title: Membrane interactions and metal ion effects on bilayer permeation of the lipophilic ion modulator DP-109.
abstract: DP-109, a lipophilic bivalent metal ion modulator currently under preclinical development for neurodegenerative disorders, was designed to have membrane-associated activity, thereby restricting its action to the vicinity of cell membranes. We describe the application of a colorimetric phospholipid/polydiacetylene (PDA) biomimetic membrane assay in elucidating DP-109 membrane interactions and penetration into lipid bilayers. In this membrane model, visible quantifiable color changes were monitored in studying membrane interactions. The colorimetric data identified a biphasic concentration-dependent interaction, with a break point around the critical micelle concentration (CMC) of DP-109. The kinetics and colorimetric dose-response profile of DP-109 indicate that the compound inserts into the lipid bilayers rather than being localized at the bilayer surface. Analysis of interactions of DP-109 with phospholipid/PDA vesicles in which ionic gradients were imposed indicates that membrane activity of DP-109 is strongly affected by electrochemical gradients imposed by K+ and Zn2+. The ionic gradient effects suggest that the insertion of DP-109 into the membrane may depend on the membrane potential.
authors.affiliation: Department of Chemistry, Ben Gurion University, Beer Sheva 84105, Israel.
authors.forename: Sofiya
authors.initials: S
authors.lastname: Kolusheva
authors.forename: Jonathan
authors.initials: J
authors.lastname: Friedman
authors.forename: Itzchak
authors.initials: I
authors.lastname: Angel
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
mesh_terms: D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007477:Ions / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D015394:Molecular Structure; D011188:Potassium / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C428063:DP-109; D007477:Ions; D008051:Lipid Bilayers; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D012964:Sodium; D015032:Zinc; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D011188:Potassium