Interactions of miltefosine with erythrocyte membrane proteins compared to those of ionic surfactants

Abstract For miltefosine (MIL), a zwitterionic alkylphospholipid approved for leishmaniasis treatment, the mechanism of action is not well established. Electron paramagnetic resonance (EPR) spectroscopy has indicated that the interaction of MIL with membrane proteins has similarities to that of ionic surfactants. A general concern about leishmanicides is their high hemolytic potential, so we decided to compare the interactions of MIL and three ionic surfactants with the erythrocyte membrane. Measurements with two different spin labels indicated that the surfactants sodium dodecyl sulfate (SDS, anionic), cetyltrimethylammonium chloride (CTAC, cationic) and N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (HPS, zwitterionic) as well as MIL increase the dynamics of erythrocyte membrane proteins in a concentration-dependent manner. SDS produced the smallest increases in protein dynamics and was also the least hemolytic for measurements in PBS and in whole blood. Spin label EPR measurements performed directly in the blood plasma detected increased albumin stiffness caused by 2.5 mM SDS due to electrostatic/hydrophobic interactions. For 10 mM concentrations of the compounds, the EPR spectra showed a fraction of albumin with greater mobility and another with the same as that of the untreated plasma. The zwitterionic compounds MIL and HPS did not present significant differences in this study.