Chemically Synthesized 1,2,3,4,6-Pentakis-O-Galloyl-β-D-Glucopyranoside Blocks SARS-CoV-2 Spike Interaction with Host ACE-2 Receptor.

IF 1.9 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Pub Date : 2024-01-01 DOI:10.2174/0115734064302693240711114948

Jazmine Ezell, Rami A Al-Horani

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: The chemically synthesized product blocked the binding of the spike trimer of SARSCoV- 2 to the human ACE2 receptor with IC₅₀=22±2 μM. It also blocked ACE2: spike RBD binding with IC₅₀=27±3 μM. Importantly, it inhibited the infectivity of SARS2-CoV2-Spike pseudotyped lentivirus on the ACE2 HEK293 cell line with IC₅₀=20±2 μM.

Conclusion: 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.

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化学合成的 1,2,3,4,6-Pentakis-O-Galloyl-β-D-Glucopyranoside 可阻断 SARS-CoV-2 Spike 与宿主 ACE-2 受体的相互作用。

背景：在寻找抗 COVID-19 疗法的过程中，有报道称从许多传统草药中分离出的天然多酚化合物 1,2,3,4,6-pentakis-O-galloyl-βD-glucopyranoside 是一种 RBD-ACE2 结合抑制剂，也是一种针对 SARSCoV-2 主要蛋白酶和 RNA 依赖性 RNA 聚合酶的广谱抗冠状病毒抑制剂。为了便于对 1,2,3,4,6-五(O-galloyl-β-Dglucopyranoside)的结构-活性关系进行研究，我们介绍了它的化学合成和表征，以及它对 SARS-CoV-2 穗状病毒与宿主 ACE2 受体相互作用的活性。方法：1,2,3,4,6-五(O-galloyl-β-D-吡喃葡萄糖苷)是由 3,4,5-三苄氧基苯甲酸和 β-D-吡喃葡萄糖苷分两步定量合成的：DCC 介导的酯化反应和钯催化的过脱苄基反应。使用 SARS-CoV-2 穗状三聚体（S1 + S2）ACE2 抑制剂筛选比色测定试剂盒、SARS-CoV2 穗状 S1 RBD ACE2 抑制剂筛选比色测定试剂盒以及使用 Spike (SARS-CoV-2) 伪原型慢病毒、ACE2-HEK293 重组细胞系进行细胞中和测定，对合成的分子进行了评估：化学合成产物阻断了 SARSCoV-2 的尖峰三聚体与人 ACE2 受体的结合，IC50=22±2 µM。它还阻断了 ACE2：尖峰 RBD 的结合，IC50=27±3 µM。重要的是，它抑制了 SARS2-CoV2-Spike 伪型慢病毒对 ACE2 HEK293 细胞系的感染性，IC50=20±2 µM：

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来源期刊

Medicinal Chemistry 医学-医药化学

CiteScore

4.30

自引率

4.30%

发文量

109

审稿时长

12 months

期刊介绍： Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.