Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus

Alicia Martinez-Lopez, Mirjana Persaud, Maritza Puray Chavez, Hongjie Zhang, Lijun Rong, Shufeng Liu, Tony T. Wang, Stefan G. Sarafianos, Felipe Diaz-Griffero

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background: Flaviviruses such as Zika cause sporadic pandemic outbreaks worldwide. There is an urgent need for anti-Zika virus (ZIKV) drugs to prevent mother-to-child transmission of ZIKV, new infections in high-risk populations, and the infection of medical personnel in ZIKV-affected areas. Methods: Here, we showed that the small molecule 6-deoxyglucose-diphyllin (DGP) exhibited anti-ZIKV activity both in vitro and in vivo. DGP potently blocked ZIKV infection across all human and monkey cell lines tested. DGP also displayed broad-spectrum antiviral activity against other flaviviruses. Remarkably, DGP prevented ZIKV-induced mortality in mice lacking the type I interferon receptor (Ifnar1−/−). Cellular and virological experiments showed that DGP blocked ZIKV at a pre-fusion step or during fusion, which prevented the delivery of viral contents into the cytosol of the target cell. Mechanistic studies revealed that DGP prevented the acidification of endosomal/lysosomal compartments in target cells, thus inhibiting ZIKV fusion with cellular membranes and infection. Findings: These investigations revealed that DGP inhibits ZIKV infection in vitro and in vivo. Interpretation: The small molecule DGP has great potential for preclinical studies and the ability to inhibit ZIKV infection in humans.

Original languageEnglish (US)
Pages (from-to)269-283
Number of pages15
JournalEBioMedicine
Volume47
DOIs
StatePublished - Sep 2019

    Fingerprint

Keywords

  • Endosomal
  • Fusion
  • Glycosylated diphyllin
  • Ifnar1
  • Zika
  • pH

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Martinez-Lopez, A., Persaud, M., Chavez, M. P., Zhang, H., Rong, L., Liu, S., Wang, T. T., Sarafianos, S. G., & Diaz-Griffero, F. (2019). Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus. EBioMedicine, 47, 269-283. https://doi.org/10.1016/j.ebiom.2019.08.060