Abstract
Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.
Highlights
Zika virus (ZIKV) is a member of the Flaviviridae family, which includes several agents of clinical significance, such as dengue (DENV), hepatitis C (HCV), West Nile (WNV) and Japanese encephalitis (JEV) viruses
Despite its relatively low sequence identity to ZIKV, the HCV enzyme structure is complexed with sofosbuvir, and the amino acids residues that interact with the drug are highly conserved among the members of the Flaviviridae family[37]
The residues critical for RNA-dependent RNA polymerase (RDRP) activity are conserved among different viral species and strains, including an African ZIKV strain from the 1950 s and those circulating currently, DENV and different genotypes of HCV38
Summary
Zika virus (ZIKV) is a member of the Flaviviridae family, which includes several agents of clinical significance, such as dengue (DENV), hepatitis C (HCV), West Nile (WNV) and Japanese encephalitis (JEV) viruses. Australia’s regulatory agency on drug administration, the Therapeutic and Goods Administration (TGA), categorizes sofosbuvir as class B1: “Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.”. This information motivated us to investigate whether the chemical structure of sofosbuvir possesses anti-ZIKV activity. We observed a direct inhibition of the viral RNA polymerase and an increase in A-to-G mutations in the viral genome due to sofosbuvir treatment, highlighting a potential secondary use of sofosbuvir
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