Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context
Alicia Martinez-Lopez,
Mirjana Persaud,
Maritza Puray Chavez,
Hongjie Zhang,
Lijun Rong,
Shufeng Liu,
Tony T. Wang,
Stefan G. Sarafianos,
Felipe Diaz-Griffero
Affiliations
Alicia Martinez-Lopez
Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USA
Mirjana Persaud
Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USA
Maritza Puray Chavez
Laboratory of Biochemical Pharmacology Emory University, Emory University, Atlanta, GA 30322, USA
Hongjie Zhang
School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, People's Republic of China
Lijun Rong
Microbiology and Immunology College of Medicine, University of Illinois at Chicago, IL 60612, USA
Shufeng Liu
Laboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USA
Tony T. Wang
Laboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USA
Stefan G. Sarafianos
Laboratory of Biochemical Pharmacology Emory University, Emory University, Atlanta, GA 30322, USA
Felipe Diaz-Griffero
Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USA; Corresponding author at: Albert Einstein College of Medicine, 1301 Morris Park, Price Center 501, New York, NY 10461, USA.
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. Keywords: Zika, Glycosylated diphyllin, Fusion, Endosomal, pH, Ifnar1−/−
