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β-Turn Modified Gramicidin S Analogues Containing Arylated Sugar Amino Acids Display Antimicrobial and Hemolytic Activity Comparable to the Natural Product

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posted on 14.06.2006, 00:00 by Gijsbert M. Grotenbreg, Annelies E. M. Buizert, Antonio L. Llamas-Saiz, Emile Spalburg, Peter A. V. van Hooft, Albert J. de Neeling, Daan Noort, Mark J. van Raaij, Gijsbert A. van der Marel, Herman S. Overkleeft, Mark Overhand
This paper describes the design and synthesis of gramicidin S (GS) analogues 10ac containing arylated sugar amino acids (SAAs) as a replacement of one of the two DPhe-Pro β-turn regions. The cyclic, amphiphilic peptides adopt a β-sheet conformation featuring an unusual reverse turn induced by the SAAs. The altered turn region induces a slight distortion of the antiparallel β-sheet, as compared to GS; the overall geometry however closely resembles that of the nonarylated GS analogue 1. GS analogues 10ac 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.