Photoresponsive G-quadruplex Ligands as Antivirals to Combat COVID-19

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In light of the recent COVID-19 pandemic, there is a pressing need to develop new therapeutics against SARS viruses including SARS-CoV-2. While limited treatments have been developed using existing antivirals, no specific antiviral drug has been developed against COVID-19. G-quadruplexes (G4s) are nucleic acid secondary structures formed from guanine rich sequences, with square planar guanine tetrads stacked to form a 3D structure. The unique structural features of G4s facilitate targeting over other biomolecular structures, providing a potential therapeutic target. The essential SARS Coronavirus protein, Nsp3, was shown to bind RNA G4 via its SARS Unique Domain (SUD), leading to Nsp3 dimerization which is key for viral replication. Importantly, G4- stabilising molecules have been shown to modulate both G4 folding and viral protein expression in SARS-CoV-2, which is promising for the development of therapeutics targeting SARS-CoV-2 specific G4 sequences. Ongoing work in the Galan group has led to the development of photoswitchable G4-targeting small molecules which allow visible light photoregulation of G4 folding under physiological conditions. These molecules show anti-pathogenic activity and have great potential for use as therapeutics, particularly as use of an external stimulus to modulate activity provides greater spatio-temporal control. This project aims to discover and develop photoswitchable G4 ligands for use as antivirals against COVID-19.