Oxazole- and imidazole-based Ser-Leu dipeptide mimetics in potent inhibitors of antigen presentation by MHC class II DR molecules.
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.
Sarabu
Ramakanth
R
Roche Research Center, Hoffmann-La Roche Inc, Nutley, New Jersey 07110, USA. ramakanth.sarabu@roche.com
Bolin
David R
DR
Campbell
Robert
R
Cooper
Joel R
JR
Cox
Donald
D
Gaizband
Diana
D
Makofske
Raymond
R
Nagy
Zoltan
Z
Olson
Gary L
GL
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*
D004151:Dipeptides; D007093:Imidazoles; D007166:Immunosuppressive Agents; D010080:Oxazoles; D012694:Serine; C029899:imidazole; D007930:Leucine