title: Gramicidin S derivatives containing cis- and trans-morpholine amino acids (MAAs) as turn mimetics.
abstract: The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.
authors.affiliation: Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Varsha V
authors.initials: VV
authors.lastname: Kapoerchan
authors.forename: Emile
authors.initials: E
authors.lastname: Spalburg
authors.forename: Albert J
authors.initials: AJ
authors.lastname: de Neeling
authors.forename: Roos H
authors.initials: RH
authors.lastname: Mars-Groenendijk
authors.forename: Daan
authors.initials: D
authors.lastname: Noort
authors.forename: José M
authors.initials: JM
authors.lastname: Otero
authors.forename: Patricia
authors.initials: P
authors.lastname: Ferraces-Casais
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Llamas-Saiz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: van Raaij
authors.forename: Joop
authors.initials: J
authors.lastname: van Doorn
authors.forename: Gijs A
authors.initials: GA
authors.lastname: van der Marel
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D006096:Gramicidin / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D004151:Dipeptides; D009025:Morpholines; D006096:Gramicidin