Development of cyclic NGR peptides with thioether linkage: structure and dynamics determining deamidation and bioactivity

J Med Chem. 2015 Feb 26;58(4):1806-17. doi: 10.1021/jm501630j. Epub 2015 Feb 16.


NGR peptides that recognize CD13 receptors in tumor neovasculature are of high interest, in particular due to their potential applications in drug targeting. Here we report the synthesis and structural analysis of novel thioether bond-linked cyclic NGR peptides. Our results show that their chemostability (resistance against spontaneous decomposition forming isoAsp and Asp derivatives) strongly depends on both sample handling conditions and structural properties. A significant correlation was found between chemostability and structural measures, such as NH(Gly)-CO(Asn-sc) distances. The side-chain orientation of Asn is a key determining factor; if it is turned away from HN(Gly), the chemostability increases. Structure stabilizing factors (e.g., H-bonds) lower their internal dynamics, and thus biomolecules become even more resistant against spontaneous decomposition. The effect of cyclic NGR peptides on cell adhesion was examined in A2058 melanoma cell lines. It was found that some of the investigated peptides gradually increased cell adhesion with long-term characteristics, indicating time-dependent formation of integrin binding isoAsp derivatives that are responsible for the adhesion-inducing effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology*
  • Structure-Activity Relationship
  • Sulfides / chemistry*
  • Thermodynamics*
  • Time Factors
  • Tumor Cells, Cultured


  • NGR peptide
  • Oligopeptides
  • Sulfides