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Cell Rep:流感怎么办?萘普生来帮忙

2019-05-14 生物谷 生物谷

5月7日,中国科学院微生物研究所刘文军课题组在Cell Reports 发表了题为Naproxen exhibits broad anti-influenza virus activity in mice by impeding viral nucleoprotein nuclear export 的研究论文。该研究发现非甾类抗炎症药物萘普生(Naproxen)具有抑制A型和B型流感病毒复制的特性

5月7日,中国科学院微生物研究所刘文军课题组在Cell Reports 发表了题为Naproxen exhibits broad anti-influenza virus activity in mice by impeding viral nucleoprotein nuclear export 的研究论文。该研究发现非甾类抗炎症药物萘普生(Naproxen)具有抑制A型和B型流感病毒复制的特性,并阐明了其通过抑制流感病毒核蛋白(nucleoprotein, NP)出核从而发挥抗流感病毒活性的新机制,表明传统“老药”萘普生不仅有抗炎症作用,而且具有抗流感病毒感染的“新功能”。

抗流感药物是流感病毒感染后最有效的治疗手段,目前获批上市的抗流感病毒药物仅有两类。一类是M2抑制剂(金刚烷胺和金刚乙胺),这类药物靶向于M2蛋白,阻断离子通道,抑制病毒RNA基因组进入细胞质。此类药物的抗病毒作用仅限于A型流感病毒,对B型流感病毒无效,但很多A型流感病毒流行毒株对该类药物产生了耐药性,已不推荐使用。另一类是NA抑制剂(奥司他韦,扎那米韦和帕拉米韦),此类药物靶向于NA蛋白,通过抑制其神经氨酸酶活性,影响流感病毒的释放过程。NA抑制剂对A型和B型流感病毒都有抗病毒效果,但近年来也出现了不少耐药病例的报告。因此,抗流感药物研发任重而道远。萘普生是一种非甾类抗炎症药物,可用于慢性关节炎、变形关节症、腰痛、急性上呼吸道炎,以及拔牙、小手术后的消炎、镇痛。该药已在临床上使用了40多年,是全球最畅销的解热镇痛类非处方药之一,但其在抗流感病毒方面的作用和调控机制尚不明确。

课题组前期的系统性研究发现,流感病毒的NP,M1,NEP等病毒蛋白及vRNP复合物的核质穿梭在病毒复制过程中发挥着非常重要的作用(Journal of Virology,2012a;2012b;2013;2014a;2014b;2015)。该研究进一步发现,萘普生能够阻断宿主的出核相关蛋白CRM1与病毒NP的结合,抑制CRM1介导的NP出核,从而发挥抗流感病毒的活性。萘普生不仅能够抑制A型流感病毒的复制,而且表现出比临床上常用的抗流感药物奥司他韦(又名达菲)更强的抗B型流感病毒的活性。因此,抑制流感病毒NP的核质穿梭是抗流感药物设计的一种非常有效的手段,核质穿梭关键靶点的筛选及相应药物的研发具有重要意义。此外,该研究发现A型流感病毒NP的Y148及B型流感病毒NP的F209位点是萘普生结合位点,序列分析显示这两个结合位点高度保守,暗示病毒对萘普生不易产生耐药性。萘普生这种老药已具备良好的安全性与可控性,这将极大地缩短其作为抗流感候选药物进入临床应用的时间。

事实上,梅斯小编还检索到,在此前也有研究发现萘普生这款老药对流感可能有用,并从结构 还等方面进行解析,并发现几种同源类似物,未来可以作为流感新药进行开发。最近,还能发现这个药物能对抗Zika病毒。同时,一项随机对照研究也证 克实,拉霉素-萘普生-奥司他韦对H3N2病毒感染要优于单用奥司他韦的作用,这项研究也结果也从侧面证实,各种药物间可能存在协同作用。

原始出处:

Zheng W, Fan W, Zhang S, Jiao P, Shang Y, Cui L, Mahesutihan M, Li J, Wang D, Gao GF, Sun L, Liu W. Naproxen Exhibits Broad Anti-influenza Virus Activity in Mice by Impeding Viral Nucleoprotein Nuclear Export. Cell Rep. 2019 May 7;27(6):1875-1885.e5. doi: 10.1016/j.celrep.2019.04.053.


相关文献:

Dilly S, Fotso Fotso A, Lejal N, Zedda G, Chebbo M, Rahman F, Companys S, Bertrand HC, Vidic J, Noiray M, Alessi MC, Tarus B, Quideau S, Riteau B, Slama-Schwok A. From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus. J Med Chem. 2018 Aug 23;61(16):7202-7217.


Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJ, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial.  Chest. 2017 May;151(5):1069-1080.


Tarus B, Bertrand H, Zedda G, Di Primo C, Quideau S, Slama-Schwok A. Structure-based design of novel naproxen derivatives targeting monomeric nucleoprotein of Influenza A virus. J Biomol Struct Dyn. 2015 Sep;33(9):1899-912.


Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother. 2013 May;57(5):2231-42


Pan T, Peng Z, Tan L, Zou F, Zhou N, Liu B, Liang L, Chen C, Liu J, Wu L, Liu G, Peng Z, Liu W, Ma X, Zhang J, Zhu X, Liu T, Li M, Huang X, Tao L, Zhang Y, Zhang H. Nonsteroidal Anti-inflammatory Drugs Potently Inhibit the Replication of Zika Viruses by Inducing the Degradation of AXL. J Virol. 2018 Sep 26;92(20). pii: e01018-18.

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    2020-04-25 维他命
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    2019-05-16 yibei
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    2019-05-14 王秀

    学习了,涨知识了!

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