STRATEGIES TO TARGET VIRAL NON-STRUCTURAL PROTEINS Peptide-based methodologies against West Nile and related emerging viruses

This thesis focuses on the development of peptide-based strategies to inhibit, diagnose, and study viral infections, with particular emphasis on West Nile virus (WNV). WNV is a neurotropic flavivirus for which no effective antiviral therapies are currently available, highlighting the need for new therapeutic approaches. The research primarily targets the viral non-structural protein NS3, a key enzyme involved in viral replication and polyprotein processing. Peptides and peptidomimetics were designed to inhibit NS3 either by targeting its protease active site or by disrupting essential protein–protein interactions. The antiviral activity of linear, cyclic, and retro-inverso peptides was evaluated, and selected compounds were assessed for blood–brain barrier permeability. In parallel, peptide sequences with high affinity for the WNV NS1 protein were identified for the development of a gold nanoparticle-based diagnostic biosensor. Finally, a collaborative study on SARS-CoV-2 investigated the allosteric regulation and cooperativity of the main protease, providing insights relevant for antiviral drug design. Overall, this work highlights the potential of peptide-based approaches in addressing current and future viral outbreaks.