What can we learn about drug membrane interaction from model lipid membranes?

MARIA LAURA FANANI

Buenos Aires

Conferencia; Reunión Conjunta de Sociedades de BioCiencias; 2017

What can we learn about drug membrane interaction from model lipid membranes?

Unlike drug selection to achieve specific interaction with protein receptors, compounds that interact with biological membranes seldom do so through specific interactions, but as a sum of weak interactions and entropic factors. The physicochemical bases that govern this phenomenon are not clearly elucidated today. In this talk, I will expose the advances that our laboratory has had in this subject through the study of the interaction of the alkyl esters of L-ascorbic acid (ASCn) to model lipid membranes. These amphiphilic drugs are potent antioxidants that are self-organized in nanostructures called coageles, which have been proposed as ocular and skin permeation enhancers, among other pharmacological uses. On the other hand, we have also studied the interaction with model lipid membranes of the amphiphilic drug hexadecylphosphocholine (HePC) or miltefosine, currently used clinically for the treatment of cutaneous lymphoma and leishmaniasis.Our studies have highlighted the importance of the structural and rheological properties of the different model lipid membranes used in the interaction of these drugs with these membranes. When an amphiphilic drug is inserted into a biomembrane it must exert a compression on the rest of the membrane components, in such a way that it opposes the lateral pressure. There, the ability of the lipid film to respond to isometric compression and lateral displacement of the components, as well as electrostatic factors (lateral repulsion or between membrane and charged amphiphilic monomers) would condition the insertion of a new molecule into the membrane. From these studies, the compressibility of the membrane is the main physical parameter that governs the incorporation of these drugs.ASCs are avidly incorporated into lipid membranes in both monolayer and bilayer systems and such incorporation affects the properties of the acceptor membranes differentially according to the length of the hydrocarbon chain of the compounds. These differences were correlated with different pharmacological uses of this family. On the other hand, we address two main issues with regard to the action of HePC: the bases for membrane selectivity and its mechanism as a perturbator agent, which is related to its pharmacological function of cellular lipid homeostasis modulator. HePC is also sensitive to the compressibility of the host membrane by penetrating more favorably into the more easily compressible membranes and less in the membranes rich in cholesterol or that mimic the stratum corneum of skin. This, in turn, alters the phase equilibrium of lipid membranes, which has the potential to modulate the activity of lipolytic enzymes acting on these membranes.In conclusion, amphiphilic drugs follow a common mechanism of insertion into lipid membranes but with subtle differences according to their chemical structure and amphipathicity, which results in properties that can be exploited in different aspects of their pharmacological use. From what has been learned from these studies we intend to advance in rationally designed, combined therapeutic strategies based on their effect on biomembranes.