The Viral Polymerase Inhibitor 7-Deaza-2'-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model

Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitor...

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Bibliographic Details
Published in:PLoS neglected tropical diseases 2016-05, Vol.10 (5), p.e0004695-e0004695
Main Authors: Zmurko, Joanna, Marques, Rafael E, Schols, Dominique, Verbeken, Erik, Kaptein, Suzanne J F, Neyts, Johan
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - pharmacology
Archives & records
Biology and life sciences
Cercopithecus aethiops
Chemokines
Control
Cytokines
Disease Models, Animal
Epidemics
Experiments
Fever
Flavivirus
Infections
Male
Medicine and Health Sciences
Mice
Microbial enzymes
Mosquitoes
Research and Analysis Methods
Studies
Tropical diseases
Tubercidin - analogs & derivatives
Tubercidin - pharmacology
Vero Cells
Viral infections
Viral vaccines
Virus replication
Virus Replication - drug effects
Zika virus
Zika Virus - drug effects
Zika Virus - physiology
Zika virus infection
Zika Virus Infection - drug therapy
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Summary:Zika virus (ZIKV) is an emerging flavivirus typically causing a dengue-like febrile illness, but neurological complications, such as microcephaly in newborns, have potentially been linked to this viral infection. We established a panel of in vitro assays to allow the identification of ZIKV inhibitors and demonstrate that the viral polymerase inhibitor 7-deaza-2'-C-methyladenosine (7DMA) efficiently inhibits replication. Infection of AG129 (IFN-α/β and IFN-γ receptor knock-out) mice with ZIKV resulted in acute neutrophilic encephalitis with viral antigens accumulating in neurons of the brain and spinal cord. Additionally, high levels of viral RNA were detected in the spleen, liver and kidney, and levels of IFN-γ and IL-18 were systematically increased in serum of ZIKV-infected mice. Interestingly, the virus was also detected in testicles of infected mice. In line with its in vitro anti-ZIKV activity, 7DMA reduced viremia and delayed virus-induced morbidity and mortality in infected mice, which also validates this small animal model to assess the in vivo efficacy of novel ZIKV inhibitors. Since AG129 mice can generate an antibody response, and have been used in dengue vaccine studies, the model can also be used to assess the efficacy of ZIKV vaccines.  .
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0004695