The disruptive impact of the COVID-19 pandemic has led the scientific community to undertake an unprecedented effort to characterize viral infection mechanisms. Among these, interactions between the viral glycosylated Spike and the human receptors ACE2 and TMPRSS2 are key to allowing virus invasion. Here, we report and test a fully rational methodology to design molecules that are capable of perturbing the interactions between these critical players in SARS-CoV-2 pathogenicity. To this end, we computationally identify substructures on the fully glycosylated Spike protein that are not intramolecularly optimized and are thus prone to being stabilized by forming complexes with ACE2 and TMPRSS2. With the aim of competing with the Spike-mediated cell entry mechanisms, we have engineered the predicted putative interaction regions in the form of peptide mimics that could compete with Spike for interaction with ACE2 and/or TMPRSS2. Experimental models of viral entry demonstrate that the designed molecules are able to interfere with viral entry into ACE2/TMPRSS2 expressing cells, while they have no effects on the entry of control viral particles that do not harbor the Spike protein or on the entry of Spike-presenting viral particles into cells that do not display its receptors on their surface.

中文翻译：

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干扰 SARS-CoV-2 刺突蛋白与其宿主细胞受体之间识别机制的分子的设计和测试


COVID-19 大流行的破坏性影响促使科学界采取了前所未有的努力来表征病毒感染机制。其中，病毒糖基化刺突与人类受体 ACE2 和 TMPRSS2 之间的相互作用是允许病毒入侵的关键。在这里，我们报告并测试了一种完全合理的方法来设计能够扰乱 SARS-CoV-2 致病性中这些关键参与者之间相互作用的分子。为此，我们通过计算鉴定了完全糖基化 Spike 蛋白上的子结构，这些子结构没有分子内优化，因此容易通过与 ACE2 和 TMPRSS2 形成复合物来稳定。为了与 Spike 介导的细胞进入机制竞争，我们以肽模拟物的形式设计了预测的推定相互作用区域，这些模拟物可以与 Spike 竞争与 ACE2 和/或 TMPRSS2 的相互作用。病毒进入的实验模型表明，设计的分子能够干扰病毒进入表达 ACE2/TMPRSS2 的细胞，而它们对不携带刺突蛋白的对照病毒颗粒的进入或刺突呈递病毒颗粒进入不在其表面显示其受体的细胞没有影响。