TU Darmstadt / ULB / TUprints

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.
In: Frontiers in Cellular and Infection Microbiology, 2022, 12
doi: 10.26083/tuprints-00022480
Article, Secondary publication, Publisher's Version

[img] Text
fcimb-12-958634.pdf
Copyright Information: CC BY 4.0 International - Creative Commons, Attribution.

Download (7MB)
[img] Text
DataSheet_1.pdf
Copyright Information: CC BY 4.0 International - Creative Commons, Attribution.

Download (1MB)
Item Type: Article
Type of entry: Secondary publication
Title: Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models
Language: English
Date: 24 October 2022
Place of Publication: Darmstadt
Year of primary publication: 2022
Publisher: Frontiers Media S.A.
Journal or Publication Title: Frontiers in Cellular and Infection Microbiology
Volume of the journal: 12
Collation: 12 Seiten
DOI: 10.26083/tuprints-00022480
Corresponding Links:
Origin: Secondary publication DeepGreen
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.

Uncontrolled Keywords: HCoV-229E, Cyclosporin A, FK506, non-immunosuppressive analogs, pHBECs, tacrolimus
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-224804
Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
Divisions: 07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
Date Deposited: 24 Oct 2022 13:15
Last Modified: 14 Nov 2023 19:05
SWORD Depositor: Deep Green
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/22480
PPN: 500851492
Export:
Actions (login required)
View Item View Item