This paper describes the design and synthesis of gramicidin S (GS) analogues 10a-c containing arylated sugar amino acids (SAAs) as a replacement of one of the two (D)Phe-Pro beta-turn regions. The cyclic, amphiphilic peptides adopt a beta-sheet conformation featuring an unusual reverse turn induced by the SAAs. The altered turn region induces a slight distortion of the antiparallel beta-sheet, as compared to GS; the overall geometry however closely resembles that of the nonarylated GS analogue 1. GS analogues 10a-c proved to be as active as the parent GS itself as antibacterial agents and are equally efficient in lysing red blood cells. These properties are in sharp contrast to the diminished biological activity displayed by 1. We conclude that the presence of aromaticity in the turn regions of GS derivatives is required for biological activity, whereas the native conformation of the beta-hairpin is not. Our findings may guide future research toward efficient and nonhemolytic GS analogues for combating bacterial infections.

The synthesis of series of diversely functionalized epsilon-morpholine amino acids (MAAs, 5a-h) starting from an epsilon-sugar amino acid and following a two-step oxidative glycol cleavage/reductive amination strategy, is described. In an alternative synthetic scheme, diastereoisomerically pure delta-MAAs (12a,b) were obtained. Oligopeptides containing MAAs were prepared either by direct incorporation of a MAA building block or by subjecting a fully assembled SAA-containing peptide to the two-step glycol cleavage/reductive amination procedure.

The synthesis of three new analogues of the cyclic cationic antimicrobial peptide Gramicidin S is described. These derivatives contain a modified turn region in which the DPhe‐Pro motif has been replaced by a constrained furanoid sugar amino acid or a flexible linear aminoethoxy acetic acid moiety. Structural analysis revealed conformational changes in the modified turn region compared to GS. The biological profile of these compounds however resembles that of Gramicidin S and previously described analogues.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The cover picture shows the cationic antimicrobial peptide Gramicidin S (GS, left structure), which disrupts the bacterial membrane, however with little selectivity over the erythrocytic membrane. This mode of action is explained by the amphiphilic β‐sheet structure of GS. Three new analogues of GS were designed in which one DPhe‐Pro β‐turn motif has been replaced by different sugar amino acids (1, 2 and 3 in the right structures). The solution structures of these new analogues were assessed by 1D and 2D NMR spectroscopy, which shows a slightly altered backbone conformation. The antibacterial and hemolytic activities of all analogues were also determined in this study. Details are discussed in the article by M. Overhand et al. on p. 4231 ff.