Elucidating the nature of the interactions of oseltamivir with the 2D model of influenza A virus lipid envelope

This study investigates the molecular interactions of the antiviral agent oseltamivir phosphate (OSL) with a two-dimensional (2D) Langmuir monolayer model of the influenza A (AH1N1) virus lipid envelope. Targeting the viral lipid envelope, which predominantly contains phosphatidylethanolamines (PE), sphingomyelin (SM), and phosphatidylserines (PS) in the AH1N1 strain, is considered an alternative strategy for developing novel antivirals. The model consists of a ternary lipid mixture (DOPE:DMPS:SM 50:35:15), prepared at the air-water interface and characterized using surface-sensitive techniques including Brewster angle microscopy (BAM), grazing incidence X-ray diffraction (GIXD), and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). OSL incorporation significantly disorganizes the ternary membrane, causing concentration-dependent shifts in surface pressure-area per molecule (π-A) isotherms toward larger areas. OSL reduces the maximum value of compression modulus (Cs^-1), resulting in a much less organized layer. Analysis of thermodynamic functions obtained from the compression-expansion cycles confirmed reduction of attractive intermolecular interactions, thereby preventing the formation of irreversible assemblies. Studies using single-component monolayers revealed that OSL-lipid interactions were electrostatic-dependent: OSL had minimal impact on neutral DOPE and SM monolayers, but showed significant concentration-dependent influence on the negatively charged DMPS monolayer. For DMPS, OSL induces fluidization, confirmed by PM-IRRAS observations of hydrogen bonding in the headgroup region and shifts in acyl chain bands to higher wavenumbers, indicative of a less ordered conformation. BAM and GIXD studies further demonstrated that OSL hinders the formation of condensed DMPS domains. These findings are crucial for understanding antiviral-lipid envelope mechanisms and designing novel targeted therapies.