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N-Terminal cysteine mediated backbone-side chain cyclization for chemically enhanced phage display
Mengmeng Zheng1, Fredrik Haeffner1, Jianmin Gao1
1Department of Chemistry, Merkert Chemistry Center, Boston College Chestnut Hill MA 02467 USA Jianmin.Gao@bc.edu.
Chemical Science
|August 3, 2022
Summary
This study introduces a new method for creating diverse nonnatural cyclic peptide libraries using phage display. This approach enables the discovery of potent inhibitors for protein targets like Keap1 and Sortase A.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Phage display technology is crucial for peptide library screening.
- Current limitations restrict phage display to natural peptides.
- Nonnatural cyclic peptides are promising for inhibiting protein-protein interactions.
Purpose of the Study:
- To develop a novel strategy for creating backbone-side chain cyclized peptide libraries on phage.
- To expand the chemical diversity of peptides accessible through phage display.
- To identify potent peptide inhibitors using the new methodology.
Main Methods:
- Utilized N-terminal cysteine (NCys) reactivity with 2-cyanobenzothiazole (CBT).
- Developed a conjugation strategy for thiol-reactive groups to facilitate cyclization.
- Screened the generated peptide library against Keap1 and Sortase A.
Main Results:
- Successfully created backbone-side chain cyclized peptide libraries on phage.
- Identified potent peptide inhibitors for both Keap1 and Sortase A.
- Achieved low nanomolar potency for certain Keap1 inhibitors.
Conclusions:
- The novel backbone-side chain cyclization strategy significantly enhances phage display capabilities.
- This method provides a valuable tool for generating nonnatural macrocyclic peptides.
- The identified inhibitors demonstrate the potential of this approach for drug discovery.
