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

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.

• Authors: Emilia J Berthold, Yue Ma-Lauer, Ashesh Chakraborty, Brigitte von Brunn, Anne Hilgendorff, Rudolf Hatz, Jürgen Behr, Felix Hausch, Claudia A Staab-Weijnitz, Albrecht von Brunn
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 12 Pg. 958634 ( 2022) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 36211973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Berthold, Ma-Lauer, Chakraborty, von Brunn, Hilgendorff, Hatz, Behr, Hausch, Staab-Weijnitz and von Brunn.

Chemical References

• Immunosuppressive Agents
• Pharmaceutical Preparations
• RNA
• Cyclosporine
• Luciferases, Renilla
• Cyclophilins
• Tacrolimus Binding Proteins
• Tacrolimus

Topics

• Coronavirus (genetics)
• Coronavirus 229E, Human (genetics)
• Coronavirus Infections (genetics)
• Cyclophilins
• Cyclosporine (chemistry, pharmacology, therapeutic use)
• HEK293 Cells
• Humans
• Immunosuppressive Agents (pharmacology)
• Luciferases, Renilla
• Pharmaceutical Preparations
• RNA
• Tacrolimus (chemistry, pharmacology, therapeutic use)
• Tacrolimus Binding Proteins (pharmacology, therapeutic use)