NEW SYNTHETIC NONPEPTIDE LIGANDS FOR CLASSICAL MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I MOLECULES

Poly-N-acylated amines, as a new class of synthetic non-peptide ligand s for the murine major histocompatibility complex (MHC) class I molecu le H-2K(b), were developed on the basis of the ovalbumin-derived pepti de epitope SIINFEKL. Non-peptidic structural elements were introduced at the C-terminal part of the ligand and include the two dominant anch ors at positions 5 and 8, Several oligomers and five different combina torial libraries were synthesized and tested for their H-2K(b)-binding capacities in an MHC stabilization assay. First, the optimal spacing and geometry of the side chains were determined using a series of olig omers with different main chain modifications. Then, based on the stru cture with the highest binding efficiency, randomized libraries were d esigned that contain 26 different aromatic, heteroaromatic, or pseudoa romatic side chains for the dominant anchor at position 5, which is de eply buried inside the MHC peptide-binding groove and is crucial for t he conformational stability of the entire peptide-MHC complex. Similar ly, a series of aliphatic side chains were tested for the second domin ant anchor at position 8, MHC-binding and MHC-stabilizing oligomers wi th defined structures were derived from these libraries by deconvoluti on.