Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 病毒蛋白与真核翻译机制相互作用，翻译抑制剂具有有效的抗病毒作用。我们发现，临床批准有限的药物 plitidepsin (aplidin) 具有抗病毒活性（90% 抑制浓度 = 0.88 nM），体外抗 SARS-CoV-2 的效果比瑞德西韦强 27.5 倍，但作用有限。细胞培养中的毒性。通过使用耐药突变体，我们证明 plitidepsin 针对 SARS-CoV-2 的抗病毒活性是通过抑制已知靶标 eEF1A（真核翻译延伸因子 1A）来介导的。我们证明了 plitidepsin 在两种 SARS-CoV-2 感染小鼠模型中的体内疗效，通过预防性治疗，肺部病毒复制减少了两个数量级。我们的结果表明 plitidepsin 是一种有前途的 COVID-19 治疗候选药物。