Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus

Abstract

The ongoing Zika virus (ZIKV) outbreaks have raised global concerns due to its unexpected clinical manifestations. Antiviral development is of high priority in response to the ZIKV emergency. In this study, we report that an adenosine analog NITD008 has potent in vitro and in vivo antiviral activity against ZIKV. The compound can effectively inhibit the historical and contemporary ZIKV strains in cultures as well as significantly reduce viremia and prevent mortality in A129 mice. Our results have demonstrated that NITD008 is potent inhibitor of ZIKV and can be used as reference inhibitor for future ZIKV antiviral drug screen and discovery.

Keywords: Zika virus; adenosine analog; antiviral; mouse model.

Figure 1.

In vitro and antiviral activity of NITD008 against Zika virus (ZIKV). Vero cells were infected with the indicated ZIKV stains at a multiplicity of infection of 0.1 followed by the treatment with the indicated concentrations of NITD008. Supernatants of the infected cells were collected and measured for viral titers using plaque assays on BHK-21 cell (A). The 50% effective concentration (EC₅₀) values were calculated by fitting the dose-response curves from a viral titer reduction assay (B) and reverse-transcription quantitative polymerase chain reaction assay (C), and the error bars represented data from 3 independent experiments.

Figure 2.

The therapeutic effects of NITD008 against Zika virus (ZIKV) challenge in A129 mice. Groups of 4-week-old A129 mice (n = 8) intraperitoneally challenged with 10⁵ plaque-forming units of ZIKV strains GZ01/2016 were orally administered with NITD008 at 50 mg/kg body weight for 5 days. Percentage survival between ZIKV-infected mice treated with mock or NITD008 was compared using the log-rank test (A). Viral ribonucleic acid loads in serum at day 1, 2, and 3 postinfection were determined by reverse-transcription quantitative polymerase chain reaction (B), and statistical analysis was performed using the unpaired, 2-tailed t-test. Differences of P < .05 were considered significant.