Therapeutic Potential of Coumarins against hRSV: Search for mechanisms, targets of viral inhibition and modulation of the inflammatory response

• Grant number: 25/06121-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2025
• End date: October 31, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Fátima Pereira de Souza
• Grantee: Jéssica Maróstica de Sá
• 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

Human Respiratory Syncytial Virus (hRSV) is among the main causative agents of severe acute respiratory infections affecting the lower respiratory tract, especially in children under two years of age and the elderly, being responsible for the majority of pneumonia and bronchiolitis cases. The increasing number of infections poses a challenge for public health and society. Currently, treatment involves prophylactic measures, such as the administration of antibodies like Palivizumab and Nirsevimab, which are costly, as well as the use of non-specific antivirals like Ribavirin. However, these drugs are mainly administered to high-risk groups due to their high cost and associated side effects. Regarding vaccination, in 2023, the FDA approved vaccines such as Arexvy® and Abrysvo¿ for the elderly and pregnant women. Although these vaccines have shown efficacy, their long-term impact remains uncertain, and the most affected group children still lacks vaccine coverage. Therefore, it is essential to invest in the search for specific therapies and new antiviral strategies. Our research group has been investigating, over the past few years, natural compounds as potential antiviral candidates for RSV, including molecules from the coumarin family, which have shown promising antiviral effects. The main objective of this proposal is to understand the mechanisms of action of coumarins in cellular protection and inhibition against hRSV, using A549 cells and differentiated primary HBE cell cultures. The mechanism of action will be explored through cell-based assays (virucidal, post-infection, and budding) and gene expression analysis. Changes in metabolites and proteins will be analyzed by nuclear magnetic resonance (NMR) and mass spectrometry, respectively. After gene expression analysis of the proteins, we will propose interference RNAs to silence replication-related genes and block their expression, contributing to the identification of target proteins of coumarins. Additionally, we intend to investigate the relationship between RSV infection progression and the action of these molecules on the production of pro-inflammatory cytokines. This investigation will enable us to map inhibition, communication, and induction pathways, as well as the routes involved in cellular defense against hRSV infection in the presence of these molecules. Our expectation is that through this work, we can propose alternative antiviral and anti-inflammatory therapies with specific targets effective against RSV. (AU)