How Insect and Mammalian Membrane Composition Affects the Non-Specific Interaction of GABAergic Insecticide Fluralaner

ASIS RODRIGUEZ M; FELSZTYNA, IVAN; GARCIA, DA; SANCHEZ BORZONE, M; MIGUEL, VIRGINIA

Córdoba

Congreso; LI Reunion Anual de la Sociedad Argentina de Biofisica; 2023

Sociedad Argentina de Biofisica

The development of new insecticides is crucial due to the increasing cases of insect-borne diseases and the high resistance among insect vectors. A primary target is the gamma-aminobutyric acid receptor (GABA receptor), responsible for inhibitory signaling in vertebrate and invertebrate central nervous systems. Compounds like fluralaner act as non-competitive antagonists, disrupting chloride ion flow and causing neuronal hyperexcitation. The GABA receptor´s interaction with ligands is influenced by cell membrane composition and lipophilic compound partitioning, altering membrane physical properties. Vertebrates adjust membrane fluidity through lipid unsaturation and cholesterol (CHOL) levels. In contrast, invertebrate cells cannot synthesize sterols and regulate fluidity via phosphatidylethanolamine (POPE)/phosphatidylcholine (POPC) ratios. To study fluralaner´s interaction with lipid membranes, we conducted in silico All Atom Molecular Dynamics Simulations of bilayers and in vitro assays using Langmuir films. Our models included a pure POPC control and binary systems of POPC-POPE (insect membrane) 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 spacer between phospholipid molecules and altering the membrane´s physical properties. CHOL and POPE presence affected the insecticide´s distribution within the bilayer, potentially influencing its selectivity for insects or mammals. We also found that high CHOL concentrations in membranes modified the region where fluralaner partitions, affecting its accessibility to the GABA receptor. In conclusion, studying GABAergic insecticides´ interactions with lipid membranes provides valuable insights into their activity and selectivity, especially considering the differences in membrane composition between insects and mammals. These findings are particularly relevant for the development of highly selective new insecticidal compounds.