title: Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.
abstract: 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 DRB10401 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.
authors.affiliation: Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Bolin
authors.forename: A L
authors.initials: AL
authors.lastname: Swain
authors.forename: R
authors.initials: R
authors.lastname: Sarabu
authors.forename: S J
authors.initials: SJ
authors.lastname: Berthel
authors.forename: P
authors.initials: P
authors.lastname: Gillespie
authors.forename: N J
authors.initials: NJ
authors.lastname: Huby
authors.forename: R
authors.initials: R
authors.lastname: Makofske
authors.forename: L
authors.initials: L
authors.lastname: Orzechowski
authors.forename: A
authors.initials: A
authors.lastname: Perrotta
authors.forename: K
authors.initials: K
authors.lastname: Toth
authors.forename: J P
authors.initials: JP
authors.lastname: Cooper
authors.forename: N
authors.initials: N
authors.lastname: Jiang
authors.forename: F
authors.initials: F
authors.lastname: Falcioni
authors.forename: R
authors.initials: R
authors.lastname: Campbell
authors.forename: D
authors.initials: D
authors.lastname: Cox
authors.forename: D
authors.initials: D
authors.lastname: Gaizband
authors.forename: C J
authors.initials: CJ
authors.lastname: Belunis
authors.forename: D
authors.initials: D
authors.lastname: Vidovic
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: R
authors.initials: R
authors.lastname: Crowther
authors.forename: U
authors.initials: U
authors.lastname: Kammlott
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Palermo
authors.forename: D
authors.initials: D
authors.lastname: Weber
authors.forename: J
authors.initials: J
authors.lastname: Guenot
authors.forename: Z
authors.initials: Z
authors.lastname: Nagy
authors.forename: G L
authors.initials: GL
authors.lastname: Olson
mesh_terms: D017951:Antigen Presentation; D001667:Binding, Competitive; D002241:Carbohydrates / Q000737:chemistry; D002401:Cathepsin B / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000737:chemistry*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D018716:Molecular Mimicry; D010452:Peptide Biosynthesis; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
chemical_list: D002241:Carbohydrates; D004151:Dipeptides; D006684:HLA-DR Antigens; D002401:Cathepsin B