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Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action

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  • Renée Roodbeen, Danish-Chinese Centre for Proteases and Cancer, Denmark
  • Berit Paaske, Danish-Chinese Centre for Proteases and Cancer, Denmark
  • Longguang Jiang, Danish-Chinese Centre for Proteases and Cancer, Denmark
  • Jan Kristian Jensen
  • Anni Christensen, Danish-Chinese Centre for Proteases and Cancer, Denmark
  • Jakob T Nielsen, Danish-Chinese Centre for Proteases and Cancer, Denmark
  • Mingdong Huang, Danish-Chinese Centre for Proteases and Cancer
  • ,
  • Frans A.A. Mulder
  • Niels Christian Nielsen
  • Peter Andreasen
  • ,
  • Knud Jørgen Jensen, Kemisk Institut, Denmark
The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide-protease interactions will aid future designs of bicyclic peptide protease inhibitors.
Translated title of the contributionBicyklisk peptid-hæmmer af urokinase-type plasminogen-aktivator: xxx
Original languageEnglish
Pages (from-to)2179–2188
Number of pages10
Publication statusPublished - 2 Oct 2013

    Research areas

  • cancer, isothermal titration calorimetry, NMR spectroscopy, peptide-protease interactions, X-ray structures

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