Oral Presentation 14th Australian Peptide Conference 2022

Optimisation of bicyclic peptides targeted to the Grb7-SH2 domain (#48)

Jacqueline A. Wilce 1 , Gabrielle Watson 1 , Ketav Kulkarni 1 , Jianrong Sang 2 , Natasha Sturre 1 , Rhys Colson 1 , Sónia T Henriques 3 , John Price 4 , Matthew C. J. Wilce 1
  1. Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  2. Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  4. College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Victoria, Australia

Peptides can be a great starting point for the development of inhibitors against protein targets of interest, with their potential to mimic and outcompete the natural binding partners of the protein. With the help of cell-permeability tags, they can even be developed to target intracellular targets. In this talk I will tell the story of the development of bicyclic inhibitor peptides against the Grb7-SH2 domain.

Grb7 is a signaling protein with critical roles in tumor cell proliferation and migration and an established cancer therapeutic target. We first structurally characterised a cyclic peptide (G7-18NATE) that is a specific inhibitor of Grb7 and inhibits cellular growth and migration in cancer cell lines [1]. Based on this we developed a series of second generation bicyclic peptides that showed enhanced affinity for the Grb7-SH2 domain [2] and further improved these peptides with the incorporation of phosphotyrosine mimetics [3]. By combining these two strategies we were able to achieve peptides with affinities in the nM range that still maintained target specificity for Grb7 over other closely related SH2 domains [4]. There were surprises along the way - but the rational approach prevailed. Upon testing the activity of the improved inhibitor in cancer cell lines, we had more surprises, with just small changes to the peptides resulting in large changes to cellular activity [5]. Our most recent work has investigated the effectiveness of the inhibitor peptides in a variety of cancer cell lines leading to further modifications for the improvement of cell permeability.

  1. Ambaye ND et al., (2011) J. Mol. Biol. 412, 397-411.
  2. Gunzburg et al., (2013) Biopolymers. 100, 543-549
  3. Watson et al., (2015) J. Med. Chem. 58, 7707-7718.
  4. Watson et al., (2017) J. Med. Chem. 60, 9349-9359.
  5. Sang et al., (2019) Molecules. 24(20):3739.