Alkylphospholipids act through stabilization of planar membranes and inhibition of membrane budding and fusion

Abstract

Alkylphospholipids (APLs) represent a novel class of anticancer drugs that disrupt lipid homeostasis by inhibiting lipid transport to the endoplasmic reticulum and altering cellular lipid metabolism. In this study, we use protein-free membrane models to investigate how the APLs miltefosine, edelfosine and perifosine influence membrane dynamics through lipid-APL interactions, resulting in the stabilization of planar membranes. This stabilization impedes critical remodelling processes such as membrane budding and fusion, essential for cellular processes. Our findings demonstrate that APLs modulate membrane curvature via geometric compensation between cone-shaped APLs and inverted cone-shaped lipids like phosphatidylethanolamine. We also explored the effects of both homogeneous and asymmetric incorporation of APLs into bilayer lipid structures, mimicking their interactions with cell membranes. The results reveal that APLs alter curved lipid structures, stabilizing planar membranes and reducing spontaneous curvature. This geometric compensation mechanism profoundly impacts membrane dynamics, where miltefosine and edelfosine exhibit greater activity compared to perifosine. These findings provide significant insights into how APLs disrupt lipid homeostasis in cellular environments.