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

Abstract

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-/{beta} and IFN-{gamma} receptor knockout) 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-{gamma} 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.\n\nArticle Summary LineA robust cell-based antiviral assay was developed that allows to screen for and validate novel inhibitors of Zika virus (ZIKV) replication. The viral polymerase inhibitor 7-deaza-2-C-methyladenosine (7DMA) was identified as a potent ZIKV inhibitor. A mouse model for ZIKV infections, which was validated for antiviral studies, demonstrated that 7DMA markedly delays virus-induced disease in this model.