title: Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir.
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.
authors.affiliation: Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Carbajo-Lozoya
authors.affiliation: Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma-Lauer
authors.affiliation: Martin-Luther-Universität Halle-Wittenberg, Institute of Biochemistry and Biotechnology, Division of Enzymology, Halle, Germany.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malešević
authors.affiliation: Max-Planck-Institute of Biophysical Chemistry Göttingen, BO Halle (Saale), Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Theuerkorn
authors.affiliation: Max-Planck-Institute of Biophysical Chemistry Göttingen, BO Halle (Saale), Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Kahlert
authors.affiliation: Max-Planck-Institute of Biophysical Chemistry Göttingen, BO Halle (Saale), Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Prell
authors.affiliation: Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: von Brunn
authors.affiliation: Institut für Virologie, Universität Bonn, Bonn, Germany.
authors.forename: Doreen
authors.initials: D
authors.lastname: Muth
authors.affiliation: Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: Institut für Virologie, Universität Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.affiliation: Max-Planck-Institute of Biophysical Chemistry Göttingen, BO Halle (Saale), Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.affiliation: Max-von-Pettenkofer Institut, Ludwig-Maximilians-Universität, München, Germany. Electronic address: vonbrunn@mvp.uni-muenchen.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: von Brunn
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D058957:Coronavirus NL63, Human / Q000187:drug effects* / Q000502:physiology*; D021984:Cyclophilin A / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021984:Cyclophilin A; C499715:alisporivir; D016559:Tacrolimus
keywords: Cyclophilin A; Cyclosporine/FK506-non-immunosuppressive derivatives; FKBP; HCoV-NL63; Inhibition of viral replication