How insect and mammalian membrane composition affects the nonspecific interaction of GABAergic insecticide Fluralaner

ASIS M; FELSZTYNA, I; GARCÍA, DA; SANCHEZ-BORZONE M; MIGUEL V

Congreso; LI Reunión Anual Sociedad Argentina de Biofísica; 2023

The development of new insecticides is crucial due to the increasing cases of insect-bornediseases and the high resistance among insect vectors. A primary target is the gammaaminobutyric acid receptor (GABA receptor), responsible for inhibitory signaling invertebrate and invertebrate central nervous systems. Compounds like fluralaner act asnon-competitive antagonists, disrupting chloride ion flow and causing neuronalhyperexcitation. The GABA receptor's interaction with ligands is influenced by cellmembrane composition and lipophilic compound partitioning, altering membranephysical properties. Vertebrates adjust membrane fluidity through lipid unsaturation andcholesterol (CHOL) levels. In contrast, invertebrate cells cannot synthesize sterols andregulate fluidity via phosphatidylethanolamine (POPE)/phosphatidylcholine (POPC) ratios.To study fluralaner's interaction with lipid membranes, we conducted in silico All AtomMolecular Dynamics Simulations of bilayers and in vitro assays using Langmuir films. Ourmodels included a pure POPC control and binary systems of POPC-POPE (insectmembrane) or POPC-CHOL (mammalian membrane), with molar ratios of 9:1, 7:3, and 1:1.Our observations showed that fluralaner partitions into the lipid phase, acting as a spacerbetween phospholipid molecules and altering the membrane's physical properties. CHOLand POPE presence affected the insecticide's distribution within the bilayer, potentiallyinfluencing its selectivity for insects or mammals. We also found that high CHOLconcentrations in membranes modified the region where fluralaner partitions, affecting itsaccessibility to the GABA receptor. In conclusion, studying GABAergic insecticides'interactions with lipid membranes provides valuable insights into their activity andselectivity, especially considering the differences in membrane composition betweeninsects and mammals. These findings are particularly relevant for the development ofhighly selective new insecticidal compounds