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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cyclosporin A ; Fk506 ; Hcov-229e ; Non-immunosuppressive Analogs ; Phbecs ; Tacrolimus
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 2235-2988
e-ISSN 2235-2988
Quellenangaben Band: 12, Heft: , Seiten: , Artikelnummer: 958634 Supplement: ,
Verlag Frontiers
Verlagsort Lausanne
Begutachtungsstatus Peer reviewed
POF Topic(s) 80000 - German Center for Lung Research
30202 - Environmental Health
Forschungsfeld(er) Lung Research
PSP-Element(e) G-501800-817
G-501600-001
G-552100-001
Förderungen Deutsches Zentrum für Lungenforschung
Helmholtz Association
Bundesinstitut für Risikobewertung
Deutsche Forschungsgemeinschaft
Deutsches Zentrum für Infektionsforschung
LOEWE Exploration
Scopus ID 85139424751
PubMed ID 36211973
Erfassungsdatum 2022-11-23