Glossary

Stapled Peptide

Structure

Stapled Peptide — A peptide with a hydrocarbon bridge constraining its alpha-helical conformation, improving cell permeability, target affinity, and protease resistance.

What Is a Stapled Peptide?

A stapled peptide is a synthetic peptide containing a hydrocarbon crosslink ("staple") that locks the molecule into an alpha-helical conformation. The technology, developed by Gregory Verdine at Harvard, uses olefin metathesis to connect non-natural amino acids positioned on the same face of the helix (i and i+4 or i and i+7 spacing), creating a covalent tether that stabilizes the helical fold.

Why Staple a Peptide

Helix stabilization: Increases helical content from ~20% (linear) to >90% (stapled), pre-organizing the binding surface
Protease resistance: The hydrocarbon staple blocks protease access to backbone amides, extending half-life
Cell permeability: Stapled peptides show enhanced cellular uptake compared to linear counterparts
Binding affinity: Pre-organization reduces the entropic cost of binding, increasing affinity 10-1000 fold

Research Applications

Stapled peptides target intracellular protein-protein interactions (PPIs) that are considered "undruggable" by small molecules. Notable targets include p53-MDM2/MDMX (cancer), BCL-2 family (apoptosis), and estrogen receptor (hormone signaling). ALRN-6924 (Aileron Therapeutics) reached Phase II clinical trials as a stapled p53-activating peptide.

Frequently Asked Questions

What is Stapled Peptide?

A peptide with a hydrocarbon bridge constraining its alpha-helical conformation, improving cell permeability, target affinity, and protease resistance.

Why is Stapled Peptide important in peptide research?

Stapled Peptide is a fundamental concept in structure as it relates to peptide science. It directly influences experimental design, compound characterization, and the reliability of research outcomes across biochemistry and molecular biology disciplines.

Authority Sources

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