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Medicinal Chemistry

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

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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

In Press, (this is not the final "Version of Record"). Available online 22 July, 2024
Author(s): Jazmine Ezell and Rami A. Al-Horani*
Published on: 22 July, 2024

DOI: 10.2174/0115734064302693240711114948

Price: $95

Abstract

Background: In the search for anti-COVID-19 therapy, 1,2,3,4,6-pentakis-O-galloyl-βD-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-CoV2 spike S1 RBD ACE2 inhibitor screening colorimetric 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.

[1]
Lu, R.; Zhao, X.; Li, J.; Niu, P.; Yang, B.; Wu, H.; Wang, W.; Song, H.; Huang, B.; Zhu, N.; Bi, Y.; Ma, X.; Zhan, F.; Wang, L.; Hu, T.; Zhou, H.; Hu, Z.; Zhou, W.; Zhao, L.; Chen, J.; Meng, Y.; Wang, J.; Lin, Y.; Yuan, J.; Xie, Z.; Ma, J.; Liu, W.J.; Wang, D.; Xu, W.; Holmes, E.C.; Gao, G.F.; Wu, G.; Chen, W.; Shi, W.; Tan, W. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 2020, 395(10224), 565-574.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
[2]
Shang, J.; Ye, G.; Shi, K.; Wan, Y.; Luo, C.; Aihara, H.; Geng, Q.; Auerbach, A.; Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature, 2020, 581(7807), 221-224.
[http://dx.doi.org/10.1038/s41586-020-2179-y] [PMID: 32225175]
[3]
Walls, A.C.; Park, Y.J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 2020, 183(6), 1735.
[http://dx.doi.org/10.1016/j.cell.2020.11.032] [PMID: 33306958]
[4]
Al-Horani, R.A.; Kar, S. Potential anti-SARS-CoV-2 therapeutics that target the post-entry stages of the viral life cycle: A comprehensive review. Viruses, 2020, 12(10), 1092.
[http://dx.doi.org/10.3390/v12101092] [PMID: 32993173]
[5]
Al-Horani, R.A.; Kar, S.; Aliter, K.F. Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials. Int. J. Mol. Sci., 2020, 21(15), 5224.
[http://dx.doi.org/10.3390/ijms21155224] [PMID: 32718020]
[6]
Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; Choe, H.; Farzan, M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 2003, 426(6965), 450-454.
[http://dx.doi.org/10.1038/nature02145] [PMID: 14647384]
[7]
Hofmann, H.; Pyrc, K.; van der Hoek, L.; Geier, M.; Berkhout, B.; Pöhlmann, S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Acad. Sci. USA, 2005, 102(22), 7988-7993.
[http://dx.doi.org/10.1073/pnas.0409465102] [PMID: 15897467]
[8]
Hoffmann, M.; Kleine-Weber, H.; Pöhlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol. Cell, 2020, 78(4), 779-784.e5.
[http://dx.doi.org/10.1016/j.molcel.2020.04.022] [PMID: 32362314]
[9]
Shang, J.; Wan, Y.; Luo, C.; Ye, G.; Geng, Q.; Auerbach, A.; Li, F. Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. USA, 2020, 117(21), 11727-11734.
[http://dx.doi.org/10.1073/pnas.2003138117] [PMID: 32376634]
[10]
Fehr, A.R.; Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol. Biol., 2015, 1282, 1-23.
[http://dx.doi.org/10.1007/978-1-4939-2438-7_1] [PMID: 25720466]
[11]
Jackson, C.B.; Farzan, M.; Chen, B.; Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol., 2022, 23(1), 3-20.
[http://dx.doi.org/10.1038/s41580-021-00418-x] [PMID: 34611326]
[12]
Lee, S.J.; Lee, H.K.; Jung, M.K.; Mar, W. In vitro antiviral activity of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose against hepatitis B virus. Biol. Pharm. Bull., 2006, 29(10), 2131-2134.
[http://dx.doi.org/10.1248/bpb.29.2131] [PMID: 17015965]
[13]
Liu, G.; Xiong, S.; Xiang, Y.F.; Guo, C.W.; Ge, F.; Yang, C.R.; Zhang, Y.J.; Wang, Y.F.; Kitazato, K. Antiviral activity and possible mechanisms of action of pentagalloylglucose (PGG) against influenza A virus. Arch. Virol., 2011, 156(8), 1359-1369.
[http://dx.doi.org/10.1007/s00705-011-0989-9] [PMID: 21479599]
[14]
Kim, K.H.; Shim, J.S.; Kim, H.J.; Son, E.D. Penta-O-galloyl-β-D-glucose from Paeonia lactiflora Pall. root extract enhances the expression of skin barrier genes via EGR3. J. Ethnopharmacol., 2020, 248, 112337.
[http://dx.doi.org/10.1016/j.jep.2019.112337] [PMID: 31655148]
[15]
Chen, R.H.; Yang, L.J.; Hamdoun, S.; Chung, S.K.; Lam, C.W.; Zhang, K.X.; Guo, X.; Xia, C.; Law, B.Y.K.; Wong, V.K.W. 1,2,3,4,6-pentagalloyl glucose, a RBD-ACE2 binding inhibitor to prevent SARS-CoV-2 infection. Front. Pharmacol., 2021, 12, 634176.
[http://dx.doi.org/10.3389/fphar.2021.634176] [PMID: 33897423]
[16]
Samandar, F.; Amiri Tehranizadeh, Z.; Saberi, M.R.; Chamani, J. 1,2,3,4,6-Pentagalloyl glucose of Pistacia lentiscus can inhibit the replication and transcription processes and viral pathogenesis of SARS-COV-2. Mol. Cell. Probes, 2022, 65, 101847.
[http://dx.doi.org/10.1016/j.mcp.2022.101847] [PMID: 35843391]
[17]
Jin, Y.H.; Lee, J.; Jeon, S.; Kim, S.; Min, J.S.; Kwon, S. Natural polyphenols, 1,2,3,4,6-O-pentagalloyglucose and proanthocyanidins, as broad-spectrum anticoronaviral inhibitors targeting Mpro and RdRp of SARS-CoV-2. Biomedicines, 2022, 10(5), 1170.
[http://dx.doi.org/10.3390/biomedicines10051170] [PMID: 35625907]
[18]
Al-Horani, R.A.; Desai, U.R. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. J. Med. Chem., 2014, 57(11), 4805-4818.
[http://dx.doi.org/10.1021/jm500311e] [PMID: 24844380]

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