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

Research output: Research - peer-reviewJournal article

  • Renée Roodbeen
    Renée RoodbeenDanish-Chinese Centre for Proteases and CancerDenmark
  • Berit Paaske
    Berit PaaskeDanish-Chinese Centre for Proteases and CancerDenmark
  • Longguang Jiang
    Longguang JiangDanish-Chinese Centre for Proteases and CancerDenmark
  • Jan Kristian Jensen
  • Anni Christensen
    Anni ChristensenDanish-Chinese Centre for Proteases and CancerDenmark
  • Jakob T Nielsen
    Jakob T NielsenDanish-Chinese Centre for Proteases and CancerDenmark
  • Mingdong Huang
    Mingdong HuangDanish-Chinese Centre for Proteases and Cancer
  • Frans A.A. Mulder
  • Niels Christian Nielsen
  • Peter Andreasen
    Peter Andreasen
  • Knud Jørgen Jensen
    Knud Jørgen JensenKemisk InstitutDenmark
The development of protease inhibitors for pharmacological
intervention has taken a new turn with the use of peptidebased
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 bicyclicpeptide–
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
Original languageEnglish
Issue number16
Pages (from-to)2179–2188
Number of pages10
StatePublished - 2 Oct 2013

    Research areas

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

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