Elsevier

Virus Research

Volume 184, 12 May 2014, Pages 44-53
Virus Research

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

https://doi.org/10.1016/j.virusres.2014.02.010Get rights and content

Highlights

  • Cyclophilin A (CypA) is a host factor for human coronavirus NL63 replication.

  • CypA is a target for anti-coronaviral therapy.

  • Non-immunosuppressive CsA derivatives (Alisporivir, NIM811) inhibit CoV replication.

  • New classes of non-immunosuppressive CsA/FK506 derivatives inhibit CoV replication.

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.

Abbreviations

EC50
50% effective inhibitory concentration
CsA/CsD
cyclosporine A/D
PPIase
peptidyl prolyl cis/trans isomerase
CypA/B
cyclophilin A/B
ALV
Alisporivir
FKBP
FK506-binding protein

Keywords

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

Cited by (0)

1

Contributed equally the work.

2

Present address: Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany.

View Abstract