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Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7.

<div class='caption-title'>Schematic showing the structures of the 6 peptides referred to in this paper.</div>
<div class='caption-title'>Structure of the G7-B1 and Grb7-SH2 domain complex in comparison to other Grb7-SH2 structures.</div>
<div class='caption-title'>Binding affinity determination of G7 peptides for Grb7-SH2.</div>
Gunzburg MJ, Kulkarni K, Watson GM, Ambaye ND, Del Borgo MP, Brandt R, Pero SC, Perlmutter P, Wilce MC, Wilce JA
OpenAccess logo Sci Rep 6 27060 (2016)
Related entries: 5eel, 5eeq

Cited: 15 times
EuropePMC logo PMID: 27257138

Abstract

The design of potent and specific peptide inhibitors to therapeutic targets is of enormous utility for both proof-of-concept studies and for the development of potential new therapeutics. Grb7 is a key signaling molecule in the progression of HER2 positive and triple negative breast cancers. Here we report the crystal structure of a stapled bicyclic peptide inhibitor G7-B1 in complex with the Grb7-SH2 domain. This revealed an unexpected binding mode of the peptide, in which the staple forms an alternative contact with the surface of the target protein. Based on this structural information, we designed a new series of bicyclic G7 peptides that progressively constrain the starting peptide, to arrive at the G7-B4 peptide that binds with an approximately 2-fold enhanced affinity to the Grb7-SH2 domain (KD = 0.83 μM) compared to G7-B1 and shows low affinity binding to Grb2-, Grb10- and Grb14-SH2 domains (KD > 100 μM). Furthermore, we determined the structure of the G7-B4 bicyclic peptide in complex with the Grb7-SH2 domain, both before and after ring closing metathesis to show that the closed staple is essential to the target interaction. The G7-B4 peptide represents an advance in the development of Grb7 inhibitors and is a classical example of structure aided inhibitor development.

Reviews - 5d0j mentioned but not cited (1)

  1. Stapled Peptides Inhibitors: A New Window for Target Drug Discovery. Ali AM, Atmaj J, Van Oosterwijk N, Groves MR, Dömling A. Comput Struct Biotechnol J 17 263-281 (2019)

Articles - 5d0j mentioned but not cited (1)

  1. Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7. Gunzburg MJ, Kulkarni K, Watson GM, Ambaye ND, Del Borgo MP, Brandt R, Pero SC, Perlmutter P, Wilce MC, Wilce JA. Sci Rep 6 27060 (2016)


Reviews citing this publication (5)

  1. Arylation Chemistry for Bioconjugation. Zhang C, Vinogradova EV, Spokoyny AM, Buchwald SL, Pentelute BL. Angew Chem Int Ed Engl 58 4810-4839 (2019)
  2. Bicyclic Peptides as Next-Generation Therapeutics. Rhodes CA, Pei D. Chemistry 23 12690-12703 (2017)
  3. Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target. Chu PY, Tai YL, Shen TL. Cells 8 E435 (2019)
  4. Phosphotyrosine isosteres: past, present and future. Cerulli RA, Kritzer JA. Org Biomol Chem 18 583-605 (2020)
  5. Design of Protein Segments and Peptides for Binding to Protein Targets. Gupta S, Azadvari N, Hosseinzadeh P. Biodes Res 2022 9783197 (2022)

Articles citing this publication (8)

  1. Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Chen K, Liu MX, Mak CS, Yung MM, Leung TH, Xu D, Ngu SF, Chan KK, Yang H, Ngan HY, Chan DW. Theranostics 8 423-436 (2018)
  2. Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions. Perell GT, Staebell RL, Hairani M, Cembran A, Pomerantz WCK. Chembiochem 18 1836-1844 (2017)
  3. GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma. Gotovac JR, Liu DS, Yates MJ, Milne JV, Macpherson AA, Simpson KJ, Eslick GD, Mitchell C, Duong CP, Phillips WA, Clemons NJ. J Pathol 252 317-329 (2020)
  4. Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target. Watson GM, Lucas WAH, Gunzburg MJ, Wilce JA. Front Mol Biosci 4 64 (2017)
  5. Direct Interaction between Calmodulin and the Grb7 RA-PH Domain. Watson GM, Wilce JA. Int J Mol Sci 21 E1336 (2020)
  6. Enhancing the Bioactivity of Bicyclic Peptides Targeted to Grb7-SH2 by Restoring Cell Permeability. Sturre NP, Colson RN, Shah N, Watson GM, Yang X, Wilce MCJ, Price JT, Wilce JA. Biomedicines 10 1145 (2022)
  7. Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity. Sang J, Kulkarni K, Watson GM, Ma X, Craik DJ, Henriques ST, Poth AG, Benfield AH, Wilce JA. Molecules 24 E3739 (2019)
  8. An Efficient Algorithm for the Detection of Outliers in Mislabeled Omics Data. Sun H, Wang J, Zhang Z, Hu N, Wang T. Comput Math Methods Med 2021 9436582 (2021)


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