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

• Type of Material: Article
• 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
• Language: English
• Date: 2019-09-01
• Publisher: Elsevier: Creative Commons
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors. CC BY NC ND 4.0
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ebiom.2019.08.060
• Title of Journal or Parent Work: EBioMedicine
• ISSN: 2352-3964
• Volume: 47
• Start Page: 269
• End Page: 283
• Grant/Funding Information: This work was supported by the Albert Einstein College of Medicine.
• Keywords: SENDAI-VIRUS; MOUSE MODEL; Life Sciences & Biomedicine; Science & Technology; SEXUAL TRANSMISSION; Research & Experimental Medicine; pH; Medicine, Research & Experimental; WEST-NILE; Fusion; Endosomal; Ifnar1(-/-); General & Internal Medicine; CELL-FUSION; BIOLOGY; PH-DEPENDENT FUSION; Medicine, General & Internal; V-ATPASE INHIBITOR; FDA-APPROVED DRUG; Zika; Glycosylated diphyllin; INFECTION
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery; Biology, Virology

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.