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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; von Brunn, Brigitte; Hilgendorff, Anne; Hatz, Rudolf; Behr, Jürgen; Hausch, Felix; Staab-Weijnitz, Claudia A; von Brunn, Albrecht.
  • Berthold EJ; Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the Comprehensive Pneumology Center Munich (CPC-M) bioArchive, Helmholtz-Zentrum München, Munich, Germany.
  • Ma-Lauer Y; Max von Pettenkofer Institute, Department of Virology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
  • Chakraborty A; Max von Pettenkofer Institute, Department of Virology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
  • von Brunn B; German Center for Infection Research, Munich, Germany.
  • Hilgendorff A; Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the Comprehensive Pneumology Center Munich (CPC-M) bioArchive, Helmholtz-Zentrum München, Munich, Germany.
  • Hatz R; Max von Pettenkofer Institute, Department of Virology, Faculty of Medicine, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
  • Behr J; German Center for Infection Research, Munich, Germany.
  • Hausch F; Institute of Lung Health and Immunity and Comprehensive Pneumology Center with the Comprehensive Pneumology Center Munich (CPC-M) bioArchive, Helmholtz-Zentrum München, Munich, Germany.
  • Staab-Weijnitz CA; Thoraxchirurgisches Zentrum, Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.
  • von Brunn A; Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität (LMU), Munich, Germany.
Front Cell Infect Microbiol ; 12: 958634, 2022.
Article in English | MEDLINE | ID: covidwho-2114014
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Infections / Coronavirus / Coronavirus 229E, Human Type of study: Experimental Studies Limits: Humans Language: English Journal: Front Cell Infect Microbiol Year: 2022 Document Type: Article Affiliation country: Fcimb.2022.958634

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Coronavirus Infections / Coronavirus / Coronavirus 229E, Human Type of study: Experimental Studies Limits: Humans Language: English Journal: Front Cell Infect Microbiol Year: 2022 Document Type: Article Affiliation country: Fcimb.2022.958634