title: Thiazole-based γ-building blocks as reverse-turn mimetic to design a gramicidin S analogue: conformational and biological evaluation.
abstract: This paper describes the ability of a new class of heterocyclic γ-amino acids named ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids) to induce turns when included in a tetrapeptide template. Both hybrid Ac-Val-(R or S)-ATC-Ile-Ala-NH2 sequences were synthesized and their conformations were studied by circular dichroism, NMR spectroscopy, MD simulations, and DFT calculations. It was demonstrated that the ATCs induced highly stable C9 pseudocycles in both compounds promoting a twist turn and a reverse turn conformation depending on their absolute configurations. As a proof of concept, a bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β-pleated sheet conformation similar to that of the natural compound. The hybrid α,γ-cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity.
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Universités Montpellier I et II, UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5 (France), Fax: (+33) 4-67-54-86-54.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Legrand
authors.forename: Loïc
authors.initials: L
authors.lastname: Mathieu
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lebrun
authors.forename: Soahary
authors.initials: S
authors.lastname: Andriamanarivo
authors.forename: Vincent
authors.initials: V
authors.lastname: Lisowski
authors.forename: Nicolas
authors.initials: N
authors.lastname: Masurier
authors.forename: Séverine
authors.initials: S
authors.lastname: Zirah
authors.forename: Young Kee
authors.initials: YK
authors.lastname: Kang
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Ludovic T
authors.initials: LT
authors.lastname: Maillard
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D009842:Oligopeptides; D013844:Thiazoles; D006096:Gramicidin
keywords: amino acids; gramicidin S; hybrid peptide; thiazoles