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Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases
Published on: August 27, 2021
Genetically Encoded Lysine-Selective Photocyclization Enables Phage Display Selection of Cyclic Peptide Binders
Xiao-Qin Yang1, Wei Ming1,2, Ze-Hao Zhang1
1State Key Laboratory of Natural Product Chemistry, Lanzhou Magnetic Resonance Center, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, P. R. China.
Angewandte Chemie (International Ed. in English)
|July 9, 2026
Summary
We developed a new method for creating cyclic peptides using a special amino acid and light. This technique generates stable, bioactive cyclic peptides for drug discovery, improving on older methods.
Area of Science:
- Biochemistry
- Molecular Biology
- Peptide Chemistry
Background:
- Phage display is limited by cysteine or unstable lysine reagents for cyclic peptide generation.
- Existing methods lack selectivity and stability for broad applications.
Purpose of the Study:
- Introduce a novel lysine-selective photocyclization platform for phage-displayed cyclic peptides.
- Establish a robust method for generating stable, bioactive cyclic peptides via noncanonical amino acid incorporation.
Main Methods:
- Incorporation of o-nitrobenzyl alcohol lysine (o-NBAK), a noncanonical amino acid, into phage-displayed peptides.
- Activation using the PANAC photoclick reaction for proximity-induced intramolecular cyclization.
- Screening of PANAC-cyclized libraries against disease-relevant protein targets.
Main Results:
- Efficient photocyclization on purified proteins and intact phage particles without loss of infectivity.
- Formation of stable indazolone macrocycles driven by o-NBAK and neighboring lysine proximity.
- Identification of cyclic peptide ligands with nanomolar to low-micromolar affinities.
- Demonstrated >10-fold enhancement in proteolytic stability of cyclized peptides.
Conclusions:
- The first lysine-selective cyclic peptide library on phage using noncanonical amino acid incorporation.
- A robust, chemoselective, and broadly applicable strategy for discovering bioactive cyclic peptides.
- PANAC photoclick reaction offers a mild and biocompatible approach for macrocyclization.
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