Computer-Aided Design, Synthesis, and Evaluation of Novel Broad-Spectrum Antiviral Agents

An important new tool in combating viral disease is the creation and use of broad-spectrumant ivirals. In the post-COVID pandemic world, the need for such drugs is more evident than ever. In this work, potential broad-spectrum antiviral agents have been developed for two families of viruses, Clade B of the New World arenaviruses, and the highly pathogenic human coronaviruses. This has been achieved by identifying conserved protein-protein interactions within the virus families using in silico techniques, for which inhibitors have been designed and synthesised, and the inhibitory activities quantified by in vitro testing. In the case of New World arenaviruses, previous work completed in group had identified two hit antiviral molecules, for which different series of diverse analogues have been synthesised and evaluated for inhibition of the interaction between the viral glycoprotein 1 and host human transferrin receptor 1, the protein-protein interaction required for cell entry for all members of Clade B. For the highly pathogenic human coronaviruses, an in-silico interaction model was created for the conserved interaction between the viral nucleocapsid protein and host mannose-binding lectin associated serine protease 2, which was used as the basis for a drug repurposing study and a virtual screening of a drug-like small molecule library, from which two hit molecules have been identified. In parallel to this structure-based approach, a ligand-based approach was also taken using a conserved amino acid sequence found in the nucleocapsid proteins that is responsible for the protein-protein interaction, from which novel peptidomimetic molecules were designed, and a synthetic route for these compounds has been optimised. Multiple series of anti-arenavirus molecules have been synthesised, identifying two species that have progressed into in vivo studies, showing improved activity over the previously identified hit molecule. A protein-protein interaction model of MASP-2 in complex with the N protein of SARS-CoV-2 has been developed, used as the basis for a virtual screening study identifying two hit molecules, with a series of peptidomimetic molecules being designed and a suitable synthetic route created based on the interacting sequence of the SARS-CoV-2 N protein.