期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 79, 期 1, 页码 -出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04085-1
关键词
SARS-CoV-2; COVID-19; Antiviral drug; Raf; MEK; ERK; MEK1; 2-inhibitor; ATR-002
资金
- Projekt DEAL
- German Research Foundation (DFG) [CRU342, SFB1009, VI 538-9-1, PO 716/11-1, PO 716/14-1]
- Interdisciplinary Center for Medical Research (IZKF) [Bru2/015/19, Re/022/20]
- Innovative Medical Research fund (IMF) of the Muenster Medical School [SC121912]
- Germany's Excellence Strategy [EXC 2155, 39087428]
- German Ministry of Education and Research (BMBF) [01KX2021, 01KI20218]
The Raf/MEK/ERK signaling pathway may represent a target for therapeutic intervention against SARS-CoV-2 infections, and ATR-002 shows promising potential as a candidate drug with strong antiviral activity and the ability to prevent COVID-19-associated inflammation.
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.
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