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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Structural Features of Antimicrobial Aza-β 3 -peptidesBaptiste Legrand 1 , Mathieu Laurencin 2 , Céline Zatylny-Gaudin 3 ,Joel Henry 3 , Arnaud Bondon 1 , and Michèle Baudy Floc'h 21 Université de Rennes 1. RMN-ILP, UMR CNRS 6026, Campus de Villejean, 35043,Rennes cedex, France; 2 Université de Rennes 1. ICMV, UMR CNRS 6226 SciencesChimiques de Rennes, 263 Avenue du Général Leclerc, 35042, Rennes Cedex, France;3 Université de Caen Basse Normandie, LBBM, UMR IFREMER, 14032,Caen Cedex, FranceIntroductionDesigning antimicrobial molecules based on pseudopeptides to increase the activity,selectivity and bioavailability of natural peptides is now widespread. Recently, numerouspeptidomimetics have been developed for biological applications including azapeptides,β-peptides, peptoids, and oligoureas. In this context, aza-β 3 -amino acids were used as newblocks to compose antimicrobial peptide sequences.From a natural antimicrobial peptide, H-ALSGDAFLRF-NH 2 (AD), depending on theaza-β 3 -residue insertions, the modifications can result either in inactive pseudopeptides, orin a drastic enhancement of the antimicrobial activity without cytotoxicity. We present herethe first NMR solution structures of peptides containing aza-β 3 -amino acids to study theirstructure-activity relationship.Results and DiscussionIn SDS micelles, the global fold of AD and AK displays disordered N-terminal regions andwell-defined amphipatic helical C-terminal moieties (5-10) (Figure 1). The Aβ3K peptideis based on AK, substituting the lysine in position 5 by an aza-β 3 -lysine (Aβ 3 K). Its globalfold is very different from the two previous peptides and do not exhibit a helical C-terminalFig. 1. AD natural cuttlefishpeptide NMR structure.part. A typical aza-β 3 residues hydrazino turn,previously described in crystals, can be also observed insolution [1-3]. Despite the two possible conformationsof the aza-β 3 lysine nitrogen stereocenter, only one set ofsignals is observable on the NMR spectra and theNOESY spectrum have numerous NOEs. Theconfiguration of the stereocenter of the aza-β 3 -Lys5 wasnot defined in the CNS topology and parameter files,and two sets of conformations can be obtained from theNMR restraints according to the configuration R or S ofthe N α stereocenter. Based on the NMR spectra, onecannot discriminate if only one conformation is presentin solution, or if two configurations are in fast exchange.Fig. 2. Aβ 3 K peptide NMR structure.240