Study of the interaction of heparin polyanion with the core domain of the transcriptional antitermination factor M2-1 of the human Respiratory Syncytial Virus

• Grant number: 23/18111-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date until: June 01, 2024
• End date until: December 31, 2024
• Field of knowledge: Health Sciences - Collective Health - Epidemiology
• Principal Investigator: Ícaro Putinhon Caruso
• Grantee: Caroline Santezi
• 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

Among the respiratory viruses circulating around the world, the human Respiratory Syncytial Virus (hRSV) stands out, one of the most common pathological agents of acute respiratory infections in newborns, children, and elderly. To date, there is no vaccine for newborns and children approved in Brazil and the only licensed treatment commonly offered, a monoclonal antibody targeting the viral fusion protein, is a high-cost medicine that has presented adverse reactions. The hRSV M2-1 protein is an important transcriptional antitermination factor of the viral polymerase complex. The role of M2-1 in the context of this complex is determined by the interaction of its core domain (cdM2-1) with RNA and the viral phosphoprotein, which makes it a potential target for the development of inhibitors against hRSV. An important molecular aspect in the structure of cdM2-1 is the occurrence of an extensive positively charged surface, which makes it a target for the binding of strongly negative molecules such as the natural polyanion heparin. In this sense, the present research project aims to characterize the interaction of low molecular weight heparin (4.5 kDa) and unfragmented heparin (14.8 kDa) with cdM2-1, using fluorescence spectroscopy, circular dichroism (CD), and Nuclear Magnetic Resonance (NMR) techniques to determine structural and biophysical-chemical aspects of the cdM2-1/heparin binding. Therefore, the present proposal can provide molecular bases for the development of a new strategy to combat infections caused by hRSV, based on the potential use of different polyanions such as heparin mimetics, synthetic and semi-synthetic, which could inhibit/block the function of M2-1 with biological partners such as the viral phosphoprotein.