Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures
Bolin, D.R.; Swain, A.L.; Sarabu, R.; Berthel, S.J.; Gillespie, P.; Huby, N.J.; Makofske, R.; Orzechowski, L.; Perrotta, A.; Toth, K.; Cooper, J.P.; Jiang, N.; Falcioni, F.; Campbell, R.; Cox, D.; Gaizband, D.; Belunis, C.J.; Vidovic, D.; Ito, K.; Crowther, R.; Kammlott, U.; Zhang, X.; Palermo, R.; Weber, D.; Guenot, J.; Nagy, Z.; Olson, G.L.
Journal of Medicinal Chemistry 43(11): 2135-2148
2000
ISSN/ISBN: 0022-2623
PMID: 10841792
DOI: 10.1021/jm000034h
Accession: 011127329
Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB1*0401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.