title: Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads.
abstract: Rheumatoid arthritis (RA) is a common human leukocyte antigen-associated disease. Most RA patients have a five-residue sequence motif called the shared epitope (SE) in the DRβ-chain of the HLA-DRB1 protein. The SE was found to activate nitric oxide (NO) production, suggesting a possible mechanism for RA development. The native conformation of the SE is presumed to be an α-helix, thus using cyclic peptides to stabilize this conformation may produce a potent SE mimetic which will have drug-like properties. We present the development of a backbone cyclic SE mimetic that activates NO production in the low nM range. Circular dichroism analysis revealed a conformational change from for the parent linear peptides to the cyclic analogs. The most active cyclic analog is completely stable towards trypsin/chymotrypsin degradation while the linear 15-mer analogs completely degraded within 30 min. The outcome of this study is a potent cyclic peptide with drug-like properties that can be used as a template for drug development.
authors: Institute of Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
authors: Shirly
authors: S
authors: Naveh
authors: Yftah
authors: Y
authors: Tal-Gan
authors: Song
authors: S
authors: Ling
authors: Amnon
authors: A
authors: Hoffman
authors: Joseph
authors: J
authors: Holoshitz
authors: Chaim
authors: C
authors: Gilon
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D008956:Models, Chemical; D009569:Nitric Oxide / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013997:Time Factors
chemical_list: D000939:Epitopes; D010455:Peptides; D010456:Peptides, Cyclic; D009569:Nitric Oxide