Miltefosine inhibits the membrane remodeling caused by phospholipase action by changing membrane physical properties

YENISLEIDY DE LAS MERCEDES ZULUETA DIAZ; ERNESTO AMBROGGIO; MARIA LUARA FANANI

Buenos Aires

Jornada; Jornadas virtuales SAB 2020. Biofísica en tiempos de COVID-19; 2020

Sociedad Argentina de Biofísica

Miltefosine (hexadecylphosphocholine or HePC) is an alkylphosphocholine approved for the treatment of visceral and cutaneous Leishmaniasis. HePC exerts its effect by interacting with lipid membranes and affecting membrane-dependent processes. The molecular geometry of HePC suggests that the pharmacological function of HePC is to alter membrane curvature. As a model system, we studied the enzyme production in model membranes of diacylglycerol (DAG) or ceramide (CER), lipids involved in cell signaling which alter the structure of membranes. Here, we studied the effect of HePC on changes in phospholipase activity and on the effect that the lipid products have on the curvature and fusogenicity of membranes where they accumulate. Our results indicate that HePC inhibits the long-time restructuring of membranes, characteristic of the DAG and CER enzyme formation processes. In addition, the drug also reduces the fusogenicity of hospholipase-derived products. We postulate that the effect of HePC is due to a nonspecifc geometric compensation of HePC to the inverted cone shape of DAG and CER products, acting as a relaxation agent of membrane curvature stress. These data are important for understanding the mechanism of action by which HePC regulates the lipid metabolism and signal transduction pathways in which these enzymes are involved.Link video en Youtube: https://youtu.be/d4jdN5o5ShM.Acknowldegments. This work was supported by the Consejo Nacional de Investigaciones Científcas y Técnicas (CONICET), Agencia Nacional de Promoción Científca y Tecnológica (ANPCyT and FONCyT). The microscopy experiments were performed at the ?Centro de Micro y Nanoscopía de Córdoba? (CEMINCO-CIQUIBIC).