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The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses.
Schreiber, André; Viemann, Dorothee; Schöning, Jennifer; Schloer, Sebastian; Mecate Zambrano, Angeles; Brunotte, Linda; Faist, Aileen; Schöfbänker, Michael; Hrincius, Eike; Hoffmann, Helen; Hoffmann, Markus; Pöhlmann, Stefan; Rescher, Ursula; Planz, Oliver; Ludwig, Stephan.
  • Schreiber A; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Viemann D; Translational Pediatrics, Department of Pediatrics, University Hospital Wuerzburg, 97080, Würzburg, Bavaria, Germany.
  • Schöning J; Center for Infection Research, University Wuerzburg, 97080, Würzburg, Bavaria, Germany.
  • Schloer S; Cluster of Excellence RESIST (EXC 2155, Hannover Medical School, 30625, Hannover, Lower Saxony, Germany.
  • Mecate Zambrano A; Translational Pediatrics, Department of Pediatrics, University Hospital Wuerzburg, 97080, Würzburg, Bavaria, Germany.
  • Brunotte L; Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, 48149, Münster, North Rhine-Westphalia, Germany.
  • Faist A; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Schöfbänker M; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Hrincius E; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Hoffmann H; CiM-IMPRS Graduate School, University of Muenster, 48149, Münster, North Rhine-Westphalia, Germany.
  • Hoffmann M; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Pöhlmann S; Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
  • Rescher U; Atriva Therapeutics GmbH, 72072, Tübingen, Baden-Württemberg, Germany.
  • Planz O; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University, 72074, Tübingen, Baden-Württemberg, Germany.
  • Ludwig S; Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany.
Cell Mol Life Sci ; 79(1): 65, 2022 Jan 10.
Article in English | MEDLINE | ID: covidwho-1616112
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / MAP Kinase Signaling System / Protein Kinase Inhibitors / Fenamates / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Vaccines Limits: Adult / Animals / Humans Language: English Journal: Cell Mol Life Sci Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00018-021-04085-1

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / MAP Kinase Signaling System / Protein Kinase Inhibitors / Fenamates / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Vaccines Limits: Adult / Animals / Humans Language: English Journal: Cell Mol Life Sci Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00018-021-04085-1