal epidemics and occasional global pandemics. These viruses can cause severe upper respiratory tract infections that contribute to high morbidity and mortality rates. The emergence of drug-resistant influenza viruses has created the need for the development of novel broad-spectrum antivirals. Here, we present a novel anti-influenza agent with new targets and mechanisms of action to address this problem. Our findings led to the discovery of a novel influenza virus inhibitor, a ligustrazine derivative known as A9. We have found that it exhibits broad-spectrum antiviral properties against influenza A and B viruses (IAV and IBV, respectively), including oseltamivir-resistant strain. Through multiple bioassays such as time-of-addition assay, indirect immunofluorescence assay, and nuclear-cytoplasmic fractionation assay, we demonstrated that A9 inhibits the nuclear export of the viral ribonucleoprotein (vRNP). Furthermore, escape mutant analyses and affinity studies determined by surface plasmon resonance indicated that A9 specifically targets the nucleoprotein. In addition, four chalcone derivatives developed from A9 (B14, B29, B31, and B32), were found to effectively inhibit the replication of influenza virus through the same mechanism of action. In this manuscript we highlight A9 and its four derivatives as potential leads for the treatment of IAV and IBV infections, and their unique and novel mechanism of action probable benefit the field of anti-influenza drug discovery.
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