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.

Accelerated Molecular Dynamics Applied to the Peptaibol Folding Problem

“…However, simulations at higher temperatures and under an electric field resulted in peptide insertion within 1 µs. Madsen et al [20] showed that incorporation of silicon-containing amino acids in Alm introduced a 20-fold increase in membrane permeability. Similarly, Das et al [21] discussed an effective strategy to improve antibacterial activity of peptaibols by capping the N-terminal with 1,2,3-triazole, and with hydrophobic substituents on C-4.…”

Solid‐Phase Synthesis of the Peptaibol Alamethicin U‐22324 by Using a Double‐Linker Strategy

“…[24] The antimicrobial values (minimum inhibitory concentration, MIC) of synthetic alamethicin 1 and analogue 5 against Grampositive S. aureus and Gram-negative E. coli were determined ( Table 1). Interestingly, recent studies have documented that substitution of the native amino acids in alamethicin with -silicon-3-amino acids results in a 20-fold increase in membrane permeability, [25] and the incorporation of α,α-substituted disilylated amino acids modified the physicochemical properties of the alamethicin analogues. [2] The antimicrobial assay showed that the replacement of the C-terminal alcohol in 1 for the C-terminal carboxylic acid in 5 had no significant effect on the activity.…”

Reactivity, Selectivity, and Synthesis of 4‐C‐Silylated Glycosyl Donors and 4‐Deoxy Analogues

“…The lack of studies of C ‐silylated carbohydrates are striking as C−Si bond formation has received considerable attention in other natural product classes, for example, peptide chemistry, and other areas of bio‐ and medicinal chemistry, examples of this are metalloprotease inhibitors [23] and pseudo‐peptides [24, 25] …”