Interaction of Antimalarial Drugs with DMPC Model Membranes

Abstract

Primaquine Diphosphate (PQD) and Chloroquine Diphosphate (CQD) are potent therapeutic agents used in the treatment of malaria. The investigation of drug-lipid interactions is pivotal for understanding their biological activity. Electron Spin Resonance (ESR) and Differential Scanning Calorimetry (DSC) were used to investigate the effects of drug binding on the lipid phase transition and acyl chain dynamics of model membranes made up of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) phospholipids. Labels located at different positions along the lipid chain were used to monitor different membrane regions. ESR results indicated that PQD is more effective in changing the membrane structure than CQD. PQD is effective in perturbing the whole chain of DMPC vesicles, whereas the effect of CQD is more pronounced near the polar headgroup region. Furthermore, the results showed a slight decrease of the membrane packing in DMPC gel phase for both drugs. However, PQD causes a slight increase of the lipid packing close to the membrane center, suggesting a deeper insertion of this molecule into DMPC bilayers. DSC thermograms revealed that PQD interacts with DMPC decreasing the main transition temperature (TM) by ca. 2°C and completely abolishing its pre-transition. On the other hand, CQD effects are mainly noticed as a decrease in the cooperativity of the main transition. Because of its lipophilic character, PQD penetrates into the bilayer hydrocarbon region causing considerable disorganization. The higher polarity of CQD is probably related with its low membrane permeability. These results shed light on the molecular mechanism of drug-lipid interaction, which may be useful for the development of lipid drug delivery systems of antimalarial drugs. Acknowledgments: FAPESP, CNPq.