Hypothetical molecular mechanism of a novel class of bacteriocin-based antivirals for the inhibition of respiratory Syncytial Virus (RSV)

Abstract

Respiratory Syncytial Virus (RSV) is a serious pathogen in vulnerable individuals and a major cause of hospitalization and death. With limited access to effective biotherapeutics for RSV treatment, antimicrobial peptides (AMPs) have been explored, including bacteriocins such as labyrinthopeptins (Labys) produced by Actinomadura namibiensis. Labys have demonstrated antiviral activity against RSV and are believed to interact with phosphatidylethanolamine (PE) in the capsid to form pores in the viral membrane. However, a greater understanding of the interaction mechanism of these bacteriocins with phospholipids like PE is needed. Our hypothesis suggests that, due to the structural plasticity of Labys, these peptides can undergo changes in their intrinsic deformability and thus bind stably to PE, mediating subsequent disruption of the lipid envelope as a new therapeutic target. Findings from modeling, classical dynamics, and ENM suggest that some Labys, such as Laby A1, interact favorably and stably with PE, with computationally predictable experimental inhibitory kinetics, and can even interact with more complex membranes rich in PE. Additionally, Laby A1 can undergo allosteric conformational changes based on its interaction with PE, adopting a “toroidal” folded conformation. This conformation is associated with peptide-lipid interactions, where the embedding of the peptide into the membrane, due to its affinity for PE, may lead to the formation of toroidal pores. This could explain the mechanism of RSV inhibition. The results support the need for further research in the development of antivirals against RSV based on Labys-like bacteriocins.