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

Abstract

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.

• Authors: Muhammad Imran, Muhammad Kashif Saleemi, Zheng Chen, Xugang Wang, Dengyuan Zhou, Yunchuan Li, Zikai Zhao, Bohan Zheng, Qiuyan Li, Shengbo Cao, Jing Ye
• Journal: Viruses (Viruses) Vol. 11 Issue 11 (10 31 2019) ISSN: 1999-4915 [Electronic] Switzerland
• PMID: 31683742 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antiviral Agents
• Viral Envelope Proteins
• decanoylRVKRchloromethylketone
• prM protein, Flavivirus
• Furin

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antiviral Agents (pharmacology)
• Cell Line
• Chlorocebus aethiops
• Encephalitis Virus, Japanese (drug effects)
• Flavivirus (drug effects)
• Furin (antagonists & inhibitors, metabolism)
• Vero Cells
• Viral Envelope Proteins (drug effects, metabolism)
• Virus Release (drug effects)
• Virus Replication (drug effects)
• Zika Virus (drug effects)