PDF(Pubmed)
Abstract：
BACKGROUND: The viral main protease (Mpro) of SARS-CoV-2 has been recently proposed as a key target to inhibit virus replication in the host. Therefore, molecules that can bind the catalytic site of Mpro could be considered as potential drug candidates in the treatment of SARS-CoV-2 infections. Here we proposed the application of a state-of-the-art analytical platform which combines metabolomics and protein structure analysis to fish-out potential active compounds deriving from a natural matrix, i.e., a blueberry extract.
METHODS: The experiments focus on finding MS covalent inhibitors of Mpro that contain in their structure a catechol/pyrogallol moiety capable of binding to the nucleophilic amino acids of the enzyme\'s catalytic site.
RESULTS: Among the potential candidates identified, the delphinidin-3-glucoside showed the most promising results. Its antiviral activity has been confirmed in vitro on Vero E6 cells infected with SARS-CoV-2, showing a dose-dependent inhibitory effect almost comparable to the known Mpro inhibitor baicalin. The interaction of delphinidin-3-glucoside with the Mpro pocket observed was also evaluated by computational studies.
CONCLUSIONS: The HRMS analytical platform described proved to be effective in identifying compounds that covalently bind Mpro and are active in the inhibition of SARS-CoV-2 replication, such as delphinidin-3-glucoside.
METHODS: The experiments focus on finding MS covalent inhibitors of Mpro that contain in their structure a catechol/pyrogallol moiety capable of binding to the nucleophilic amino acids of the enzyme\'s catalytic site.
RESULTS: Among the potential candidates identified, the delphinidin-3-glucoside showed the most promising results. Its antiviral activity has been confirmed in vitro on Vero E6 cells infected with SARS-CoV-2, showing a dose-dependent inhibitory effect almost comparable to the known Mpro inhibitor baicalin. The interaction of delphinidin-3-glucoside with the Mpro pocket observed was also evaluated by computational studies.
CONCLUSIONS: The HRMS analytical platform described proved to be effective in identifying compounds that covalently bind Mpro and are active in the inhibition of SARS-CoV-2 replication, such as delphinidin-3-glucoside.
摘要：
背景：最近提出了SARS-CoV-2的病毒主要蛋白酶（Mpro）作为抑制病毒在宿主中复制的关键靶标。因此,可以结合Mpro催化位点的分子可以被认为是治疗SARS-CoV-2感染的潜在药物候选物。在这里，我们提出了一个最先进的分析平台的应用，该平台结合了代谢组学和蛋白质结构分析，以挖掘源自天然基质的潜在活性化合物。即，蓝莓提取物.
方法：实验的重点是寻找Mpro的MS共价抑制剂，其结构中含有能够与酶催化位点的亲核氨基酸结合的儿茶酚/连苯三酚部分。
结果：在确定的潜在候选人中，delphinidin-3-葡萄糖苷显示了最有希望的结果。已在体外对感染SARS-CoV-2的VeroE6细胞证实了其抗病毒活性，显示出与已知的Mpro抑制剂黄芩苷几乎相当的剂量依赖性抑制作用。还通过计算研究评估了飞跃素-3-葡萄糖苷与Mpro口袋的相互作用。
结论：所描述的HRMS分析平台被证明可有效地鉴定共价结合Mpro的化合物，并且在抑制SARS-CoV-2复制方面具有活性，如Delphinidin-3-葡萄糖苷。
方法：实验的重点是寻找Mpro的MS共价抑制剂，其结构中含有能够与酶催化位点的亲核氨基酸结合的儿茶酚/连苯三酚部分。
结果：在确定的潜在候选人中，delphinidin-3-葡萄糖苷显示了最有希望的结果。已在体外对感染SARS-CoV-2的VeroE6细胞证实了其抗病毒活性，显示出与已知的Mpro抑制剂黄芩苷几乎相当的剂量依赖性抑制作用。还通过计算研究评估了飞跃素-3-葡萄糖苷与Mpro口袋的相互作用。
结论：所描述的HRMS分析平台被证明可有效地鉴定共价结合Mpro的化合物，并且在抑制SARS-CoV-2复制方面具有活性，如Delphinidin-3-葡萄糖苷。
