Incorporation of β-Silicon-β3-Amino Acids in the Antimicrobial Peptide Alamethicin Provides a 20-Fold Increase in Membrane Permeabilization

• Published in: Chemistry : a European journal Vol. 22; no. 24; pp. 8358 - 8367
• Main Authors: Madsen, Julie L. H., Hjørringgaard, Claudia U., Vad, Brian S., Otzen, Daniel, Skrydstrup, Troels
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 06-06-2016
• Subjects: Alamethicin - analogs & derivatives; Alamethicin - chemical synthesis; Alamethicin - pharmacology; amino acids; Amino Acids - chemistry; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; antibiotics; Antimicrobial Cationic Peptides - chemical synthesis; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Cell Membrane Permeability - drug effects; Circular Dichroism; Liposomes - chemistry; Liposomes - metabolism; membrane proteins; peptidomimetics; Protein Structure, Secondary; silicon; Silicon - chemistry; Solid-Phase Synthesis Techniques; peptidomimetics; membrane proteins; silicon; antibiotics; amino acids
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201600445

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.
Permeabilized by silicon: Incorporation of β‐silicon‐β3‐amino acids into the antimicrobial peptide alamethicin improves the membrane permeabilizing action of the peptide. A synthetic procedure to access β‐silicon‐β3‐amino acids was developed and the amino acid analogues were incorporated into alamethicin at different positions (see scheme). The overall lipophilicity of the peptide was improved, resulting in a 20‐fold increase in calcein release as compared with wild‐type alamethicin.