Synthesis and immunosuppressive activity of cyclolinopeptide A analogues containing homophenylalanine

Immune response suppressors are used in the medical praxis to prevent graft rejection after organ transplantation and in the therapy of some autoimmune diseases. Cyclolinopeptide A, naturally existing immunomodulatory peptide, was modified with homophenylalanine in positions 3 (4), 4 (5) or both 3 and 4 (6). The conformational influence of the replacement of Phe by Hphe was analyzed by NMR spectroscopy. Peptides 4–6 exist as single isomers with all trans peptide bonds except cis Pro–Pro peptide bond. The peptides were tested for their ability to suppress the proliferative response of mouse splenocytes to T- and B-cell mitogens and the secondary humoral immune response to sheep erythrocytes in vitro in parallel with a reference drug – cyclosporine A. The substitution of Phe with Hphe in positions 3 and 4 of CLA led to three different activities in the studied immunological assays. Very potent inhibition of AFC number of peptide 4 was not associated with cell toxicity. This compound caused a complete block of T- and B-cell proliferation. Peptides 5 and 6, containing Hphe in position 3 or 3 and 4, respectively, gave similar effects on the proliferative response of splenocytes to mitogens. Peptide 6 was a moderate suppressor of the humoral immune response, peptide 5 was exceptionally inhibitory. The presence of Hphe in position 4 of CLA backbone markedly reduced the viability of the tested cell line, however addition of the second Hphe in position 3 improved cell survival in comparison with the solvent.

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