Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, Von-Esmarch-Straße 56, 48149, Münster, North Rhine-Westphalia, Germany.
Translational Pediatrics, Department of Pediatrics, University Hospital Wuerzburg, 97080, Würzburg, Bavaria, Germany.
Cell Mol Life Sci. 2022 Jan 10;79(1):65. 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.
新型冠状病毒病 2019（COVID-19），一种由新型冠状病毒引起的疾病，现称为严重急性呼吸综合征冠状病毒 2（SARS-CoV-2），迄今为止已导致超过 2.6 亿例确诊感染和 500 万人死亡。虽然疫苗接种是控制大流行传播的有力工具，但仍缺乏用于缓解 COVID-19 相关症状和减轻疾病进展的药物，特别是在高危患者中。在这项研究中，我们探讨了快速加速纤维肉瘤/有丝分裂原激活的蛋白激酶/细胞外信号调节激酶（Raf/MEK/ERK）通路作为治疗 SARS-CoV-2 感染的可用药靶的适用性。我们发现 SARS-CoV-2 在早期感染阶段短暂激活 Raf/MEK/ERK 信号通路，并且 ERK1/2 敲低可限制细胞培养模型中的病毒复制。我们证明，ATR-002 是一种特异性 MEK1/2 激酶抑制剂，目前正在临床试验中作为抗流感药物进行评估，它在细胞系以及原代气液界面上皮细胞（ALI）培养物中具有强大的抗 SARS-CoV-2 活性，具有安全且选择性的治疗窗。我们还观察到 ATR-002 治疗可削弱 SARS-CoV-2 诱导的促炎细胞因子的表达，因此可能预防 COVID-19 相关的过度炎症，这是 COVID-19 进展的关键因素。因此，我们的数据表明，Raf/MEK/ERK 信号级联可能是针对 SARS-CoV-2 感染的治疗干预策略的靶标，并且 ATR-002 是进一步药物评估的有前途的候选药物。
