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Berthold, E. ; Ma-Lauer, Y.* ; Chakraborty, A. ; von Brunn, B.* ; Hilgendorff, A. ; Hatz, R.A.* ; Behr, J.* ; Hausch, F.* ; Staab-Weijnitz, C.A. ; von Brunn, A. *

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.

Front. Cell. Infect. Microbiol. 12:958634 (2022)

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Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cyclosporin A ; Fk506 ; Hcov-229e ; Non-immunosuppressive Analogs ; Phbecs ; Tacrolimus

ISSN (print) / ISBN 2235-2988

e-ISSN 2235-2988

Journal Frontiers in Cellular and Infection Microbiology

Quellenangaben Volume: 12, Article Number: 958634

Publisher Frontiers

Publishing Place Lausanne

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)

Grants Deutsches Zentrum für Lungenforschung
Helmholtz Association
Bundesinstitut für Risikobewertung
Deutsche Forschungsgemeinschaft
Deutsches Zentrum für Infektionsforschung
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