Peptide and Peptide Mimetic Inhibitors of Antigen Presentation by HLA-DR Class II MHC Molecules. Design, Structure−Activity Relationships, and X-ray Crystal Structures

David R. Bolin, Amy L. Swain,*^§ Ramakanth Sarabu, Steven J. Berthel, Paul Gillespie, Nicholas J. S. Huby, Raymond Makofske, Lucja Orzechowski, Agostino Perrotta, Katherine Toth, Joel P. Cooper, Nan Jiang, Fiorenza Falcioni, Robert Campbell, Donald Cox, Diana Gaizband, Charles J. Belunis, Damir Vidovic, Kouichi Ito, Robert Crowther, Ursula Kammlott, Xiaolei Zhang, Robert Palermo, David Weber, Jeanmarie Guenot, Zoltan Nagy, and Gary L. Olson*^†

J. Med. Chem., 2000, 43 (11), pp 2135–2148

DOI: 10.1021/jm000034h

Publication Date (Web): May 12, 2000

Copyright © 2000 American Chemical Society

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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.