Analysis of the interaction between respiratory syncytial virus F protein and neutrophilic myeloperoxidase: a molecular modeling study

• Grant number: 22/14220-1
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Effective date (Start): January 05, 2023
• Effective date (End): March 26, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Karina Alves de Toledo
• Grantee: Leonardo da Silva Pinto
• Supervisor: Diana Andreia Pereira Lousa
• Host Institution: Faculdade de Ciências e Letras (FCL-ASSIS). Universidade Estadual Paulista (UNESP). Campus de Assis. Assis , SP, Brazil
• Research place: Universidade Nova de Lisboa, Portugal
• Associated to the scholarship: 21/05107-4 - Evaluation of potential protein ligands for RSV on the neutrophil extracellular traps, BP.IC

Abstract

Respiratory Syncytial Virus (hRSV) is the main etiologic agent of acute viral infections of the lower respiratory tract, against which there is still no financially accessible specific treatment or approved vaccine. In the lung tissue of the infected patient, there is an intense accumulation of neutrophils. In the sustained presence of external stimuli (microorganisms, parasites and inflammatory mediators), activated neutrophils secrete their nuclear content, carrying with them cytoplasmic and granular material. The extracellular structure generated is called "Neutrophil Extracellular Traps" or NETs, which have microbicidal functions, capturing and/or inactivating bacteria, viruses, fungi and parasites. Excess NETs, cellular debris and mucus, resulting from hRSV infection, form a consistent mucus that is difficult to expectorate that accumulates in the lumen of the bronchioles, drastically restricting airflow, aggravating the patient's clinical condition. NETs interact with hRSV viral particles and data published by our research group indicate that this contact results in a virucidal action, with the participation of serine proteases that cleave the viral F protein [1]. Recently, data generated by the candidate's scientific initiation project revealed the identity of a ligand from NETs to RSV. This is myeloperoxidase (MPO), a neutrophilic enzyme whose anti-hRSV activity has already been described. The current proposal aims to detail those results obtained in western blotting, immunoprecipitation and protein sequencing assays, which demonstrate an interaction between hRSV and MPO. Therefore, the interaction between MPO and the F protein of the virus will be investigated in silico, through computational analysis of molecular docking, using MaSIF [2], Rosetta [3] and AlphaFold2 (AF2) [4] software. The hRSV F protein is the main target for the development of new drugs and vaccines, and the cited software has been successful in predicting protein-protein interactions. The training acquired during the development of BEPE will serve as support for the student to complete his studies in Brazil, when the interaction of MPO with the G protein of the virus will also be evaluated in silico. The data generated in this study, in addition to those already described in the literature, may direct new strategies in the treatment of patients with hRSV, from improving respiratory quality to blocking viral spread. (AU)