Synthesis of Targeted Antiviral Nucleosides

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This project tackles the unmet need for antiviral drugs targeted against SARS-Cov-2. We will construct a set of new carbocyclic C-nucleosides and test them as inhibitors of the virus which causes COVID-19. Antiviral therapies are urgently required to tackle this rapidly transmitted viral disease, which has resulted in over 3,000,000 infections and over 200,000 deaths globally (as of 28th April 2020). We have new technology which will enable the rapid construction of a library of carbocyclic Cnucleosides. Despite their promising biological activity as non-natural nucleoside mimics, this motifis underexplored as an antiviral therapy on account of its difficult synthesis. The proposed approach enables the efficient synthesis of a diverse range of structures, resulting in a compound library primed for structure-activity relationship studies and the discovery of effective antiviral therapies. There is much similarity between the targets we propose and those in clinical trials, with the key difference being replacement of the oxygen atom in the sugar ring with a carbon atom. An important feature of our approach is the ability to produce a wide range of related compounds.The synthesis of the library will be followed by biological testing in inhibition assays against the SARS-Cov-2 virus conducted by Ervin Fodor, with additional support from Chris Schofield on assay development and viral enzymology. Promising compounds will be subjected to structural studies,in collaboration with Jonathan Grimes. All project partners are at the University of Oxford. Probing the nature of the interaction between the small molecules and the RNA virus replication machinery will increase our understanding of the mode of action of nucleoside therapeutics andenable the design of small molecules with even greater activity.