title: Synthesis, conformational analysis and immunological activity of beta3Phe-substituted Cyclolinopeptide A analogues.
abstract: CLA, a natural, highly hydrophobic cyclic nonapeptide with sequence c(Pro(1)-Pro(2)-Phe(3)-Phe(4)-Leu(5)-Ile(6)-Ile(7)-Leu(8)-Val(9)-), isolated from linseed oil, was found to possess a strong immunosuppressive activity comparable, in low doses, with that of CsA, with a mechanism that depends on the inhibition of the interleukin-1 and interleukin-2 action. Structural analysis of CLA and its related compounds has underlined that the presence of the tetrapeptide Pro-Pro-Phe-Phe sequence, the Pro-Pro cis amide bond, and the 'edge-to-face' interaction are possible important features for the immunosuppressive activity of CLA. To evaluate the role and significance of 'edge-to-face' interaction in the process of molecular recognition by receptors, we have synthesised three linear precursors and three cyclic analogues of CLA, in which one or both Phe residues have been replaced by beta(3)Phe residues. A conformational analysis by NMR in CD(3)CN/H(2)O mixture has been carried out on the CLA analogue, in which Phe(3) has been replaced by a betaPhe, to study the influence of the mutation on the three-dimensional structure. All linear and cyclic CLA analogues containing betaPhe have been tested in the humoral and cellular immune response in vivo assays in mice. The peptide activities have been compared with CsA, as a reference drug.
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Łódź, Zeromskiego 116, 90-924 Łódź, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kaczmarek
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Farina
authors.forename: Paweł
authors.initials: P
authors.lastname: Zubrzak
authors.forename: Stefan
authors.initials: S
authors.lastname: Jankowski
authors.forename: Michał
authors.initials: M
authors.lastname: Zimecki
authors.forename: Piotr
authors.initials: P
authors.lastname: Suder
authors.forename: Ettore
authors.initials: E
authors.lastname: Benedetti
authors.forename: Roberto
authors.initials: R
authors.lastname: Fattorusso
authors.forename: Michele
authors.initials: M
authors.lastname: Saviano
authors.forename: Janusz
authors.initials: J
authors.lastname: Zabrocki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology*; D010649:Phenylalanine / Q000737:chemistry; D017433:Protein Structure, Secondary
chemical_list: D010456:Peptides, Cyclic; C055018:cyclolinopeptide A; D010649:Phenylalanine