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Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Short Communication

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

Author(s): Jazmine Ezell and Rami A. Al-Horani*

Volume 20, Issue 10, 2024

Published on: 22 July, 2024

Page: [986 - 991] Pages: 6

DOI: 10.2174/0115734064302693240711114948

Price: $65

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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.

Keywords: Pentagalloylglucose, SARS-CoV-2, ACE2, spike protein, viral entry, HEK293.

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