Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules

We have identified a heptapeptide with high affinity to rheumatoid arthriti s-associated class II major histocompatibility (MHC) molecules. Using a mod el of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino aci ds and dipeptide mimetics were found to be appropriate substituents and cou ld be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fo ld to more than a thousand-fold more potent than the original peptide in in hibiting T-cell responses to processed protein antigens presented by the ta rget MHC molecules. Peptidomimetic compounds of this type could find therap eutic use as MHC-selective antagonists of antigen presentation in the treat ment of autoimmune diseases.