This review catalogs the full landscape of peptide stapling techniques — categorized by anchoring residue types — for designing stable, cell-permeable peptide drugs that block protein-protein interactions.
3 residue categoriesNatural amino acids, non-natural amino acids, or combinations — each with distinct stapling properties
What the researchers found
Stapled peptide design should consider anchoring residue type, cross-linker chemistry, staple length, and staple position — each significantly affects helicity, stability, cell permeability, and target binding.
Why it matters
Protein-protein interactions drive most diseases but are "undruggable" by small molecules. Stapled peptides are the leading approach to crack this target class, and this review provides a practical design guide.
The numbers in context
3 anchoring residue categories; covers stability, permeability, PPI inhibition; reversibility, bio-orthogonal, photoisomerization features
How the study worked
Comprehensive literature review categorizing peptide stapling methodologies by anchoring residue chemistry, with analysis of biophysical and biological properties.
Who was studied
N/A (literature review)
What this study cannot tell us
Review — no new experimental data; the field evolves rapidly with new stapling chemistries being developed continuously.
How to read the evidence
N/A — comprehensive review and methodology reference; no new experimental data.
When this study was published
Published in 2020; new stapling chemistries and clinical candidates have emerged since.
The bigger picture
Stapled peptides are entering clinical trials for cancer and other diseases. A comprehensive understanding of stapling chemistry is essential for expanding this drug class.
Questions still open
- Which anchoring residue strategy gives the best balance of stability and target affinity?
- Can photoswitchable staples enable spatiotemporally controlled peptide drugs?
- How close are stapled peptides to becoming mainstream therapeutics?
Common questions
What are protein-protein interactions and why are they hard to drug?
What makes one stapling method better than another?
Read the original research
Stapled Helical Peptides Bearing Different Anchoring Residues.
Chemical reviews, 120(18), 10079-10144
Citation
Li, Xiang; Chen, Si; Zhang, Wei-Dong; Hu, Hong-Gang. (2020). Stapled Helical Peptides Bearing Different Anchoring Residues.. Chemical reviews, 120(18), 10079-10144. https://doi.org/10.1021/acs.chemrev.0c00532