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Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir.
Virus Res. 2014 May 12; 184:44-53.VR

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-Weβels, 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+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24566223

Citation

Carbajo-Lozoya, Javier, et al. "Human Coronavirus NL63 Replication Is Cyclophilin A-dependent and Inhibited By Non-immunosuppressive Cyclosporine A-derivatives Including Alisporivir." Virus Research, vol. 184, 2014, pp. 44-53.
Carbajo-Lozoya J, Ma-Lauer Y, Malešević M, et al. Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir. Virus Res. 2014;184:44-53.
Carbajo-Lozoya, J., Ma-Lauer, Y., Malešević, M., Theuerkorn, M., Kahlert, V., Prell, E., von Brunn, B., Muth, D., Baumert, T. F., Drosten, C., Fischer, G., & von Brunn, A. (2014). Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir. Virus Research, 184, 44-53. https://doi.org/10.1016/j.virusres.2014.02.010
Carbajo-Lozoya J, et al. Human Coronavirus NL63 Replication Is Cyclophilin A-dependent and Inhibited By Non-immunosuppressive Cyclosporine A-derivatives Including Alisporivir. Virus Res. 2014 May 12;184:44-53. PubMed PMID: 24566223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir. AU - Carbajo-Lozoya,Javier, AU - Ma-Lauer,Yue, AU - Malešević,Miroslav, AU - Theuerkorn,Martin, AU - Kahlert,Viktoria, AU - Prell,Erik, AU - von Brunn,Brigitte, AU - Muth,Doreen, AU - Baumert,Thomas F, AU - Drosten,Christian, AU - Fischer,Gunter, AU - von Brunn,Albrecht, Y1 - 2014/02/22/ PY - 2014/01/15/received PY - 2014/02/12/revised PY - 2014/02/13/accepted PY - 2014/2/26/entrez PY - 2014/2/26/pubmed PY - 2014/12/15/medline KW - Cyclophilin A KW - Cyclosporine/FK506-non-immunosuppressive derivatives KW - FKBP KW - HCoV-NL63 KW - Inhibition of viral replication SP - 44 EP - 53 JF - Virus research JO - Virus Res. VL - 184 N2 - 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-Weβels, 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. SN - 1872-7492 UR - https://www.unboundmedicine.com/medline/citation/24566223/Human_coronavirus_NL63_replication_is_cyclophilin_A_dependent_and_inhibited_by_non_immunosuppressive_cyclosporine_A_derivatives_including_Alisporivir_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-1702(14)00063-X DB - PRIME DP - Unbound Medicine ER -