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

Kata Nóra Enyedi, András Czajlik, Krisztina Knapp, András Láng, Zsuzsa Majer, Eszter Lajkó, László Kohidai, András Perczel, Gábor Mezo

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9 Citations (Scopus)


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 NHGly-COAsn-sc distances. The side-chain orientation of Asn is a key determining factor; if it is turned away from HNGly, 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.

Original languageEnglish
Pages (from-to)1806-1817
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - Feb 26 2015


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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