Cell-line dependent antiviral activity of sofosbuvir against Zika virus

Abstract

The recent epidemic of Zika virus (ZIKV) in the Americas and its association with fetal and neurological complications has shown the need to develop a treatment. Repurposing of drugs that are already FDA approved or in clinical development may shorten drug development timelines in case of emerging viral diseases like ZIKV. Initial studies have shown conflicting results when testing sofosbuvir developed for treatment of infections with another Flaviviridae virus, hepatitis C virus. We hypothesized that the conflicting results could be explained by differences in intracellular processing of the compound. We assessed the antiviral activity of sofosbuvir and mericitabine against ZIKV using Vero, A549, and Huh7 cells and measured the level of the active sofosbuvir metabolite by mass spectrometry. Mericitabine did not show activity, while sofosbuvir inhibited ZIKV with an IC of ∼4 μM, but only in Huh7 cells. This correlated with differences in intracellular concentration of the active triphosphate metabolite of sofosbuvir, GS-461203 or 007-TP, which was 11-342 times higher in Huh7 cells compared to Vero and A549 cells. These results show that a careful selection of cell system for repurposing trials of prodrugs is needed for evaluation of antiviral activity. Furthermore, the intracellular levels of 007-TP in tissues and cell types that support ZIKV replication in vivo should be determined to further investigate the potential of sofosbuvir as anti-ZIKV compound.

The A–Z of Zika drug discovery

“…This correlated with differences in the intracellular concentration of the active metabolite of sofosbuvir, which was higher in Huh7 cells compared with the other cells. These results highlight the importance of a careful selection of cell system for repurposing trials of prodrugs to evaluate antiviral activity [106].…”

“…Mumtaz and co-workers tested sofosbuvir against ZIKV using Vero, A549 and Huh7 cells, measuring the level of the active sofosbuvir metabolite by mass spectrometry [106]. Sofosbuvir showed a cell-type-dependent activity, inhibiting ZIKV with an IC 50 of $4 mM (but only in Huh7 cells) [106]. This correlated with differences in the intracellular concentration of the active metabolite of sofosbuvir, which was higher in Huh7 cells compared with the other cells.…”

Drug Repurposing for Viral Infectious Diseases: How Far Are We?

“…Studies reporting the repurposing potential against ZIKV of drugs approved for the treatment HCV infections, that is, ribavirin and sofosbuvir, are worth mentioning, although conflicting results on the efficacy of the latter have been reported [15][16][17][18][19][20]. Discrepancies may be due to the different cell lines or animal models used and should be explained at a molecular level; moreover, deeper investigation on the safety of sofosbuvir during pregnancy is needed before considering this anti-HCV drug as a candidate for the treatment of ZIKV fetal infections.…”

Untold stories of the Zika virus epidemic in Brazil

“…Zika virus treatment and prevention strategies are currently under intense investigation. Antivirals used for treatment of hepatitis C virus such as sofosbuvir and broad‐spectrum antiviral agents such as favipiravir were explored in in vitro and animal models for potential use as treatment of ZIKV infection. Sofosbuvir increased survival and reduced neurological impairment in ZIKV‐infected mice, but studies in humans are still unavailable.…”