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Virus Res. 2014 May 12;184:44-53. doi: 10.1016/j.virusres.2014.02.010. Epub 2014 Feb 22.

Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir.

Author information

1
Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany.
2
Martin-Luther-Universität Halle-Wittenberg, Institute of Biochemistry and Biotechnology, Division of Enzymology, Halle, Germany.
3
Max-Planck-Institute of Biophysical Chemistry Göttingen, BO Halle (Saale), Germany.
4
Institut für Virologie, Universität Bonn, Bonn, Germany.
5
Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France.
6
Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany. Electronic address: vonbrunn@mvp.uni-muenchen.de.

Abstract

Until recently, there were no effective drugs available blocking coronavirus (CoV) infection in humans and animals. We have shown before that CsA and FK506 inhibit coronavirus replication (Carbajo-Lozoya, J., Müller, M.A., Kallies, S., Thiel, V., Drosten, C., von Brunn, A. Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506. Virus Res. 2012; Pfefferle, S., Schöpf, J., Kögl, M., Friedel, C., Müller, M.A., Stellberger, T., von Dall'Armi, E., Herzog, P., Kallies, S., Niemeyer, D., Ditt, V., Kuri, T., Züst, R., Schwarz, F., Zimmer, R., Steffen, I., Weber, F., Thiel, V., Herrler, G., Thiel, H.-J., Schwegmann-Weßels, C., Pöhlmann, S., Haas, J., Drosten, C. and von Brunn, A. The SARS-Coronavirus-host interactome: identification of cyclophilins as target for pan-Coronavirus inhibitors. PLoS Pathog., 2011). Here we demonstrate that CsD Alisporivir, NIM811 as well as novel non-immunosuppressive derivatives of CsA and FK506 strongly inhibit the growth of human coronavirus HCoV-NL63 at low micromolar, non-cytotoxic concentrations in cell culture. We show by qPCR analysis that virus replication is diminished up to four orders of magnitude to background levels. Knockdown of the cellular Cyclophilin A (CypA/PPIA) gene in Caco-2 cells prevents replication of HCoV-NL63, suggesting that CypA is required for virus replication. Collectively, our results uncover Cyclophilin A as a host target for CoV infection and provide new strategies for urgently needed therapeutic approaches.

KEYWORDS:

Cyclophilin A; Cyclosporine/FK506-non-immunosuppressive derivatives; FKBP; HCoV-NL63; Inhibition of viral replication

PMID:
24566223
DOI:
10.1016/j.virusres.2014.02.010
[Indexed for MEDLINE]

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