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Comprehensive Peptide Cyclization Examination Yields Optimized APP Scaffolds with Improved Affinity toward Mint2.

Christian R O Bartling1, Flora Alexopoulou1, Sarah Kuschert2

  • 1Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100Copenhagen, Denmark.

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|February 7, 2023
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Summary

Cyclic peptides offer improved therapeutic potential by enhancing stability and cell permeability. Systematic examination of cyclization strategies, particularly all-hydrocarbon stapling, optimizes peptide drug leads.

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Biotechnology

Background:

  • Peptides targeting protein-protein interactions are promising therapeutics for previously undruggable targets.
  • Linear peptides face challenges with metabolic stability and membrane permeability.
  • Peptide cyclization, including side-chain stapling, enhances stability and can induce specific secondary structures.

Purpose of the Study:

  • To systematically evaluate cyclization strategies for optimizing peptide scaffolds.
  • To identify cyclic peptide analogs with improved affinity and drug-like properties.
  • To investigate the impact of different cyclization methods on peptide stability and permeability.

Main Methods:

  • Comprehensive analysis of peptide cyclization strategies (position, chemistry, length).
  • Design and synthesis of cyclic APP dodecamer peptides.
  • Affinity assessment for the phosphotyrosine binding domain of Mint2.
  • Evaluation of metabolic stability, secondary structure, and membrane permeability.

Main Results:

  • Systematic cyclization strategy examination identified optimal peptide scaffolds.
  • Developed cyclic APP dodecamer peptides with significantly enhanced affinity for Mint2.
  • All-hydrocarbon stapling demonstrated superior metabolic stability and secondary structure stabilization.
  • Improved membrane permeability was observed with specific cyclization approaches.

Conclusions:

  • A thorough understanding of cyclization parameters is crucial for designing effective cyclic peptide therapeutics.
  • Optimized cyclic peptides, particularly via all-hydrocarbon stapling, show promise for overcoming limitations of linear peptides.
  • This work provides a framework for developing metabolically stable and cell-permeable peptide drug candidates.