title: High-affinity small molecule-phospholipid complex formation: binding of siramesine to phosphatidic acid.
abstract: Siramesine (SRM) is a sigma-2 receptor agonist which has been recently shown to inhibit growth of cancer cells. Fluorescence spectroscopy experiments revealed two distinct binding sites for this drug in phospholipid membranes. More specifically, acidic phospholipids retain siramesine on the bilayer surface due to a high-affinity interaction, reaching saturation at an apparent 1:1 drug-acidic phospholipid stoichiometry, where after the drug penetrates into the hydrocarbon core of the membrane. This behavior was confirmed using Langmuir films. Of the anionic phospholipids, the highest affinity, comparable to the affinities for the binding of small molecule ligands to proteins, was measured for phosphatidic acid (PA, mole fraction of X(PA) = 0.2 in phosphatidylcholine vesicles), yielding a molecular partition coefficient of 240 +/- 80 x 10(6). An MD simulation on the siramesine:PA interaction was in agreement with the above data. Taking into account the key role of PA as a signaling molecule promoting cell growth our results suggest a new paradigm for the development of anticancer drugs, viz. design of small molecules specifically scavenging phospholipids involved in the signaling cascades controlling cell behavior.
authors.affiliation: Helsinki Biophysics & Biomembrane Group, Institute of Biomedicine, University of Helsinki, Finland.
authors.forename: Mikko J
authors.initials: MJ
authors.lastname: Parry
authors.forename: Juha-Matti I
authors.initials: JM
authors.lastname: Alakoskela
authors.forename: Himanshu
authors.initials: H
authors.lastname: Khandelia
authors.forename: Subramanian Arun
authors.initials: SA
authors.lastname: Kumar
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Mahalka
authors.forename: Paavo K J
authors.initials: PK
authors.lastname: Kinnunen