Developing Sweet Prophylactics: Targeting Glycans to Prevent COVID-19 Spread

The devastating COVID-19 pandemic caused by the coronavirus SARS-CoV-2 continues to be prolonged by the ability of the virus to evolve into more transmissible and vaccine-resistant variants of concern (VOC). These fast-evolving VOC demonstrate the need for broad-acting antivirals against coronaviruses. As with several other human-infecting viruses, SARS-CoV-2 initiates attachment to host cells by binding to complex cell-surface carbohydrates known as glycans. These glycans are used by the virus to recognize and concentrate virions on the host cell surface and facilitate binding to less abundant entry receptors, like ACE2 for SARS-CoV-2. Due to most viruses using glycans to initiate infection, we therefore hypothesize that glycans are a worthy target for broad-acting antivirals. While monovalent carbohydrate-protein interactions are weak and have a low affinity, virions exploit multivalent interactions and the attachment of viruses to the cell is relatively strong. Therefore, one strategy in building a broad-based antiviral is to develop multivalent prophylactic antivirals that blocks this initial attachment of SARS-CoV-2 to glycans in the upper respiratory tract by targeting these carbohydrate-protein interactions. This thesis will describe an approach we are developing to synthesize multivalent carbohydrate-based antivirals for SARS-CoV-2 by targeting initial glycan-mediated interactions involved in viral attachment. Four preliminary targets for SARS-CoV-2 have been identified: mannose, galactose, N-acetylneuraminic acid, and gallic acid. These targets are functionalized with linkers bearing an azide functionality to facilitate conjugation to multivalent dendrimers scaffolds comprised of 3-24 alkyne moieties. The azide and alkyne functionalities allow for quick conjugation of the glycan mimetic derivatives through copper-catalyzed azide-alkyne cycloaddition (CuAAC), creating multivalent glycan-based dendrimers. The efficacy of these dendrimers as inhibitors will be tested using a SARS-CoV-2 viral entry assay using A549 epithelial cells with and without overexpression of the ACE2 receptor protein and lentivirus pseudo-typed with spike protein, with viral entry being measured by luciferase reporter activity.