title: Incorporation of β-Silicon-β3-Amino Acids in the Antimicrobial Peptide Alamethicin Provides a 20-Fold Increase in Membrane Permeabilization.
abstract: Incorporation of silicon-containing amino acids in peptides is known to endow the peptide with desirable properties such as improved proteolytic stability and increased lipophilicity. In the presented study, we demonstrate that incorporation of β-silicon-β3-amino acids into the antimicrobial peptide alamethicin provides the peptide with improved membrane permeabilizing properties. A robust synthetic procedure for the construction of β-silicon-β3-amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions of the hydrophobic face of the amphipathic helix by using SPPS. The incorporation was shown to provide up to 20-fold increase in calcein release as compared with wild-type alamethicin.
authors.affiliation: Department of Chemistry and, Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
authors.forename: Julie L H
authors.initials: JL
authors.lastname: Madsen
authors.affiliation: Department of Chemistry and, Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Hjørringgaard
authors.affiliation: Department of Molecular Biology and Genetics and, Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Vad
authors.affiliation: Department of Molecular Biology and Genetics and, Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark. dao@inano.au.dk.
authors.forename: Daniel
authors.initials: D
authors.lastname: Otzen
authors.affiliation: Department of Chemistry and, Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark. ts@chem.au.dk.
authors.forename: Troels
authors.identifier: 0000-0001-8090-5050
authors.initials: T
authors.lastname: Skrydstrup
mesh_terms: D000408:Alamethicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000596:Amino Acids / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002942:Circular Dichroism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D012825:Silicon / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000596:Amino Acids; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D008081:Liposomes; D000408:Alamethicin; D012825:Silicon
keywords: amino acids; antibiotics; membrane proteins; peptidomimetics; silicon