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Table 1. Sequences and MIC activity of the natural peptide and of five synthetic analogues(MIC: Minimum Inhibitory Concentration in µM; na: not active; nd: not determined)Name Primary sequence S. aureus E. coliAD H-ALSGDAFLRF-NH 2 na 584AK H-ALSGKAFLRF-NH 2 262 65Aβ 3 K H-ALSG-aza-β 3 K-AFLRF-NH 2 na naK2Nal7 H-ALSGKA-aza-β 3 -1Nal-LRF-NH 2 nd 268K-1Nal H-ALSGKA-aza-β 3 -1Nal-LR-aza-β 3 -Nal-NH 2 15 30K-2Nal H-ALSGKA-aza-β 3 -2Nal-LR-aza-β 3 -Nal-NH 2 30 118Two new peptides, named K2Nal7 and K2Nal, were designed with subsequent substitutionof the phenylalanine by aza-β 3 -naphtylalanine amino acids (aza-β 3 Nal). As AD and AK,only their C-terminal moeities are ordered but not folded in helix. They share a similar turnwhich approaches the two hydrophobic aromatic residues in position 7 and 10.Nevertheless, in each case, they are too far to pack each other (~9 Å) and no NOEs can bedetected between the residues 7 and 10 aromatic protons. The K2Nal7 and K2Nal dominantstructures do not have a hydrazino-turn, indeed the hydrazino-turn NOEs marker previouslynoticed on the Aβ 3 K NOESY spectrum cannot be detected for these peptides.The incorporation of aza-β 3 residues broke the helical structures to induce differentpeptide folds. The Aβ 3 K structure is quite rigid and shows a hydrazino-turn surrounded bytwo β-turn (Figure 2). However, despite the presence of aza-β 3 amino-acids, the K2Nal7and K2Nal appear to be quite flexible, their structures do not have a stable hydrazino-turnand only the C-terminal part is well defined.Structural parameters, such as peptide helicity, hydrophobicity, hydrophobic moment,peptide charge and the size of the hydrophobic/hydrophilic domain, could increase theantibacterial activity and improve the prokaryotic selectivity of natural peptides andanalogues.AcknowledgmentsWe thank SERB Laboratories and the "Région Bretagne" for their financial support.References1. Cheguillaume, A., et al. J. Org. Chem. 66, 4923-4929 (2001).2. Salaün, A., Potel, M., Gall, P., Le Grel, P. J. Org. Chem. 70, 6499-6502 (2005).3. Le Grel, P., Salaün, A., Potel, M., Le Grel, B., Lassagne, F. J. Org. Chem. 71, 5638-5645 (2006).241