Synthesis, conformational analysis and immunological activity of β3Phe-substituted Cyclolinopeptide A analogues

CLA, a natural, highly hydrophobic cyclic nonapeptide with sequence c(Pro1-Pro2- Phe3-Phe4- Leu5-Ile6- Ile7-Leu8- Val9-), 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we have synthesised three linear precursors and three cyclic analogues of CLA, in which one or both Phe residues have been replaced by β3Phe residues. A conformational analysis byNMR in CD3CN/H2O mixture has been carried out on the CLA analogue, in which Phe3 has been replaced by a βPhe, to study the influence of the mutation on the three-dimensional structure.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.