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

• Authors: Alicia Martinez-Lopez, Albert Einstein College of Medicine; Mirjana Persaud, Albert Einstein College of Medicine; Maritza Puray Chavez, Emory University; Hongjie Zhang, Hong Kong Baptist University; Lijun Rong, University of Illinois; Shufeng Liu, Center for Biologics Evaluation and Research; Tony T. Wang, Center for Biologics Evaluation and Research; Stefan Sarafianos, Emory University; Felipe Diaz-Griffero, Albert Einstein College of Medicine
• Journal Title: EBioMedicine
• Volume: Volume 47
• Publisher: Elsevier: Creative Commons | 2019-09-01, Pages 269-283
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.ebiom.2019.08.060
• Subjects: Health Sciences, Pharmacology; Biology, Virology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, General & Internal; Medicine, Research & Experimental; General & Internal Medicine; Research & Experimental Medicine; Zika; Glycosylated diphyllin; Fusion; Endosomal; pH; Ifnar1(-/-); V-ATPASE INHIBITOR; PH-DEPENDENT FUSION; FDA-APPROVED DRUG; SENDAI-VIRUS; SEXUAL TRANSMISSION; CELL-FUSION; MOUSE MODEL; WEST-NILE; INFECTION; BIOLOGY

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.