title: Oxazole- and imidazole-based Ser-Leu dipeptide mimetics in potent inhibitors of antigen presentation by MHC class II DR molecules.
abstract: Imidazole and oxazole derivatives 1 to 4 were designed and prepared as dipeptide mimetics to replace the Ser-Leu dipeptide sequence of Ro-25-9980 (Ac-(Cha)-RAMA-S-L-NH2), a peptidic inhibitor of antigen binding to major histocompatibility complex (MHC) class II DR molecules linked to rheumatoid arthritis (RA). The most potent analog in binding assays (IC50 = 30 nM in DRB1*0401 binding; 1.6 times as potent as Ro 25-9980) was 16, Ac-(Cha)RAMA-(S)S-psi(oxazole)-L-NH2. The SAR of peptide hybrids 10 to 24, prepared by incorporating the dipeptide mimetics 1 to 4 is discussed. Of these hybrids, 23 and 24, analogs that incorporated the imidazole and oxazole mimetics as well as optimized variants at positions 3 to 5, were found to have 70 to 80 nM binding affinity comparable to the parent peptide in DRB 1*0401 binding and were also active in DRB1*0101 binding, while being resistant to proteolysis by cathepsin B. Both of these compounds showed inhibitory activity in an antigen-stimulated T-cell proliferation assay, indicating their potential to suppress autoimmune responses and as leads for therapeutic agents to treat RA.
authors.affiliation: Roche Research Center, Hoffmann-La Roche Inc, Nutley, New Jersey 07110, USA. ramakanth.sarabu@roche.com
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
authors.forename: David R
authors.initials: DR
authors.lastname: Bolin
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.forename: Joel R
authors.initials: JR
authors.lastname: Cooper
authors.forename: Donald
authors.initials: D
authors.lastname: Cox
authors.forename: Diana
authors.initials: D
authors.lastname: Gaizband
authors.forename: Raymond
authors.initials: R
authors.lastname: Makofske
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Nagy
authors.forename: Gary L
authors.initials: GL
authors.lastname: Olson
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects* / Q000502:physiology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D005802:Genes, MHC Class II / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007930:Leucine / Q000737:chemistry*; D018716:Molecular Mimicry / Q000276:immunology; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D007093:Imidazoles; D007166:Immunosuppressive Agents; D010080:Oxazoles; D012694:Serine; C029899:imidazole; D007930:Leucine