COMPARATIVE ANALYSIS OF THE INTERACTIONS BETWEEN THE MONOCLONAL ANTIBODY NIRSEVIMAB AND ITS DERIVED PEPTIDE WITH THE PREFUSION F PROTEIN OF hRSV SUBTYPES A AND B

Introduction: Human respiratory syncytial virus (hRSV) is a globally relevant pathogen that causes significant morbidity in infants, the elderly, and immunocompromised individuals, often leading to severe bronchiolitis and pneumonia. The fusion glycoprotein (F protein) is essential for viral entry, mediating membrane fusion between virus and host cells. A recent milestone in prevention has been the approval of the monoclonal antibody Nirsevimab, already implemented in the Brazilian Unified Health System (SUS). Despite its promise, the high cost and limited knowledge of its molecular interactions with the F protein remain critical challenges. Objective: This study investigated the interactions of Nirsevimab and a peptide derived from its binding region with the F protein of hRSV subtypes A and B, with the aim of determining conservation of binding across subtypes and assessing the peptide’s therapeutic potential. Methods: Conserved regions of the F protein were identified through sequence alignments. Molecular docking was then applied to predict binding modes between the viral protein, the antibody, and the peptide. Molecular dynamics simulations were subsequently performed to evaluate stability and possible conformational rearrangements over time. Results and Discussion: The F proteins of subtypes A and B showed high structural similarity. Nevertheless, subtype A exhibited more stable interactions with both Nirsevimab and the derived peptide, particularly at the Ø site, a critical determinant of viral neutralisation. Both the light and heavy chains of the antibody remained stably bound in all complexes, though stability was greater with subtype A. Importantly, the peptide reproduced much of the binding behaviour of the full antibody across both subtypes, suggesting that smaller fragments may retain substantial functional activity. Conclusions: The data support the efficacy of Nirsevimab against both hRSV subtypes, underscoring the central role of the Ø site in neutralisation. Furthermore, the derived peptide’s performance indicates that antibody-inspired fragments could represent cost-effective therapeutic alternatives, maintaining efficacy while reducing production costs. Such strategies may facilitate broader access to treatment within public health systems.