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

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  • Renée Roodbeen, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Berit Paaske, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Longguang Jiang, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Jan Kristian Jensen
  • Anni Christensen, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Jakob T Nielsen, Danish-Chinese Centre for Proteases and Cancer, Danmark
  • Mingdong Huang, Danish-Chinese Centre for Proteases and Cancer
  • ,
  • Frans A.A. Mulder
  • Niels Christian Nielsen
  • Peter Andreasen
  • ,
  • Knud Jørgen Jensen, Kemisk Institut, Danmark
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
Sider (fra-til)2179–2188
Antal sider10
StatusUdgivet - 2 okt. 2013

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