Nonapeptide analogues containing (R)-3-hydroxybutanoate and beta-homoalanine oligomers: Synthesis and binding affinity to a class I major histocompatibility complex protein

Crystal structures of antigenic peptides bound to class I MHC proteins sugg est that chemical modifications of the central part of the bound peptide sh ould not alter binding affinity to the MHC restriction protein but could pe rturb the T-cell response to the parent epitope. In our effort in designing nonpeptidic high-affinity ligands for class I MHC proteins, oligomers of ( R)-3-hydroxybutanoate and(or) beta-homoalanine have been substituted for th e central part of a HLA-B27-restricted T-cell epitope of viral origin. The affinity of six modified peptides to the B*2705 allele was determined by an in vitro stabilization assay. Four out of the six designed analogues prese nted an affinity similar to that of the parent peptide. Two compounds, shar ing the same stereochemistry (R,R,S,S) at the four stereogenic centers of t he nonpeptidic spacer, bound to B*2705 with a 5-6-fold decreased affinity. Although the chiral spacers do not strongly interact with the protein activ e site, there are configurations which are not accepted by the MHC binding groove, probably because of improper orientation of some lateral substituen ts in the bound state and different conformational behavior in the free sta te, However we demonstrate that beta-amino acids can be incorporated in the sequence of viral T-cell epitopes without impairing MHC binding. The prese nted structure-activity relationships open the door to the rational design of peptide-based vaccines and of nonnatural T-cell receptor antagonists aim ed at blocking peptide-specific T-cell responses in MHC-associated autoimmu ne diseases.