Synthesizing Multivalent Displays of Mannose and Gallic Acid for the Inhibition of SARS-CoV-2 Viral Attachment
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Authors
Hutton, Joshua Kenneth
Date
2025-02-03
Type
thesis
Language
eng
Keyword
Glycans , Organic Chemistry , Carbohydrate Chemistry , Virology
Alternative Title
Abstract
A lack of pharmaceutical intervention available for the first year after the emergence of SARS-CoV-2 has emphasized the need for broad-acting antivirals which can be employed quickly in the event of another coronavirus pandemic. Many viruses, including SARS-CoV-2, use cell-surface carbohydrates called glycans as attachment cofactors, enabling them to dock on the cell surface and subsequently locate their respective entry receptors. For example, the SARS-CoV-2 spike protein is decorated with high-mannose (Man) glycans, which can be used to bind to lectins on the cell surface. Previous work by the Capicciotti Lab and Colpitts Lab has indicated that Man-based dendrimers with valences of 3 and 12 Man units are capable of inhibiting infectivity of VSV-SARS-CoV-2 virions in A549-ACE2 cells. Other work has indicated that epigallocatechin gallate (EGCG) is capable of inhibiting viral attachment in viruses which use heparan sulfate as an attachment cofactor. Gallic acid (GA) is an EGCG mimetic which could be used to target this interaction.
This thesis will outline the development of novel antivirals based on Man and GA. Azide-functionalized derivatives of both Man and GA were developed and attempted to be conjugated to various alkyne-adorned core scaffolds using copper-catalyzed azide-alkyne cycloaddition (CuAAC). Three novel Man-dendrimers were to be synthesized with valences of 4 and 6, and 12. In addition, new routes will be explored to access an azidated GA derivative using a combination of amide coupling reactions and protecting-group chemistry. Attempts were also made to conjugate this azidated GA derivative to alkyne-adorned core scaffolds to form GA dendrimers with valences of 3 and 4. Once synthesized, these dendrimers will be tested in viral infectivity assays to assess their potential as viral attachment inhibitors.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution 4.0 International