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

Shirly Naveh, Yftah Tal-Gan, Song Ling, Amnon Hoffman, Joseph Holoshitz, Chaim Gilon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageAmerican English
Pages (from-to)493-496
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number1
DOIs
StatePublished - 1 Jan 2012

Keywords

  • Backbone cyclization
  • Peptidomimetics
  • Rheumatoid arthritis

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