Peptide bicycles that inhibit the Grb2 SH2 domain
Justin S Quartararo1, Pianpian Wu, Joshua A Kritzer
1Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, MA 02155, USA.
Chembiochem : a European Journal of Chemical Biology
|June 13, 2012
Summary
We developed a peptide-bicycle strategy to stabilize short peptides, enhancing their potency and selectivity. This approach creates robust peptide inhibitors for protein-protein interactions, including those involving SH2 domains.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Molecular Biology
Background:
- Developing short peptides into effective probes and therapeutics is challenging.
- Structural rigidification improves peptide properties, but effective strategies are needed.
- Short peptides often lack the stability and specificity required for therapeutic applications.
Purpose of the Study:
- To develop a novel strategy for stabilizing peptide macrocycles using side-chain-to-side-chain staples.
- To create peptide bicycles with enhanced affinity, selectivity, and resistance to degradation.
- To design potent and selective inhibitors for specific protein-protein interactions, such as those involving SH2 domains.
Main Methods:
- Synthesized homodetic peptide bicycles entirely on-resin with high yields.
- Applied a side-chain-to-side-chain stapling strategy to stabilize peptide macrocycles.
- Iteratively designed and optimized peptide bicycles, exemplified by BC1 targeting the Grb2 SH2 domain.
Main Results:
- Developed peptide bicycle BC1, demonstrating a 60-fold increase in potency and a 200-fold increase in selectivity compared to the parent peptide G1.
- Achieved complete stability of BC1 in human serum for 24 hours, whereas G1 was fully degraded.
- Successfully synthesized peptide bicycles with high yields using an on-resin approach.
Conclusions:
- The peptide-bicycle approach offers a robust method for stabilizing peptides and enhancing their therapeutic potential.
- This strategy is promising for developing selective inhibitors of SH2 domains and other phosphotyrosine-binding proteins.
- Peptide bicycles represent a valuable platform for targeting various protein-protein interactions.
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