Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

Eyer, Luděk; Valdés, James J.; Gil, Víctor; Nencka, Radim; Hřebabecký, Hubert; Šála, Michal; Salát, Jiřı́; Černý, Jiří; Palus, Martin; Clercq, Erik De; Růžek, Daniel

doi:10.1128/aac.00807-15

Cited by 83 publications

(58 citation statements)

References 53 publications

(69 reference statements)

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“…Plaque assays were performed in Vero cells (for ZIKV and WNV titers) or in the PS cells (to determine TBEV titers) as described previously [23][24][25]. The obtained viral titer values were recalculated to percentages of viral titer inhibition, applied to constructing the dose-response and inhibition curves, and used to calculate the 50% effective concentration (EC 50 ).…”

Section: Plaque Assaymentioning

confidence: 99%

FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells

et al. 2020

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Vector-borne flaviviruses (VBFs) affect human health worldwide, but no approved drugs are available specifically to treat VBF-associated infections. Here, we performed in silico screening of a library of U.S. Food and Drug Administration-approved antiviral drugs for their interaction with Zika virus proteins. Twelve hit drugs were identified by the docking experiments and tested in cell-based antiviral assay systems. Efavirenz, tipranavir, and dasabuvir at micromolar concentrations were identified to inhibit all VBFs tested; i.e., two representatives of mosquito-borne flaviviruses (Zika and West Nile viruses) and one representative of flaviviruses transmitted by ticks (tick-borne encephalitis virus). The results warrant further research into these drugs, either individually or in combination, as possible pan-flavivirus inhibitors.

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Section: Plaque Assaymentioning

confidence: 99%

FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells

et al. 2020

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“…Further studies were performed with the adenosine analogue NITD008, which was considered a potentially efficient panflaviviral inhibitor (128). Additionally, high antiviral activity along with low cytotoxicity were observed ex vivo with a 7-deaza-2=-C-methyladenosine nucleoside analogue, which might be another antiviral candidate in the future (129).…”

Section: Prevention Control and Treatmentmentioning

confidence: 99%

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

2018

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SUMMARYThe tick-borne pathogen Powassan virus is a rare cause of encephalitis in North America and the Russian Far East. The number of documented cases described since the discovery of Powassan virus in 1958 may be <150, although detection of cases has increased over the past decade. In the United States, the incidence of Powassan virus infections expanded from the estimated 1 case per year prior to 2005 to 10 cases per year during the subsequent decade. The increased detection rate may be associated with several factors, including enhanced surveillance, the availability of improved laboratory diagnostic methods, the expansion of the vector population, and, perhaps, altered human activities that lead to more exposure. Nonetheless, it remains unclear whether Powassan virus is indeed an emerging threat or if enzootic cycles in nature remain more-or-less stable with periodic fluctuations of host and vector population sizes. Despite the low disease incidence, the approximately 10% to 15% case fatality rate of neuroinvasive Powassan virus infection and the temporary or prolonged sequelae in >50% of survivors make Powassan virus a medical concern requiring the attention of public health authorities and clinicians. The medical importance of Powassan virus justifies more research on developing specific and effective treatments and prevention and control measures.

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“…7DMA was originally developed by Merck Research Laboratories as an inhibitor of hepatitis C virus replication (31), but was also shown to inhibit the replication of multiple flaviviruses, [i.e. dengue virus, yellow fever virus as well as West Nile and tick-borne encephalitis virus] with EC50 values ranging between 5 and 15 μM, which is thus comparable to the EC 50 values for inhibition of in vitro ZIKV replication (31,32,33). In line with its presumed mechanism of action, i.e.…”

Section: Discussionmentioning

confidence: 99%

The viral polymerase inhibitor 7-deaza-2'-C-methyladenosine is a potent inhibitor of in 1 vitro Zika virus replication and delays disease progression in a robust mouse infection model

Zmurko

Marques

Schols

et al. 2016

Preprint

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16Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but 17 neurological complications, such as microcephaly in newborns, have potentially been linked to 18 this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV 19 inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine 20 (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-21 out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating 22 in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in 23 the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in 24 serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected 25 mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-26 induced morbidity and mortality in infected mice, which also validates this small animal model 27 to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an 28 antibody response, and have been used in dengue vaccine studies, the model can also be used to 29 assess the efficacy of ZIKV vaccines. 30 31 Article Summary Line: A robust cell-based antiviral assay was developed that allows to screen 32 for and validate novel inhibitors of Zika virus (ZIKV) replication. The viral polymerase inhibitor 33 7-deaza-2'-C-methyladenosine (7DMA) was identified as a potent ZIKV inhibitor. A mouse 34 model for ZIKV infections, which was validated for antiviral studies, demonstrated that 7DMA 35 markedly delays virus-induced disease in this model.36 37

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Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

Cited by 83 publications

References 53 publications

FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells

FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

The viral polymerase inhibitor 7-deaza-2'-C-methyladenosine is a potent inhibitor of in 1 vitro Zika virus replication and delays disease progression in a robust mouse infection model

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