Fragment screening and rational design of mimetic peptides to search for antiviral candidates at the M2-1/phosphoprotein interaction site of human Respiratory Syncytial Virus

Abstract

Human Respiratory Syncytial Virus (hRSV) is one of the main causes of acute respiratory diseases such as bronchiolitis and pneumonia in newborns, children, and elderly. To date, there is no effective vaccine against hRSV, and the only licensed treatment commonly offered, a monoclonal antibody targeting the viral fusion protein, is a high-cost drug that has presented adverse reactions. The hRSV M2-1 protein is an important transcriptional termination factor of the viral polymerase complex. The role of M2-1 in the context of this complex is determined by the interaction of its globular domain (dgM2-1) with viral messenger RNA and the region of residues 90-110 of phosphoprotein P (P90-110). This scenario of intermolecular interactions makes dgM2-1 a potential target for the development of inhibitors of the viral replication cycle. In this sense, the present research project aims to identify ligands (fragments and peptides) with potential to inhibit the interaction site of dgM2-1 with viral RNA and phosphoprotein. For that, systematic approaches to fragment screening and rational design of P90-110 peptide mimetics will be employed, using experimental techniques of Nuclear Magnetic Resonance (NMR) and fluorescence spectroscopy together with computational simulations of molecular docking, molecular dynamics, and calculations of binding free energy. Therefore, the development of the present project will contribute to the design of an alternative strategy to fight infections caused by hRSV targeting dgM2-1, since its results will provide relevant molecular information for proposals for potential drugs with antiviral action against this respiratory virus. (AU)