Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.
Coronavirus
/ genetics
Coronavirus 229E, Human
/ genetics
Coronavirus Infections
/ genetics
Cyclophilins
Cyclosporine
/ chemistry
HEK293 Cells
Humans
Immunosuppressive Agents
/ pharmacology
Luciferases, Renilla
Pharmaceutical Preparations
RNA
Tacrolimus
/ chemistry
Tacrolimus Binding Proteins
/ pharmacology
Cyclosporin A
FK506
HCoV-229E
non-immunosuppressive analogs
pHBECs
tacrolimus
Journal
Frontiers in cellular and infection microbiology
ISSN: 2235-2988
Titre abrégé: Front Cell Infect Microbiol
Pays: Switzerland
ID NLM: 101585359
Informations de publication
Date de publication:
2022
2022
Historique:
received:
31
05
2022
accepted:
29
08
2022
entrez:
10
10
2022
pubmed:
11
10
2022
medline:
12
10
2022
Statut:
epublish
Résumé
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. 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 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. 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.
Identifiants
pubmed: 36211973
doi: 10.3389/fcimb.2022.958634
pmc: PMC9534297
doi:
Substances chimiques
Immunosuppressive Agents
0
Pharmaceutical Preparations
0
RNA
63231-63-0
Cyclosporine
83HN0GTJ6D
Luciferases, Renilla
EC 1.13.12.5
Cyclophilins
EC 5.2.1.-
Tacrolimus Binding Proteins
EC 5.2.1.-
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
958634Informations de copyright
Copyright © 2022 Berthold, Ma-Lauer, Chakraborty, von Brunn, Hilgendorff, Hatz, Behr, Hausch, Staab-Weijnitz and von Brunn.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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