Schreiber A, Viemann D, Schoening J, Schloer S, Zambrano AM, Brunotte L, Faist A, Schoefbaenker M, Hrincius E, Hoffmann H, Hoffmann M, Poehlmann S, Rescher U, Planz O, Ludwig S (2022)
Publication Type: Journal article
Publication year: 2022
Book Volume: 79
Article Number: 65
Journal Issue: 1
DOI: 10.1007/s00018-021-04085-1
Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air–liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.
APA:
Schreiber, A., Viemann, D., Schoening, J., Schloer, S., Zambrano, A.M., Brunotte, L.,... Ludwig, S. (2022). The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses. Cellular and Molecular Life Sciences, 79(1). https://doi.org/10.1007/s00018-021-04085-1
MLA:
Schreiber, Andre, et al. "The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses." Cellular and Molecular Life Sciences 79.1 (2022).
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