ArticleScientific reports2016
Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- Enhancing the Bioactivity of Bicyclic Peptides Targeted to Grb7-SH2 by Restoring Cell Permeability.Biomedicines · 2022Article
- Design of Protein Segments and Peptides for Binding to Protein Targets.Biodesign research · 2022Review
- An Efficient Algorithm for the Detection of Outliers in Mislabeled Omics Data.Computational and mathematical methods in medicine · 2021Article
- GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma.The Journal of pathology · 2020Article
- Direct Interaction between Calmodulin and the Grb7 RA-PH Domain.International journal of molecular sciences · 2020Article
- Phosphotyrosine isosteres: past, present and future.Organic & biomolecular chemistry · 2020Review
- Evaluation of Cyclic Peptide Inhibitors of the Grb7 Breast Cancer Target: Small Change in Cargo Results in Large Change in Cellular Activity.Molecules (Basel, Switzerland) · 2019Article
- Review
- Arylation Chemistry for Bioconjugation.Angewandte Chemie (International ed. in English) · 2019Review
- Stapled Peptides Inhibitors: A New Window for Target Drug Discovery.Computational and structural biotechnology journal · 2019Review
- Methylation-associated silencing ofTheranostics · 2018Article
- Bicyclic Peptides as Next-Generation Therapeutics.Chemistry (Weinheim an der Bergstrasse, Germany) · 2017Review
- Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target.Frontiers in molecular biosciences · 2017Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.