The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Here we present a pivotal molecular mechanism of viral protein translation that relies on the mitochondrial translation machinery. We found that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for the regulation of viral protein expression. SARS-CoV-2 controls the translation of its spike gene by hijacking host mitochondria through 5' leader and 3'UTR sequences that contain mitochondrial localization signals and activate the EGR1 pathway. Mitochondrial-targeted drugs such as lonidamine and polydatin significantly repress rare codon-driven gene expression and viral replication. This study identifies an unreported viral protein translation mechanism and opens up a novel avenue for developing antiviral drugs.

中文翻译：

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一种新型的病毒蛋白翻译机制揭示线粒体为抗病毒药物开发的目标

正在进行中的严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）大流行强烈表明需要确定新的病毒感染治疗策略。在这里，我们介绍了依赖线粒体翻译机制的病毒蛋白翻译的关键分子机制。我们发现稀有密码子（例如Leu-TTA）在许多病毒（包括SARS-CoV-2）中高度富集，并且这些密码子对于调节病毒蛋白表达至关重要。SARS-CoV-2通过通过包含线粒体定位信号并激活EGR1途径的5'前导序列和3'UTR序列劫持宿主线粒体来控制其刺突基因的翻译。以线粒体为靶标的药物（如lonidamine和polydatin）可显着抑制稀有密码子驱动的基因表达和病毒复制。