Investigation of the landscape of RSV M protein with quercetin and acetylated quercetin in the search for antivirals

Human Respiratory Syncytial Virus (hRSV) is a major causative agent of severe respiratory infections in infants, the elderly and immuno-compromised individuals. The hRSV genome synthesizes eleven proteins, two of which are non-structural. Among its structural proteins, the matrix (M) protein plays a pivotal role in viral assembly and budding, making it a strategic target for the development of novel antiviral approaches. In this study, we investigated the interaction of the M protein with quercetin (Q), a natural flavonoid, as well as with two acetylated derivatives, peracetylated quercetin (Q1) and tetraacetylated quercetin (Q2), using spectroscopic techniques in combination with computational biophysics methods. The results showed specific interactions in a 1:1 stoichiometry, characterized through moderate affinity and a predominance of hydrophobic forces. Acetylation enhanced conformational stability and increased the binding affinity of the complexes, with Q1 exhibiting the strongest capacity for molecular recognition. Molecular dynamics simulations supported these findings, showing that chemical modification introduced additional contact points, including new hydrogen bonds, thereby conferring greater structural stability to the complexes. Overall, these findings contribute to the understanding of the molecular mechanisms that regulate the interaction between the M protein and small ligands and point to acetylated flavonoids as potential antiviral candidates capable of interfering with hRSV assembly and maturation processes.