The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses

André Schreiber,Stephan Ludwig,Markus Hoffmann,Stefan Pöhlmann,Oliver Planz,Ursula Rescher,Angeles Mecate Zambrano,Jennifer Schöning,Eike Hrincius,Linda Brunotte,Dorothee Viemann,Aileen Faist,Sebastian Schloer,Helen Hoffmann,Michael Schöfbänker

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.

Highlights

Since the emergence of the highly pathogenic and transmissible new betacoronavirus SARS-CoV-2 (2019-nCoV) in Wuhan City, China, in December 2019 [1], more than 260 million confirmed cases of SARS-CoV-2-elicited coronavirus disease 2019 (COVID-19) and over 5 million deaths worldwide were recorded [2]
An alternative approach is the repurposing of already licensed drugs to target either viral components or cellular mechanisms involved in SARS-CoV-2 replication
We explored the involvement of the cellular Raf/MEK/ERK pathway in the SARS-CoV-2 infection, and assessed its antiviral potential and the suitability of the MEK1/2-inhibitor ATR-002 as a potential drug repurposing candidate

Summary

Introduction

Since the emergence of the highly pathogenic and transmissible new betacoronavirus SARS-CoV-2 (2019-nCoV) in Wuhan City, China, in December 2019 [1], more than 260 million confirmed cases of SARS-CoV-2-elicited coronavirus disease 2019 (COVID-19) and over 5 million deaths worldwide were recorded [2]. Fatigue, and dry cough are commonly experienced upon SARS-CoV-2 infection [3], severe COVID-19 symptoms such as pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ failure occur in approximately 15% of the patients and are mainly caused by a virus infection-induced cytokine storm [4, 5]. Multiple vaccines have been licensed less than 18 months after the first reported case [6,7,8,9], making the global vaccination campaign against COVID-19 an unprecedented success. Because disease progression is dynamic, with late stages of severe COVID-19 driven by a harmful hyperinflammatory response, direct targeting antivirals (DTA) such as Remdesivir or monoclonal antibodies cannot efficiently improve health of severely diseased patients, albeit showing good effects when administered early in infection [13, 14]

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