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

Berthold, Emilia J. ; Ma-Lauer, Yue ; Chakraborty, Ashesh ; Brunn, Brigitte von ; Hilgendorff, Anne ; Hatz, Rudolf ; Behr, Jürgen ; Hausch, Felix ; Staab-Weijnitz, Claudia A. ; Brunn, Albrecht von (2022):
Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models. (Publisher's Version)
In: Frontiers in Cellular and Infection Microbiology, 12, Frontiers Media S.A., e-ISSN 2235-2988,
DOI: 10.26083/tuprints-00022480,
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Item Type: Article
Origin: Secondary publication DeepGreen
Status: Publisher's Version
Title: Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models
Language: English
Abstract:

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.

Journal or Publication Title: Frontiers in Cellular and Infection Microbiology
Volume of the journal: 12
Place of Publication: Darmstadt
Publisher: Frontiers Media S.A.
Collation: 12 Seiten
Uncontrolled Keywords: HCoV-229E, Cyclosporin A, FK506, non-immunosuppressive analogs, pHBECs, tacrolimus
Classification DDC: 500 Naturwissenschaften und Mathematik > 540 Chemie
500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Divisions: 07 Department of Chemistry > Fachgebiet Biochemie
Date Deposited: 24 Oct 2022 13:15
Last Modified: 28 Oct 2022 06:21
DOI: 10.26083/tuprints-00022480
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-224804
SWORD Depositor: Deep Green
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/22480
PPN: 500851492
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