A TRICYCLIC RING-SYSTEM REPLACES THE VARIABLE REGIONS OF PEPTIDES PRESENTED BY 3 ALLELES OF HUMAN MHC CLASS-I MOLECULES

Background: Cytotoxic T-lymphocytes (CTLs) recognize complexes of short peptides with major histocompatibility complex (MHC) class I molecules. MHC molecules are polymorphic, and the products of different MHC alleles bind to different subsets ofpeptides. This is due to differences in the shape of the peptide-binding groove on the surface of the MHC protein, especially the 'pockets' into which anchor residues at each end of the peptide fit. Nonpeptidic ligands for class I molecules may be useful clinically. Results: By applying computer-aided design methods guided by X-ray structures, we designed and synthesized several MHC class I ligands, based on known peptide ligands, in which the tricyclic, aromatic compound phenanthridine replaced the central amino acids of the peptides. These semi-peptidic fluorescent ligands bound with high affinity and with allelic specificity to the peptide-binding groove of different MHC class I molecules, forming crystallizable complexes. Conclusions: Specificity for binding to different MHC class I molecules can be imparted to the common phenanthridine element by judicious choice of terminal peptidic elements from either nonamer or decamer peptides. The phenanthridine-based ligands have a long bound half-life, as do antigenic peptides.