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

Bioorg Med Chem Lett. 2012 Jan 1;22(1):493-6. doi: 10.1016/j.bmcl.2011.10.098. Epub 2011 Nov 4.


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.

MeSH terms

  • Arthritis, Rheumatoid / drug therapy*
  • Chemistry, Pharmaceutical / methods*
  • Circular Dichroism
  • Dose-Response Relationship, Drug
  • Drug Design
  • Epitopes / chemistry
  • Humans
  • Inflammation
  • Models, Chemical
  • Nitric Oxide / chemistry
  • Peptides / chemistry
  • Peptides, Cyclic / chemistry*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Time Factors


  • Epitopes
  • Peptides
  • Peptides, Cyclic
  • Nitric Oxide