Improved solid-phase synthesis of α,α-dialkylated amino acid-rich peptides with antimicrobial activity

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A homologous series of nonapeptides and their acetylated versions were successfully prepared using solid-phase synthetic techniques. Each nonapeptide was rich in α,α-dialkylated amino acids [one 4-aminopiperidine-4- carboxylic acid (Api) and six α-aminoisobutyric acid (Aib) residues] and also included lysines or lysine analogs (two residues). The incorporation of the protected dipeptide 9-fluorenylmethyloxycarbonyl (Fmoc)-Aib-Aib-OH improved the purity and overall yields of these de novo designed peptides. The helix preference of each nonapeptide was investigated in six different solvent environments, and each peptide's antimicrobial activity and cytotoxicity were studied. The 310-helical, amphipathic design of these peptides was born out most prominently in the N-terminally acetylated peptides. Most of the peptides exhibited modest activity against Escherichia coli and no activity against Staphylococcus aureus. The nonacetylated peptides (concentrations ≤ 100 μM) and the acetylated peptides (concentrations ≤ 200 μM) did not exhibit any significant cytotoxicity with normal (nonactivated) murine macrophages. © 2005 The Authors Journal compilation © 2005 Blackwell Munksgaard.

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Journal of Peptide Research

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