Phage-encoded bismuth bicycles enable instant access to targeted bioactive peptides

Area of Science:

• Biochemistry
• Peptide Chemistry
• Drug Discovery

Background:

• Genetically encoded libraries are vital for discovering high-affinity macrocyclic peptides.
• Bicyclic peptides with metal centers (e.g., bismuth) offer enhanced affinity, stability, and membrane permeability.
• Previous methods for peptide modification often require organic co-solvents and can be less biocompatible.

Purpose of the Study:

• To genetically encode peptide-bismuth and peptide-arsenic bicycles using phage display.
• To introduce a water-soluble bismuth reagent for simplified library modification and peptide preparation.
• To explore arsenic as an alternative thiophilic element for bicyclic peptide construction.

Main Methods:

• Genetic encoding of peptide-bismuth and peptide-arsenic bicycles within phage display libraries.
• Utilizing bismuth tripotassium dicitrate (gastrodenol) as a water-soluble bismuth(III) reagent.
• In situ preparation of bicyclic peptides without organic co-solvents.
• Exploring arsenic(III) for analogous bicyclic peptide formation.

Main Results:

• Demonstrated the instantaneous and biocompatible modification of phage libraries and peptides with bismuth and arsenic.
• Achieved significant enrichment of bicyclic peptides targeting streptavidin.
• Identified bicyclic peptides with dissociation constants two orders of magnitude lower than linear counterparts.

Conclusions:

• Genetic encoding of metal-containing bicyclic peptides is feasible and offers advantages over conventional methods.
• The use of water-soluble bismuth reagents simplifies the process and enhances biocompatibility.
• Structural constraint via bicyclic peptide formation significantly improves ligand binding affinity.