Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads

作者：Naveh Shirly; Tal Gan Yftah; Ling Song; Hoffman Amnon; Holoshitz Joseph; Gilon Chaim^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(1): 493-496.

DOI：10.1016/j.bmcl.2011.10.098

• Rheumatoid arthritis
• Backbone cyclization
• Peptidomimetics

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 DR beta-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 alpha-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.

• 出版日期2012-1-1