Synthesis of Targeted Antiviral Nucleosides

The emergence and rapid spread of the SARS-Cov-2 virus is a major health threat to the UK and to the rest of the world. Accordingly, major research effort has been made to tackle the virus, with current focus on the development of vaccines and the repurposing of existing antiviral therapies not originally designed for SARS-Cov-2. Unfortunately, it is entirely feasible that a vaccine cannot be developed in time, and that existing therapeutics are ineffective. Therefore, novel antivirals targeted to SARS-Cov-2 are urgently required. In order to meet the critical need for new antivirals with targeted activity, this project will enable the rapid generation of structures primed for testing against the viral replication machinery. Whilst a viable mechanism to shut down viral replication is known, the identification of a molecule able to achieve this in the clinic has not been successful. In this project, we are targeting motifs whose biological activity as non-natural nucleoside analogues is known, but currently underexplored as they are difficult to make. They have high similarity to molecules currently being tested against SARS-Cov-2, Remdesivir, Galidesivir, and EIDD-2801, but contain unique motifs that may overcome the limitations of these current therapies. The exploration of these molecules - their biological testing and accompanying structural studies - will teach us more about the mode of action of these antiviral therapies, allow the design of more active species, and lead the way for the discovery of a new, effective treatment.