Molecular selection and initial characterization of a new inducer and a new destabilizer of non-bilayer phospholipid arrangements

Abstract

Abstract The mouse model of a lupus-like disease developed by our research group is unique, because it’s obtained by the stabilization of lipidic structures called non-bilayer phospholipid arrangements (NPAs), which induce the production of anti-NPA antibodies that trigger the disease in mice, which are in turn detected in patients with systemic lupus erythematosus. NPAs are produced when a lipid bilayer composed of conic and cylindric phospholipids, is modified by certain drugs (procainamide, chlorpromazine) or the manganese cation. Usually, drugs/substances are chosen to be tested as NPA inducers when they are known to trigger a lupus-like disease in humans. However, here we selected a group of molecules only by their structural similarity with the known inducers and the known destabilizer (chloroquine) and experimentally tested their effect on the formation or destabilization of NPAs in liposomes by flow cytometry. Firstly, we identified promethazine and procaine, similar to chlorpromazine and chloroquine, respectively. Promethazine acted as an inducer, with a broader range of concentrations of action in comparison with chlorpromazine, but it was more sensitive to the destabilizer. Procaine was found to be a weaker destabilizer than chloroquine, as it has an effect only at higher concentrations. This strategy showed that molecular characteristics could also be good predictors of their action on lipid bilayers and NPAs formation.