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Synthesis, conformational analysis and immunological activity of β 3 Phe‐substituted Cyclolinopeptide A analogues
Author(s) -
Kaczmarek Krzysztof,
Farina Biancamaria,
Zubrzak Paweł,
Jankowski Stefan,
Zimecki Michał,
Suder Piotr,
Benedetti Ettore,
Fattorusso Roberto,
Saviano Michele,
Zabrocki Janusz
Publication year - 2009
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1099
Subject(s) - tetrapeptide , chemistry , stereochemistry , cyclic peptide , peptide , receptor , in vivo , amide , mechanism of action , biochemistry , in vitro , biology , microbiology and biotechnology
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we have synthesised three linear precursors and three cyclic analogues of CLA, in which one or both Phe residues have been replaced by β 3 Phe residues. A conformational analysis by NMR in CD 3 CN/H 2 O mixture has been carried out on the CLA analogue, in which Phe 3 has been replaced by a βPhe, to study the influence of the mutation on the three‐dimensional structure. All linear and cyclic CLA analogues containing βPhe 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. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.