Enhancement of peptide binding to MHC class I molecules by small compounds - a combined biochemical and computational investigation

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In this application, we propose to investigate a novel mechanism for enhancing the binding of antigenic peptides to Major Histocompatibility Complex (MHC)1 class I molecules, which we have discovered in our in vitro model system for loading class I molecules with peptides in the lumen of microsomal membranes. This enhancement effect has promising potential applications in basic research and in immunotherapy. We will first aim to better understand the enhancement effect and use it to elucidate the mechanism of peptide binding to class I molecules under physiological conditions. Second, based on the structures of successful peptides and their pharmacophores with respect to the enhancement effect, we will screen a large number of nonpeptidic small molecules to find a peptidomimetic enhancer of peptide binding to class I. Both approaches rely on close cooperation of computational and laboratory investigations.