Division of Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, Louisiana 70125, USA.
Med Chem. 2024;20(10):986-991. doi: 10.2174/0115734064302693240711114948.
In the search for anti-COVID-19 therapy, 1,2,3,4,6-pentakis-O-galloyl-β- D-glucopyranoside, a natural polyphenolic compound isolated from many traditional medicinal herbs, has been reported as an RBD-ACE2 binding inhibitor and as a broad-spectrum anticoronaviral inhibitor targeting the main protease and RNA-dependent RNA polymerase of SARSCoV- 2. To facilitate the structure-activity relationship studies of 1,2,3,4,6-pentakis-O-galloyl-β-Dglucopyranoside, we describe its chemical synthesis and characterization, as well as its activity towards the SARS-CoV-2 spike interaction with host ACE2 receptor.
1,2,3,4,6-Pentakis-O-galloyl-β-D-glucopyranoside was synthesized in two quantitative steps from 3,4,5-tribenzyloxybenzoic acid and β-D-glucopyranoside: DCC-mediated esterification and palladium-catalyzed per-debenzylation. The synthesized molecule was evaluated using a SARS-CoV-2 spike trimer (S1 + S2) ACE2 inhibitor screening colorimetric assay kit, SARS-CoV- 2 spike S1 RBD ACE2 inhibitor screening assay kit, and a cellular neutralization assay using the Spike (SARS-CoV-2) Pseudotyped Lentivirus, ACE2-HEK293 recombinant cell line.
The chemically synthesized product blocked the binding of the spike trimer of SARSCoV- 2 to the human ACE2 receptor with IC=22±2 μM. It also blocked ACE2: spike RBD binding with IC=27±3 μM. Importantly, it inhibited the infectivity of SARS2-CoV2-Spike pseudotyped lentivirus on the ACE2 HEK293 cell line with IC=20±2 μM.
Overall, the chemically synthesized 1,2,3,4,6-pentakis-O-galloyl-β-D-glucopyranoside represents a lead molecule to develop anti-SARS-CoV-2 therapies that block the initial stage of the viral infection by blocking the virus entry to the host cell.
在寻找抗 COVID-19 疗法的过程中，从许多传统草药中分离出的天然多酚化合物 1,2,3,4,6-五-O-没食子酰基-β-D-吡喃葡萄糖苷已被报道为 RBD-ACE2 结合抑制剂和广谱抗冠状病毒抑制剂，针对 SARSCoV-2 的主要蛋白酶和 RNA 依赖性 RNA 聚合酶。为了促进 1,2,3,4,6-五-O-没食子酰基-β-D-吡喃葡萄糖苷的构效关系研究，我们描述了其化学合成和表征，以及它对 SARS-CoV-2 刺突与宿主 ACE2 受体相互作用的活性。
从 3,4,5-三苄氧基苯甲酸和β-D-吡喃葡萄糖苷出发，通过 DCC 介导的酯化和钯催化的全脱苄基化两步反应定量合成 1,2,3,4,6-五-O-没食子酰基-β-D-吡喃葡萄糖苷：使用 SARS-CoV-2 刺突三聚体（S1+S2）ACE2 抑制剂筛选比色法试剂盒、SARS-CoV-2 刺突 S1 RBD ACE2 抑制剂筛选测定试剂盒和 Spike（SARS-CoV-2）假型慢病毒、ACE2-HEK293 重组细胞系的细胞中和测定评估合成的分子。
化学合成的产物阻断了 SARSCoV-2 的刺突三聚体与人类 ACE2 受体的结合，IC=22±2 μM。它还阻断了 ACE2：刺突 RBD 结合，IC=27±3 μM。重要的是，它抑制了 SARS2-CoV2-Spike 假型慢病毒在 ACE2 HEK293 细胞系上的感染性，IC=20±2 μM。
总的来说，化学合成的 1,2,3,4,6-五-O-没食子酰基-β-D-吡喃葡萄糖苷代表了一种开发抗 SARS-CoV-2 疗法的先导分子，该疗法通过阻断病毒进入宿主细胞来阻断病毒感染的初始阶段。
