Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression
Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, w...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/14/6/1308 |
| _version_ | 1827655826842583040 |
|---|---|
| author | Maja C. Mezger Carina Conzelmann Tatjana Weil Pascal von Maltitz Dan P. J. Albers Jan Münch Thomas Stamminger Eva-Maria Schilling |
| author_facet | Maja C. Mezger Carina Conzelmann Tatjana Weil Pascal von Maltitz Dan P. J. Albers Jan Münch Thomas Stamminger Eva-Maria Schilling |
| author_sort | Maja C. Mezger |
| collection | DOAJ |
| description | Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19. |
| first_indexed | 2024-03-09T22:13:03Z |
| format | Article |
| id | doaj.art-31ab1fcea7894ab4bb95e84558ae3c0a |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T22:13:03Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-31ab1fcea7894ab4bb95e84558ae3c0a2023-11-23T19:27:14ZengMDPI AGViruses1999-49152022-06-01146130810.3390/v14061308Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin ExpressionMaja C. Mezger0Carina Conzelmann1Tatjana Weil2Pascal von Maltitz3Dan P. J. Albers4Jan Münch5Thomas Stamminger6Eva-Maria Schilling7Institute of Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Virology, Ulm University Medical Center, 89081 Ulm, GermanyInstitute of Virology, Ulm University Medical Center, 89081 Ulm, GermanyScreening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.https://www.mdpi.com/1999-4915/14/6/1308SARS-CoV-2COVID-19protein kinase inhibitorALK5TFG-βfurin |
| spellingShingle | Maja C. Mezger Carina Conzelmann Tatjana Weil Pascal von Maltitz Dan P. J. Albers Jan Münch Thomas Stamminger Eva-Maria Schilling Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression Viruses SARS-CoV-2 COVID-19 protein kinase inhibitor ALK5 TFG-β furin |
| title | Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression |
| title_full | Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression |
| title_fullStr | Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression |
| title_full_unstemmed | Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression |
| title_short | Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression |
| title_sort | inhibitors of activin receptor like kinase 5 interfere with sars cov 2 s protein processing and spike mediated cell fusion via attenuation of furin expression |
| topic | SARS-CoV-2 COVID-19 protein kinase inhibitor ALK5 TFG-β furin |
| url | https://www.mdpi.com/1999-4915/14/6/1308 |
| work_keys_str_mv | AT majacmezger inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT carinaconzelmann inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT tatjanaweil inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT pascalvonmaltitz inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT danpjalbers inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT janmunch inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT thomasstamminger inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression AT evamariaschilling inhibitorsofactivinreceptorlikekinase5interferewithsarscov2sproteinprocessingandspikemediatedcellfusionviaattenuationoffurinexpression |