N-hydroxy-amide analogues of MHC-class I peptide ligands with nanomolar binding affinities

A novel class of major histocompatibility complex class I (MHC-I) ligands c ontaining an N-hydroxyamide bond was designed on the basis of the natural e pitope SIINFEKL, and synthesized on solid phase. The capacity of these comp ounds to bind to the MHC-I molecule H-2K(b) and to induce T cell responses was analysed in comparison with the corresponding glycine containing varian t of SIINFEKL. Binding to the MHC molecule was diminished by the N-hydroxy group at positions 2 and 3 of the oligomer and improved in the case of posi tions 4, 5, 6 and 7. No change was seen for position 1. The efficacy of T c ell stimulation was strongly reduced by the modification of all positions e xcept for position 1. A complete loss of activity was found for the N-hydro xy variant in positions 4 and 6. N-Hydroxy amide-containing peptides displa yed an enhanced stability to enzymatic degradation. This new class of MHC l igand can become instrumental as immunomodulatory reagent in Various diseas e situations. (C) 1998 European Peptide Society and John Wiley Br Sons, Ltd .