Plitidepsin is a broad-spectrum antiviral that transiently inhibits viral 1 protein translation and shapes a protective proteostatic cellular response

Plitidepsin is a safe antiviral for COVID-19 patients that impairs SARS-CoV-2 replication by targeting host factors implicated in protein translation. Here we used deep quantitative proteomics coupled to infectious assays and transmission electron microscopy to dissect its antiviral activity. Plitidepsin inhibited the synthesis of all SARS-CoV-2 proteins, including R1AB required for double membrane vesicle formation needed for viral replication. Yet, less than 14% of the cellular proteome was affected by plitidepsin, which up-regulated translation factors such as eIF4A2 and eIF2S3 and ribosomal proteins associated to protein biosynthesis. At a concentration of 50nM, plitidepsin resulted in a compensatory proteostasis that rescued protein translation. Moreover, plitidepsin inhibited other RNA-dependent and non-integrated DNA viruses from the Flaviviridae, Pneumoviridae, and Herpesviridae families, but failed to block DNA-integrated proviruses from the Retroviridae family. Unraveling the mechanism of action of host-directed therapies like plitidepsin is essential to develop broad-spectrum antivirals ready to deploy when future pandemics begin.

普利地普辛（Plitidepsin）是一款用于新型冠状病毒肺炎（COVID-19）患者的安全抗病毒药物，可通过靶向参与蛋白质翻译的宿主因子，抑制严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的复制。本研究借助深度定量蛋白质组学结合感染性实验与透射电子显微镜（transmission electron microscopy），解析了该药物的抗病毒活性机制。普利地普辛可抑制所有SARS-CoV-2蛋白的合成，包括病毒复制所需双膜囊泡形成过程中必需的R1AB蛋白。然而，仅不到14%的细胞蛋白质组会受到普利地普辛的影响；该药物可上调eIF4A2、eIF2S3等翻译因子，以及参与蛋白质生物合成的核糖体蛋白。在50nM浓度下，普利地普辛可诱导产生代偿性蛋白稳态（proteostasis），进而恢复蛋白质翻译过程。此外，普利地普辛还可抑制黄病毒科（Flaviviridae）、肺病毒科（Pneumoviridae）与疱疹病毒科（Herpesviridae）所属的其他RNA依赖性及非整合型DNA病毒，但无法阻断逆转录病毒科（Retroviridae）的整合型DNA前病毒。阐明普利地普辛这类靶向宿主的治疗手段的作用机制，对于开发可在未来大流行爆发时快速部署的广谱抗病毒药物具有至关重要的意义。