tetano
Editor, Senior Moderator
Cell Mol Life Sci
. 2022 Jan 10;79(1):65.
doi: 10.1007/s00018-021-04085-1.
The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses
André Schreiber[SUP] 1 [/SUP], Dorothee Viemann[SUP] 2 3 4 [/SUP], Jennifer Schöning[SUP] 2 [/SUP], Sebastian Schloer[SUP] 5 [/SUP], Angeles Mecate Zambrano[SUP] 1 [/SUP], Linda Brunotte[SUP] 1 [/SUP], Aileen Faist[SUP] 1 6 [/SUP], Michael Schöfbänker[SUP] 1 [/SUP], Eike Hrincius[SUP] 1 [/SUP], Helen Hoffmann[SUP] 7 8 [/SUP], Markus Hoffmann[SUP] 9 10 [/SUP], Stefan Pöhlmann[SUP] 9 10 [/SUP], Ursula Rescher[SUP] 5 11 [/SUP], Oliver Planz[SUP] 7 8 [/SUP], Stephan Ludwig[SUP] 12 13 [/SUP]
Affiliations
Abstract
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.
Keywords: ATR-002; Antiviral drug; COVID-19; MEK1/2-inhibitor; Raf/MEK/ERK; SARS-CoV-2.
. 2022 Jan 10;79(1):65.
doi: 10.1007/s00018-021-04085-1.
The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses
André Schreiber[SUP] 1 [/SUP], Dorothee Viemann[SUP] 2 3 4 [/SUP], Jennifer Schöning[SUP] 2 [/SUP], Sebastian Schloer[SUP] 5 [/SUP], Angeles Mecate Zambrano[SUP] 1 [/SUP], Linda Brunotte[SUP] 1 [/SUP], Aileen Faist[SUP] 1 6 [/SUP], Michael Schöfbänker[SUP] 1 [/SUP], Eike Hrincius[SUP] 1 [/SUP], Helen Hoffmann[SUP] 7 8 [/SUP], Markus Hoffmann[SUP] 9 10 [/SUP], Stefan Pöhlmann[SUP] 9 10 [/SUP], Ursula Rescher[SUP] 5 11 [/SUP], Oliver Planz[SUP] 7 8 [/SUP], Stephan Ludwig[SUP] 12 13 [/SUP]
Affiliations
- PMID: 35013790
- DOI: 10.1007/s00018-021-04085-1
Abstract
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.
Keywords: ATR-002; Antiviral drug; COVID-19; MEK1/2-inhibitor; Raf/MEK/ERK; SARS-CoV-2.