The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed millions of lives worldwide, not to mention innumerable losses in the global economy and disruptions in social relationships. Unfortunately, state-of-the-art treatments still lag behind the fast emergence of new variants of concern. The key to resolve this issue is to develop broad-spectrum antivirals with innovative antiviral mechanisms in which coronaviruses are deactivated regardless of their variant development. Herein, we report a new antiviral strategy involving extracellular disintegration of viral proteins that are indispensable for viral infection with hyperanion-grafted enediyne molecules. The sulfate groups ensure low cellular permeability and rather low cytotoxicity of the molecules, while the core enediyne generates reactive radical species and causes significant damage to the spike (S) protein of coronavirus. The enediyne compounds exhibit antiviral activity at micromolar to nanomolar concentrations, and the selectivity index of up to 20,000 against four kinds of human coronaviruses, including the SARS-CoV-2 omicron variant, suggesting the high potential of this new strategy in combating the COVID-19 pandemic.

中文翻译：

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病毒蛋白的细胞外崩解作为开发针对冠状病毒的广谱抗病毒药物的创新策略

由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的 2019 年冠状病毒病 (COVID-19) 大流行已夺去全球数百万人的生命，更不用说全球经济的无数损失和社会关系的破坏。不幸的是，最先进的治疗方法仍然落后于快速出现的新变种。解决这个问题的关键是开发具有创新抗病毒机制的广谱抗病毒药物，无论其变异发展如何，冠状病毒都会被灭活。在此，我们报告了一种新的抗病毒策略，涉及病毒蛋白的细胞外分解，这些病毒蛋白对于高阴离子接枝的烯二炔分子的病毒感染是必不可少的。硫酸基确保分子的低细胞渗透性和相当低的细胞毒性，而核心烯二炔会产生活性自由基物质，并对冠状病毒的刺突蛋白 (S) 造成显着损害。烯二炔化合物在微摩尔到纳摩尔浓度下表现出抗病毒活性，对包括 SARS-CoV-2 omicron 变体在内的四种人类冠状病毒的选择性指数高达 20,000，表明这种新策略在对抗 COVID- 19大流行。