Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage.,Viruses

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Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage.
Viruses ( IF 3.8 ) Pub Date : 2019-10-31 , DOI: 10.3390/v11111011
Muhammad Imran _{1,

2,

3,

4} , Muhammad Kashif Saleemi ₄ , Zheng Chen _{1,

2,

3} , Xugang Wang _{1,

2,

3} , Dengyuan Zhou _{1,

2,

3} , Yunchuan Li _{1,

2,

3} , Zikai Zhao _{1,

2,

3} , Bohan Zheng _{1,

2,

3} , Qiuyan Li _{1,

2,

3} , Shengbo Cao _{1,

2,

3} , Jing Ye _{1,

2,

3}

Affiliation

Flaviviruses, such as Zika virus (ZIKV), Japanese encephalitis virus (JEV), Dengue virus (DENV), and West Nile virus (WNV), are important arthropod-borne pathogens that present an immense global health problem. Their unpredictable disease severity, unusual clinical features, and severe neurological manifestations underscore an urgent need for antiviral interventions. Furin, a host proprotein convertase, is a key contender in processing flavivirus prM protein to M protein, turning the inert virus to an infectious particle. For this reason, the current study was planned to evaluate the antiviral activity of decanoyl-Arg-Val-Lys-Arg-chloromethylketone, a specific furin inhibitor, against flaviviruses, including ZIKV and JEV. Analysis of viral proteins revealed a significant increase in the prM/E index of ZIKV or JEV in dec-RVKR-cmk-treated Vero cells compared to DMSO-treated control cells, indicating dec-RVKR-cmk inhibits prM cleavage. Plaque assay, qRT-PCR, and immunofluorescence assay revealed a strong antiviral activity of dec-RVKR-cmk against ZIKV and JEV in terms of the reduction in virus progeny titer and in viral RNA and protein production in both mammalian cells and mosquito cells. Time-of-drug addition assay revealed that the maximum reduction of virus titer was observed in post-infection treatment. Furthermore, our results showed that dec-RVKR-cmk exerts its inhibitory action on the virus release and next round infectivity but not on viral RNA replication. Taken together, our study highlights an interesting antiviral activity of dec-RVKR-cmk against flaviviruses.

中文翻译：

癸酰基-Arg-Val-Lys-Arg-氯甲基酮：一种抗病毒化合物，通过抑制弗林蛋白酶介导的prM裂解而对抗黄病毒。

黄病毒，例如寨卡病毒（ZIKV），日本脑炎病毒（JEV），登革热病毒（DENV）和西尼罗河病毒（WNV），是节肢动物传播的重要病原体，它们带来了巨大的全球健康问题。它们不可预测的疾病严重程度，异常的临床特征和严重的神经系统表现突出了对抗病毒干预的迫切需求。弗林蛋白酶是宿主的前蛋白转化酶，是将黄病毒prM蛋白加工为M蛋白，将惰性病毒转变为感染性颗粒的关键因素。因此，本研究计划评估一种特定的弗林蛋白酶抑制剂癸酰基-Arg-Val-Lys-Arg-氯甲基酮对黄病毒（包括ZIKV和JEV）的抗病毒活性。病毒蛋白分析显示，与DMSO处理的对照细胞相比，dec-RVKR-cmk处理的Vero细胞中ZIKV或JEV的prM / E指数显着增加，表明dec-RVKR-cmk抑制prM裂解。噬菌斑测定，qRT-PCR和免疫荧光测定显示，在哺乳动物细胞和蚊子细胞中，病毒后代效价的降低以及病毒RNA和蛋白质产生的减少方面，dec-RVKR-cmk对ZIKV和JEV具有很强的抗病毒活性。药物添加时间分析显示，在感染后治疗中观察到病毒效价的最大降低。此外，我们的结果表明dec-RVKR-cmk对病毒释放和下一轮感染具有抑制作用，但对病毒RNA复制没有抑制作用。在一起

更新日期：2019-11-01

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