Controlling Tricyclic Peptide Architecture in mRNA Display through Orthogonal Reactivity on Rotationally Flexible...

Area of Science:

• Medicinal Chemistry
• Biotechnology
• Drug Discovery

Background:

• Macrocyclization enhances peptide drug candidate conformational control and function.
• Genetically encoded display platforms facilitate discovery of conformationally restricted peptides.

Purpose of the Study:

• To integrate tetrafunctional scaffolds into mRNA display for direct discovery of tricyclic peptides.
• To overcome topological challenges in macrocyclization using scaffold rotational flexibility.

Main Methods:

• Utilized mRNA display with tetrafunctional scaffolds.
• Employed orthogonal reactions with cysteine and azidohomoalanine residues.
• Generated single, well-defined tricyclic peptide architectures.

Main Results:

• Discovered tricyclic peptides targeting an antibody and the Fzd5 receptor.
• Achieved low nanomolar affinity for top peptide candidates.
• Demonstrated minimal peptide degradation in serum after 24 hours.
• Confirmed target engagement in cell culture.

Conclusions:

• This method enables direct generation of advanced multicyclic peptide drug candidates.
• The approach streamlines peptide drug discovery by yielding conformationally constrained and stable molecules.
• Potential to accelerate the development of novel peptide therapeutics.