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      Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry

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          Abstract

          The re-emergence of Zika virus (ZIKV) and Ebola virus (EBOV) poses serious and continued threats to the global public health. Effective therapeutics for these maladies is an unmet need. Here, we show that emetine, an anti-protozoal agent, potently inhibits ZIKV and EBOV infection with a low nanomolar half maximal inhibitory concentration (IC 50) in vitro and potent activity in vivo. Two mechanisms of action for emetine are identified: the inhibition of ZIKV NS5 polymerase activity and disruption of lysosomal function. Emetine also inhibits EBOV entry. Cephaeline, a desmethyl analog of emetine, which may be better tolerated in patients than emetine, exhibits a similar efficacy against both ZIKV and EBOV infections. Hence, emetine and cephaeline offer pharmaceutical therapies against both ZIKV and EBOV infection.

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          Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

          Miao Xu, Emily M Lee, Zhexing Wen … (2016)
          In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
          Article 0 comments Cited 267 times – based on 0 reviews     Review now
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            Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes.

            Monique Gannagé, Dorothee Dormann, Randy A. Albrecht … (2009)
            Influenza A virus is an important human pathogen causing significant morbidity and mortality every year and threatening the human population with epidemics and pandemics. Therefore, it is important to understand the biology of this virus to develop strategies to control its pathogenicity. Here, we demonstrate that influenza A virus inhibits macroautophagy, a cellular process known to be manipulated by diverse pathogens. Influenza A virus infection causes accumulation of autophagosomes by blocking their fusion with lysosomes, and one viral protein, matrix protein 2, is necessary and sufficient for this inhibition of autophagosome degradation. Macroautophagy inhibition by matrix protein 2 compromises survival of influenza virus-infected cells but does not influence viral replication. We propose that influenza A virus, which also encodes proapoptotic proteins, is able to determine the death of its host cell by inducing apoptosis and also by blocking macroautophagy.
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              Evaluation of Ebola Virus Inhibitors for Drug Repurposing.

              Peter B Madrid, Rekha G Panchal, Travis K Warren … (2015)
              A systematic screen of FDA-approved drugs was performed to identify compounds with in vitro antiviral activities against Ebola virus (EBOV). Compounds active (>50% viral inhibition and <30% cellular toxicity) at a single concentration were tested in dose-response assays to quantitate the antiviral activities in replication and viral entry assays as well as cytotoxicity in the Vero cell line used to conduct these assays. On the basis of the approved human dosing, toxicity/tolerability, and pharmacokinetic data, seven of these in vitro hits from different pharmacological classes (chloroquine (CQ), amiodarone, prochlorperazine, benztropine, azithromycin, chlortetracycline, and clomiphene) were evaluated for their in vivo efficacy at a single dose and were administered via either intraperitoneal (ip) or oral route. Initially, azithromycin (100 mg/kg, twice daily, ip), CQ (90 mg/kg, twice daily, ip), and amiodarone (60 mg/kg, twice daily, ip) demonstrated significant increases in survival in the mouse model. After repeat evaluation, only CQ was found to reproducibly give significant efficacy in the mouse model with this dosing regimen. Azithromycin and CQ were also tested in a guinea pig model of EBOV infection over a range of doses, but none of the doses increased survival, and drug-related toxicity was observed at lower doses than in the mouse. These results show the benefits and specific challenges associated with drug repurposing and highlight the need for careful evaluation of approved drugs as rapidly deployable countermeasures against future pandemics.
              Article 0 comments Cited 115 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiangguo Qiu: Xiangguo.qiu@canada.ca
                Alexey V. Terskikh: terskikh@sbpdiscovery.org
                Hengli Tang: tang@bio.fsu.edu
                Hongjun Song: shongju1@jhmi.edu
                Wei Zheng:
                ORCID: http://orcid.org/0000-0003-1034-0757
                wzheng@mail.nih.gov
                Journal
                Journal ID (nlm-ta): Cell Discov
                Journal ID (iso-abbrev): Cell Discov
                Title: Cell Discovery
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2056-5968
                Publication date (Electronic): 5 June 2018
                Publication date PMC-release: 5 June 2018
                Publication date Collection: 2018
                Volume: 4
                Electronic Location Identifier: 31
                Affiliations
                [1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Center for Advancing Translational Sciences, , National Institutes of Health, ; 9800 Medical Center Drive, Bethesda, MD 20892 USA
                [2 ]ISNI 0000 0004 0472 0419, GRID grid.255986.5, Department of Biological Science, , Florida State University, ; Tallahassee, FL 32306 USA
                [3 ]ISNI 0000 0001 0163 8573, GRID grid.479509.6, Development, Aging and Regeneration Program, , Sanford Burnham Prebys Medical Discovery Institute, ; La Jolla, CA 92037 USA
                [4 ]ISNI 0000 0001 0805 4386, GRID grid.415368.d, Special Pathogens Program, National Microbiology Laboratory, , Public Health Agency of Canada, ; Winnipeg, Manitoba R3E 3R2 Canada
                [5 ]ISNI 0000 0004 0472 0419, GRID grid.255986.5, Department of Biomedical Sciences, , Florida State University, ; Tallahassee, FL 32306 USA
                [6 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Pharmacology & Molecular Sciences, , Johns Hopkins School of Medicine, ; Baltimore, MD USA
                [7 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Microbiology and Global Health and Emerging Pathogens Institute, , Icahn School of Medicine at Mount Sinai, ; New York, NY 10029 USA
                [8 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Department of Medicine, Miller School of Medicine, , University of Miami, ; Miami, FL 33136 USA
                [9 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Neuroscience and Mahoney Institute for Neurosciences, , University of Pennsylvania, ; Philadelphia, PA 19104 USA
                [10 ]ISNI 0000 0004 1936 9609, GRID grid.21613.37, Department of Medical Microbiology, , University of Manitoba, ; Winnipeg, Manitoba R3E 0J9 Canada
                Author information
                http://orcid.org/0000-0002-4652-8818
                http://orcid.org/0000-0002-8426-2889
                http://orcid.org/0000-0002-2517-6075
                http://orcid.org/0000-0003-1034-0757
                Article
                Publisher ID: 34
                DOI: 10.1038/s41421-018-0034-1
                PMC ID: 5986771
                PubMed ID: 29872540
                SO-VID: 4472df34-7918-4100-b816-50393c6cc26d
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 4 January 2018
                Date revision received : 13 April 2018
                Date accepted : 23 April 2018
                Categories
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                issue-copyright-statement © The Author(s) 2018

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