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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.
In: Frontiers in Cellular and Infection Microbiology, 12
doi: 10.3389/fcimb.2022.958634
Artikel, Bibliographie

Dies ist die neueste Version dieses Eintrags.

Kurzbeschreibung (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.

Typ des Eintrags: Artikel
Erschienen: 2022
Autor(en): 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
Art des Eintrags: Bibliographie
Titel: Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models
Sprache: Englisch
Publikationsjahr: 2022
Ort: Darmstadt
Verlag: Frontiers Media S.A.
Titel der Zeitschrift, Zeitung oder Schriftenreihe: Frontiers in Cellular and Infection Microbiology
Jahrgang/Volume einer Zeitschrift: 12
Kollation: 12 Seiten
DOI: 10.3389/fcimb.2022.958634
Zugehörige Links:
Kurzbeschreibung (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.

Freie Schlagworte: HCoV-229E, Cyclosporin A, FK506, non-immunosuppressive analogs, pHBECs, tacrolimus
Sachgruppe der Dewey Dezimalklassifikatin (DDC): 500 Naturwissenschaften und Mathematik > 540 Chemie
500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Fachbereich(e)/-gebiet(e): 07 Fachbereich Chemie
07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie
07 Fachbereich Chemie > Clemens-Schöpf-Institut
Hinterlegungsdatum: 02 Aug 2024 12:43
Letzte Änderung: 02 Aug 2024 12:43
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