Abstract
Arthropod-borne flaviviruses are human pathogens of global medical importance, against which no effective small molecule-based antiviral therapy has currently been reported. Arbidol (umifenovir) is a broad-spectrum antiviral compound approved in Russia and China for prophylaxis and treatment of influenza. This compound shows activities against numerous DNA and RNA viruses. The mode of action is based predominantly on impairment of critical steps in virus-cell interactions. Here we demonstrate that arbidol possesses micromolar-level anti-viral effects (EC50 values ranging from 10.57 ± 0.74 to 19.16 ± 0.29 µM) in Vero cells infected with Zika virus, West Nile virus, and tick-borne encephalitis virus, three medically important representatives of the arthropod-borne flaviviruses. Interestingly, no antiviral effects of arbidol are observed in virus infected porcine stable kidney cells (PS), human neuroblastoma cells (UKF-NB-4), and human hepatoma cells (Huh-7 cells) indicating that the antiviral effect of arbidol is strongly cell-type dependent. Arbidol shows increasing cytotoxicity when tested in various cell lines, in the order: Huh-7 < HBCA < PS < UKF-NB-4 < Vero with CC50 values ranging from 18.69 ± 0.1 to 89.72 ± 0.19 µM. Antiviral activities and acceptable cytotoxicity profiles suggest that arbidol could be a promising candidate for further investigation as a potential therapeutic agent in selective treatment of flaviviral infections.
Highlights
Arthropod-borne flaviviruses include human pathogens of global medical importance such as dengue virus (DENV), Yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Zika virus (ZIKV), Kyasanur Forest disease virus (KFDV), Omsk hemorrhagic fever virus (OHFV) and tick-borne encephalitis virus (TBEV)
Porcine kidney stable (PS) cells [16] were cultured in Leibovitz (L-15) medium, human brain cortical astrocytes (HBCA) (ScienCell, Carlsbad, CA, USA) were cultivated in Astrocyte medium (Thermo Fisher Scientific, Weltham, MA, USA), human neuroblastoma UKF-NB-4 cells [17] were cultured in Iscove’s modified Dulbecco’s medium (IMDM), Vero cells (ATCC CCL-81, African Green Monkey, adult kidney, epithelial) and human hepatocellular carcinoma cells (Huh-7) were grown in Dulbecco’s modified Eagle’s medium (DMEM)
(for Huh-7), 0–25 μM, 0–30 μM, or 0–50 μM of arbidol and incubated for 24 h
Summary
Arthropod-borne flaviviruses (genus Flavivirus, family Flaviviridae) include human pathogens of global medical importance such as dengue virus (DENV), Yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Zika virus (ZIKV), Kyasanur Forest disease virus (KFDV), Omsk hemorrhagic fever virus (OHFV) and tick-borne encephalitis virus (TBEV). These viruses are Viruses 2018, 10, 184; doi:10.3390/v10040184 www.mdpi.com/journal/viruses. Arbidol may be immunomodulatory, and as such be capable of interferon induction and/or macrophage activation [13] Due to such broad-spectrum antiviral activities, arbidol represents a promising candidate for treatment of viral infections in humans. Since antiviral compounds are extensively inactivated/metabolized in the intracellular environment [14,15], different cell lines were utilized to assess simultaneously both the antiviral and corresponding cytotoxic effects of arbidol
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