Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419305833 |
| _version_ | 1818543639797694464 |
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| author | Alicia Martinez-Lopez Mirjana Persaud Maritza Puray Chavez Hongjie Zhang Lijun Rong Shufeng Liu Tony T. Wang Stefan G. Sarafianos Felipe Diaz-Griffero |
| author_facet | Alicia Martinez-Lopez Mirjana Persaud Maritza Puray Chavez Hongjie Zhang Lijun Rong Shufeng Liu Tony T. Wang Stefan G. Sarafianos Felipe Diaz-Griffero |
| author_sort | Alicia Martinez-Lopez |
| collection | DOAJ |
| description | 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−/− |
| first_indexed | 2024-12-11T22:38:03Z |
| format | Article |
| id | doaj.art-c501f0f7912b4b21a318e5ad574195a1 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T22:38:03Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-c501f0f7912b4b21a318e5ad574195a12022-12-22T00:47:54ZengElsevierEBioMedicine2352-39642019-09-0147269283Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in contextAlicia Martinez-Lopez0Mirjana Persaud1Maritza Puray Chavez2Hongjie Zhang3Lijun Rong4Shufeng Liu5Tony T. Wang6Stefan G. Sarafianos7Felipe Diaz-Griffero8Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461, USALaboratory of Biochemical Pharmacology Emory University, Emory University, Atlanta, GA 30322, USASchool of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, People's Republic of ChinaMicrobiology and Immunology College of Medicine, University of Illinois at Chicago, IL 60612, USALaboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USALaboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USALaboratory of Biochemical Pharmacology Emory University, Emory University, Atlanta, GA 30322, USADepartment 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−/−http://www.sciencedirect.com/science/article/pii/S2352396419305833 |
| spellingShingle | Alicia Martinez-Lopez Mirjana Persaud Maritza Puray Chavez Hongjie Zhang Lijun Rong Shufeng Liu Tony T. Wang Stefan G. Sarafianos Felipe Diaz-Griffero Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context EBioMedicine |
| title | Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context |
| title_full | Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context |
| title_fullStr | Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context |
| title_full_unstemmed | Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context |
| title_short | Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virusResearch in context |
| title_sort | glycosylated diphyllin as a broad spectrum antiviral agent against zika virusresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419305833 |
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