title: Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues: synthesis and conformational analysis.
abstract: The collagen telopeptides play an important role for lysyl oxidase-mediated crosslinking, a process which is deregulated during tumour progression. The DEKS motif which is located within the N-terminal telopeptide of the α1 chain of type I collagen has been suggested to adopt a βI-turn conformation upon docking to its triple-helical receptor domain, which seems to be critical for lysyl oxidase-catalysed deamination and subsequent crosslinking by Schiff-base formation. Herein, the design and synthesis of cyclic peptides which constrain the DEKS sequence in a β-turn conformation will be described. Lysine-side chain attachment to 2-chlorotrityl chloride-modified polystyrene resin followed by microwave-assisted solid-phase peptide synthesis and on-resin cyclisation allowed for an efficient access to head-to-tail cyclised DEKS-derived cyclic penta- and hexapeptides. An N(ε)-(4-fluorobenzoyl)lysine residue was included in the cyclopeptides to allow their potential radiolabelling with fluorine-18 for PET imaging of lysyl oxidase. Conformational analysis by (1)H NMR and chiroptical (electronic and vibrational CD) spectroscopy together with MD simulations demonstrated that the concomitant incorporation of a D-proline and an additional lysine for potential radiolabel attachment accounts for a reliable induction of the desired βI-turn structure in the DEKS motif in both DMSO and water as solvents. The stabilised conformation of the cyclohexapeptide is further reflected by its resistance to trypsin-mediated degradation. In addition, the deaminated analogue containing allysine in place of lysine has been synthesised via the corresponding ε-hydroxynorleucine containing cyclohexapeptide. Both ε-hydroxynorleucine and allysine containing cyclic hexapeptides have been subjected to conformational analysis in the same manner as the lysine-based parent structure. Thus, both a conformationally restricted lysyl oxidase substrate and product have been synthetically accessed, which will enable their potential use for molecular imaging of these important enzymes.
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany. r.loeser@hzdr.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Wodtke
authors.forename: Gloria
authors.initials: G
authors.lastname: Ruiz-Gómez
authors.forename: Manuela
authors.initials: M
authors.lastname: Kuchar
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: Pavlina
authors.initials: P
authors.lastname: Novotná
authors.forename: Marie
authors.initials: M
authors.lastname: Urbanová
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Reik
authors.initials: R
authors.lastname: Löser
mesh_terms: D000595:Amino Acid Sequence; D002855:Chromatography, Thin Layer; D002942:Circular Dichroism; D003094:Collagen / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D010455:Peptides; D003094:Collagen