Lin Lin, Chen Da-Yuan, Scartelli Christina, Xie Huanzhang, Merrill-Skoloff Glenn, Yang Moua, Sun Lijun, Saeed Mohsan, Flaumenhaft Robert
Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
College of Materials and Chemical Engineering, Minjiang University, Fuzhou Institute of Oceanography, Fuzhou, China.
iScience. 2023 Aug 10;26(9):107602. doi: 10.1016/j.isci.2023.107602. eCollection 2023 Sep 15.
Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and as therapies for COVID-19 on the basis of their safety profile and widespread availability. The SARS-CoV-2 main protease (Mpro) has been implicated as a target for flavonoids . Yet no comprehensive testing of flavonoid activity against SARS-CoV-2 Mpro has heretofore been performed. We screened 1,019 diverse flavonoids for their ability to inhibit SARS-CoV-2 Mpro. Multiple structure-activity relationships were identified among active compounds such as enrichment of galloylated flavonoids and biflavones, including multiple biflavone analogs of apigenin. In a cell-based SARS-CoV-2 replication assay, the most potent inhibitors were apigenin and the galloylated pinocembrin analog, pinocembrin 7-O-(3''-galloyl-4'',6''-(S)-hexahydroxydiphenoyl)-beta-D-glucose (PGHG). Molecular dynamic simulations predicted that PGHG occludes the S1 binding site via a galloyl group and induces a conformational change in Mpro. These studies will advance the development of plant-based flavonoids-including widely available natural products-to target β-coronaviruses.
基于植物的类黄酮因其安全性和广泛可得性，已被评估为β冠状病毒复制的抑制剂以及治疗新冠肺炎的药物。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶（Mpro）被认为是类黄酮的作用靶点。然而，迄今为止尚未对类黄酮针对SARS-CoV-2 Mpro的活性进行全面测试。我们筛选了1019种不同的类黄酮，以评估它们抑制SARS-CoV-2 Mpro的能力。在活性化合物中确定了多种构效关系，如没食子酰化类黄酮和双黄酮的富集，包括芹菜素的多种双黄酮类似物。在基于细胞的SARS-CoV-2复制试验中，最有效的抑制剂是芹菜素和没食子酰化的皮诺cembrin类似物，皮诺cembrin 7-O-（3''-没食子酰基-4''，6''-（S）-六羟基二苯甲酰基）-β-D-葡萄糖（PGHG）。分子动力学模拟预测，PGHG通过没食子酰基封闭S1结合位点，并诱导Mpro的构象变化。这些研究将推动基于植物的类黄酮（包括广泛可得的天然产物）靶向β冠状病毒的开发。
