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, 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. View Full-Text

Keywords: SARS-CoV-2; COVID-19; protein kinase inhibitor; ALK5; TFG-β; furin

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Mezger, M.C.; Conzelmann, C.; Weil, T.; von Maltitz, P.; Albers, D.P.J.; Münch, J.; Stamminger, T.; Schilling, E.-M. 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 2022, 14, 1308. https://doi.org/10.3390/v14061308

AMA Style

Mezger MC, Conzelmann C, Weil T, von Maltitz P, Albers DPJ, Münch J, Stamminger T, Schilling E-M. 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. 2022; 14(6):1308. https://doi.org/10.3390/v14061308

Chicago/Turabian Style

Mezger, Maja C., Carina Conzelmann, Tatjana Weil, Pascal von Maltitz, Dan P.J. Albers, Jan Münch, Thomas Stamminger, and Eva-Maria Schilling. 2022. "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 14, no. 6: 1308. https://doi.org/10.3390/v14061308

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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

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