title: A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption.
abstract: LTX 109 is a synthetic antimicrobial peptidomimetic (SAMP) currently in clinical phase II trials for topical treatment of infections of multiresistant bacterial strains. All possible eight stereoisomers of the peptidomimetic have been synthesized and tested for antimicrobial effect, hemolysis, and hydrophobicity, revealing a strong and unusual dependence on the stereochemistry for a molecule proposed to act on a general membrane mechanism. The three-dimensional structures were assessed using nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations in aqueous solution and in phospholipid bilayers. The solution structures of the most active stereoisomers are perfectly preorganized for insertion into the membrane, whereas the less active isomers need to pay an energy penalty in order to enter the lipid bilayer. This effect is also found to be reinforced by a significantly improved water solubility of the less active isomers due to a guanidyl-π stacking that helps to solvate the hydrophobic surfaces.
authors: Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway.
authors: Johan
authors: J
authors: Isaksson
authors: Bjørn O
authors: BO
authors: Brandsdal
authors: Magnus
authors: M
authors: Engqvist
authors: Gøril Eide
authors: GE
authors: Flaten
authors: John S Mjøen
authors: JS
authors: Svendsen
authors: Wenche
authors: W
authors: Stensen
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D020404:Glycerophospholipids / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012996:Solutions; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D023181:Antimicrobial Cationic Peptides; D020404:Glycerophospholipids; D008051:Lipid Bilayers; D008081:Liposomes; D009842:Oligopeptides; D057786:Peptidomimetics; D012996:Solutions; C568461:L-arginyl-2,5,7-tris(1,1-dimethylethyl)-L-tryptophyl-N-(2-phenylethyl)-L-argininamide