title: Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules.
abstract: We have identified a heptapeptide with high affinity to rheumatoid arthritis-associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.
authors.affiliation: Department of Immunology, Hoffmann-LaRoche, Inc., Nutley, NJ 07110, USA.
authors.forename: F
authors.initials: F
authors.lastname: Falcioni
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: D
authors.initials: D
authors.lastname: Vidovic
authors.forename: C
authors.initials: C
authors.lastname: Belunis
authors.forename: R
authors.initials: R
authors.lastname: Campbell
authors.forename: S J
authors.initials: SJ
authors.lastname: Berthel
authors.forename: D R
authors.initials: DR
authors.lastname: Bolin
authors.forename: P B
authors.initials: PB
authors.lastname: Gillespie
authors.forename: N
authors.initials: N
authors.lastname: Huby
authors.forename: G L
authors.initials: GL
authors.lastname: Olson
authors.forename: R
authors.initials: R
authors.lastname: Sarabu
authors.forename: J
authors.initials: J
authors.lastname: Guenot
authors.forename: V
authors.initials: V
authors.lastname: Madison
authors.forename: J
authors.initials: J
authors.lastname: Hammer
authors.forename: F
authors.initials: F
authors.lastname: Sinigaglia
authors.forename: M
authors.initials: M
authors.lastname: Steinmetz
authors.forename: Z A
authors.initials: ZA
authors.lastname: Nagy
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D006684:HLA-DR Antigens; D009842:Oligopeptides; D002403:Cathepsins