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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

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...

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Autores principales: Imran, Muhammad, Saleemi, Muhammad Kashif, Chen, Zheng, Wang, Xugang, Zhou, Dengyuan, Li, Yunchuan, Zhao, Zikai, Zheng, Bohan, Li, Qiuyan, Cao, Shengbo, Ye, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893617/
https://www.ncbi.nlm.nih.gov/pubmed/31683742
http://dx.doi.org/10.3390/v11111011
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author Imran, Muhammad
Saleemi, Muhammad Kashif
Chen, Zheng
Wang, Xugang
Zhou, Dengyuan
Li, Yunchuan
Zhao, Zikai
Zheng, Bohan
Li, Qiuyan
Cao, Shengbo
Ye, Jing
author_facet Imran, Muhammad
Saleemi, Muhammad Kashif
Chen, Zheng
Wang, Xugang
Zhou, Dengyuan
Li, Yunchuan
Zhao, Zikai
Zheng, Bohan
Li, Qiuyan
Cao, Shengbo
Ye, Jing
author_sort Imran, Muhammad
collection PubMed
description 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.
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spelling pubmed-68936172019-12-23 Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage Imran, Muhammad Saleemi, Muhammad Kashif Chen, Zheng Wang, Xugang Zhou, Dengyuan Li, Yunchuan Zhao, Zikai Zheng, Bohan Li, Qiuyan Cao, Shengbo Ye, Jing Viruses Article 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. MDPI 2019-10-31 /pmc/articles/PMC6893617/ /pubmed/31683742 http://dx.doi.org/10.3390/v11111011 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Imran, Muhammad
Saleemi, Muhammad Kashif
Chen, Zheng
Wang, Xugang
Zhou, Dengyuan
Li, Yunchuan
Zhao, Zikai
Zheng, Bohan
Li, Qiuyan
Cao, Shengbo
Ye, Jing
Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title_full Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title_fullStr Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title_full_unstemmed Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title_short Decanoyl-Arg-Val-Lys-Arg-Chloromethylketone: An Antiviral Compound That Acts against Flaviviruses through the Inhibition of Furin-Mediated prM Cleavage
title_sort decanoyl-arg-val-lys-arg-chloromethylketone: an antiviral compound that acts against flaviviruses through the inhibition of furin-mediated prm cleavage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893617/
https://www.ncbi.nlm.nih.gov/pubmed/31683742
http://dx.doi.org/10.3390/v11111011
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