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Design and testing of bicyclic inhibitors of Grb7--are two cycles better than one?

Menachem J Gunzburg1, Nigus D Ambaye, Mark P Del Borgo

  • 1Department of Biochemistry and Molecular Biology, Monash University, VIC, 3800, Australia.

Biopolymers
|March 19, 2013
PubMed

Insights

Researchers improved a cancer-targeting peptide (G7-18NATE) by adding a second linkage, enhancing its binding affinity to the Grb7 protein. This modification reduces entropic loss, paving the way for more effective cancer inhibitors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Grb7 is an adapter protein crucial for cancer cell migration and proliferation.
  • G7-18NATE, a thioether-cyclized peptide, inhibits Grb7 by targeting its SH2 domain with micromolar affinity.

Purpose of the Study:

  • To enhance the binding affinity of the G7-18NATE peptide to Grb7.
  • To investigate the effect of introducing a second linkage on peptide conformation and binding thermodynamics.
  • To develop improved second-generation Grb7 inhibitors.

Main Methods:

  • Design and synthesis of modified peptides with additional covalent linkages (O-ally ser, disulfide bond).
  • Isothermal Titration Calorimetry (ITC) to measure binding affinity and thermodynamics.
  • Comparison of binding affinities between original and modified peptides.

Main Results:

  • An O-ally ser linkage between residues 1 and 8 enhanced peptide affinity for Grb7.
  • ITC confirmed reduced entropic loss upon binding with the O-ally ser linkage.
  • Replacing thioether-cyclization with an amide linkage reduced affinity, but a disulfide bond at the same positions enhanced binding.

Conclusions:

  • Introducing a second covalent linkage can successfully enhance peptide affinity by reducing entropic penalties.
  • The G7-18NATE scaffold can be modified to create more potent inhibitors of Grb7.
  • This study provides a foundation for developing novel anti-cancer agents targeting Grb7.
Keywords:
ITCSH2 domain inhibitorSPRbicyclic peptidering closing methathesis

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