Frontiers in Chemistry ( IF 5.5 ) Pub Date : 2020-12-15 , DOI: 10.3389/fchem.2020.628609 Simone Di Micco , Simona Musella , Maria C. Scala , Marina Sala , Pietro Campiglia , Giuseppe Bifulco , Alessio Fasano
The most severe outcome of COVID-19 infection is the development of interstitial pneumonia causing acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), both responsible for the infected patients' mortality. ALI and ARDS are characterized by a leakage of plasma components into the lungs, compromising their ability to expand and optimally engage in gas exchange with blood, resulting in respiratory failure. We have previously reported that zonulin, a protein dictating epithelial and endothelial permeability in several districts, including the airways, is involved in ALI pathogenesis in mouse models, and that its peptide inhibitor Larazotide acetate (also called AT1001) ameliorated ALI and subsequent mortality by decreasing mucosal permeability to fluid and extravasation of neutrophils into the lungs. With the recent crystallographic resolution of the SARS-CoV-2 main protease (Mpro), an enzyme fundamental in the viral lifecycle, bound to peptidomimetic inhibitors N3 and 13b, we were able to perform molecular modeling investigation showing that AT1001 presents structural motifs similar to co-crystallized ligands. Specifically, molecular docking, MM-GBSA-based predictions and molecular dynamics showed that AT1001 docks extremely well in the Mpro catalytic domain through a global turn conformational arrangement without any unfavorable steric hindrance. Finally, we have observed that AT1001 can be superimposed onto the crystallized structures of N3 and 13b, establishing a higher number of interactions and accordingly a tighter binding.
中文翻译:
电脑模拟分析显示,Zonulin抑制剂Larazotide Acetate具有潜在的抗SARS-CoV-2主要蛋白酶活性
COVID-19感染最严重的结果是间质性肺炎的发展,引起急性肺损伤(ALI)和/或急性呼吸窘迫综合征(ARDS),这两者都是导致感染患者死亡的原因。ALI和ARDS的特征是血浆成分泄漏到肺部,损害了它们的扩张能力,无法与血液进行最佳气体交换,从而导致呼吸衰竭。我们以前曾报道过,zonulin是一种在多个区域(包括气道)指示上皮和内皮通透性的蛋白质,其参与小鼠模型的ALI发病机理,并且其肽抑制剂醋酸Larazotide乙酸酯(也称为AT1001)通过降低ALI改善了随后的死亡率。粘膜对液体的渗透性和中性粒细胞向肺的渗出。pro)(一种病毒生命周期中的基本酶,与拟肽抑制剂N3和13b结合),我们能够进行分子建模研究,显示AT1001呈现出与共结晶的配体相似的结构基序。具体而言,基于分子对接,基于MM-GBSA的预测和分子动力学表明,AT1001通过全局转弯构象排列在M pro催化域中非常牢固地对接,而没有任何不利的空间位阻。最后,我们观察到AT1001可以叠加到N3和13b的结晶结构上,从而建立更多数量的相互作用并因此获得更紧密的结合。