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Non-symmetric cysteine stapling in native peptides and proteins
Sven Ullrich1, Bishvanwesha Panda1, Upamali Somathilake1
1Research School of Chemistry, College of Science, Australian National University, Canberra 2601 ACT, Australia. sullrich@g.ecc.u-tokyo.ac.jp.
Chemical Communications (Cambridge, England)
|December 16, 2024
Summary
We developed a new method using 2-chloromethyl-6-cyanopyridine to create stapled peptides. This technique enhances peptide affinity, stability, and potency, aiding peptide drug discovery.
Area of Science:
- Chemical Biology
- Medicinal Chemistry
- Biotechnology
Background:
- Peptide stapling is a technique used to modify peptide structure.
- Current methods for peptide stapling have limitations.
Purpose of the Study:
- To introduce a novel reagent, 2-chloromethyl-6-cyanopyridine, for non-symmetric peptide stapling.
- To demonstrate the utility of this method for creating diverse peptide macrocycles.
Main Methods:
- Utilized 2-chloromethyl-6-cyanopyridine for covalent linkage of N-terminal and internal cysteines.
- Applied the method to native peptides and proteins.
Main Results:
- Achieved non-symmetric stapling of peptides.
- Produced diverse peptide macrocycles with improved properties.
- Demonstrated enhanced affinity, stability, and inhibitory potency of stapled peptides.
Conclusions:
- The developed method is biocompatible and versatile.
- This approach holds significant potential for peptide drug discovery platforms.
- Applicable to both synthetic peptides and native proteins.
