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Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry

1
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK
2
Section of Virology, Department of Medicine, School of Medicine, Imperial College London, London W2 1PG, UK
3
Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London NW3 2QG, UK
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Medical Microbiology, Cardiff University School of Medicine, Cardiff CF14 4XN, UK
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Bundeswehr Institute of Microbiology, 80937 Munich, Germany
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University of Sussex, Brighton BN1 9RH, UK
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Medway School of Pharmacy, University of Kent, Chatham ME4 4TB, UK
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School of Pharmacy, University College London, London WC1N 1AX, UK
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Faculty of Medical Sciences, UCL Medical School, London NW3 2QG, UK
*
Authors to whom correspondence should be addressed.
Deceased.
Viruses 2019, 11(2), 176; https://doi.org/10.3390/v11020176
Received: 25 January 2019 / Revised: 13 February 2019 / Accepted: 18 February 2019 / Published: 20 February 2019
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy. View Full-Text
Keywords: broad-spectrum antivirals; host-targeted antivirals; alphaviruses; flaviviruses; endocytosis; virus entry; Zika; dengue; Semliki Forest virus; phenotypic screening broad-spectrum antivirals; host-targeted antivirals; alphaviruses; flaviviruses; endocytosis; virus entry; Zika; dengue; Semliki Forest virus; phenotypic screening
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MDPI and ACS Style

Mazzon, M.; Ortega-Prieto, A.M.; Imrie, D.; Luft, C.; Hess, L.; Czieso, S.; Grove, J.; Skelton, J.K.; Farleigh, L.; Bugert, J.J.; Wright, E.; Temperton, N.; Angell, R.; Oxenford, S.; Jacobs, M.; Ketteler, R.; Dorner, M.; Marsh, M. Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry. Viruses 2019, 11, 176. https://doi.org/10.3390/v11020176

AMA Style

Mazzon M, Ortega-Prieto AM, Imrie D, Luft C, Hess L, Czieso S, Grove J, Skelton JK, Farleigh L, Bugert JJ, Wright E, Temperton N, Angell R, Oxenford S, Jacobs M, Ketteler R, Dorner M, Marsh M. Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry. Viruses. 2019; 11(2):176. https://doi.org/10.3390/v11020176

Chicago/Turabian Style

Mazzon, Michela, Ana M. Ortega-Prieto, Douglas Imrie, Christin Luft, Lena Hess, Stephanie Czieso, Joe Grove, Jessica K. Skelton, Laura Farleigh, Joachim J. Bugert, Edward Wright, Nigel Temperton, Richard Angell, Sally Oxenford, Michael Jacobs, Robin Ketteler, Marcus Dorner, and Mark Marsh. 2019. "Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry" Viruses 11, no. 2: 176. https://doi.org/10.3390/v11020176

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