1-palmitoyl-2-oleoylphosphatidylcholine and decalin

Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.

Topics: Animals; Anions; Bacterial Proteins; Cell Membrane; Cell Proliferation; Cell Survival; Chlorine; Cyclohexanes; Cystic Fibrosis Transmembrane Conductance Regulator; Dogs; Drug Carriers; Drug Design; Electrophysiological Phenomena; Epithelial Cells; HeLa Cells; Humans; Hydrogen Bonding; Ion Transport; Luminescent Proteins; Madin Darby Canine Kidney Cells; Microscopy, Fluorescence; Molecular Structure; Naphthalenes; Phosphatidylcholines; Rats, Inbred F344; Steroids

The Amber Lipid14 force field is expanded to include cholesterol parameters for all-atom cholesterol and lipid bilayer molecular dynamics simulations. The General Amber and Lipid14 force fields are used as a basis for assigning atom types and basic parameters. A new RESP charge derivation for cholesterol is presented, and tail parameters are adapted from Lipid14 alkane tails. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers are simulated at a range of cholesterol contents. Experimental bilayer structural properties are compared with bilayer simulations and are found to be in good agreement. With this parameterization, another component of complex membranes is available for molecular dynamics with the Amber Lipid14 force field.

Topics: Alkanes; Cholesterol; Dimyristoylphosphatidylcholine; Glycerylphosphorylcholine; Lipid Bilayers; Molecular Dynamics Simulation; Naphthalenes; Neutron Diffraction; Phosphatidylcholines; Temperature; X-Ray Diffraction