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Comparative Analysis of Cyclization Techniques in Stapled Peptides: Structural Insights into Protein-Protein
Sára Ferková1, Ulrike Froehlich1, Marie-Édith Nepveu-Traversy1
1Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
International Journal of Molecular Sciences
|January 11, 2024
Summary
Researchers compared various chemical methods to create stapled peptides, which stabilize protein structures. A lactam-stapled peptide from human ACE2 showed high helicity and antiviral activity against SARS-CoV-2.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Structural Biology
Background:
- Peptidomimetics offer a strategy to develop therapeutic molecules by mimicking protein functions.
- Stapled peptides stabilize helical structures, crucial for protein-protein interactions (PPIs).
- Systematic comparisons of different stapling methods for helix stabilization are lacking.
Purpose of the Study:
- To compare chemically diverse helix-inducing staples (lactam, hydrocarbon, triazole, thioether) for their efficacy in stabilizing short peptide sequences.
- To evaluate the secondary structure and PPI inhibitory potential of stapled peptides derived from human ACE2 (hACE2).
- To correlate stapled peptide secondary structures with their ability to inhibit PPIs using a topical model system.
Main Methods:
- Exploited chemically diverse i, i + 4 constraints for stapling peptides.
- Utilized circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy for structural characterization.
- Performed in silico alanine scanning and assessed antiviral activity using bioreporter and pseudovirus assays.
Main Results:
- Compared five distinct stapling methods on two short hACE2-derived sequences.
- Identified a 9-mer lactam-stapled peptide (His34-Gln42) from hACE2 exhibiting 55% maximal helicity.
- Demonstrated antiviral activity of the lactam-stapled peptide in functional assays.
Conclusions:
- The study provides a sequence-independent comparison of α-helix-inducing staples.
- Lactam stapling is effective for stabilizing hACE2-derived peptides, yielding significant helicity.
- This work represents a comprehensive investigation into stapled peptide generation, secondary structure, and PPI inhibition for SARS-CoV-2 and hACE2 interaction.
