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NMR-based fragment screening to search for antiviral candidates at the viral RNA and phosphoprotein binding site in the globular domain of the M2-1 protein of human Respiratory Syncytial Virus

Grant number: 23/06367-5
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): October 01, 2023
Effective date (End): January 31, 2025
Field of knowledge:Health Sciences - Collective Health - Epidemiology
Principal Investigator:Ícaro Putinhon Caruso
Grantee:Sérgio Luís Ferreira Júnior
Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil

Abstract

The 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. So far, there is no effective vaccine against hRSV and the only commonly offered licensed treatment, a monoclonal antibody directed at the viral fusion protein, is a costly drug that has had adverse reactions. The hRSV M2-1 protein is an important transcriptional anti-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 P phosphoprotein. This scenario of intermolecular interactions makes dgM2-1 a potential target for the development of inhibitors of the viral replication cycle. In this sense, this research project aims to identify ligands (molecular fragments) with the potential to inhibit the interaction site of dgM2-1 with viral RNA and phosphoprotein. To this end, the systematic approach of Nuclear Magnetic Resonance (NMR)-based fragment screening will be used, followed by the characterization of the binding site and dissociation constants of the most promising fragments based on measurements of Saturation Transfer Difference (STD) and 1H-15N HSQC by NMR and fluorescence spectroscopy. Therefore, the development of this project will contribute to the design of an alternative strategy to combat infections caused by hRSV targeting dgM2-1, since its results will provide relevant molecular information for proposals for potential drugs with antiviral action against hRSV.

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