Detailed Explanation
A peptide with a synthetic hydrocarbon cross-link ('staple') that locks it into an alpha-helical conformation. The staple bridges two non-natural amino acids (typically olefin-bearing residues at i and i+4 or i+7 positions) via olefin metathesis.
Stapling dramatically improves three properties: protease resistance (the rigid helix resists enzymatic cleavage), cell permeability (the hydrocarbon staple increases hydrophobicity, enabling membrane crossing), and target affinity (pre-organizing the helix reduces the entropic penalty of binding). Developed by Gregory Verdine's lab at Harvard, stapled peptides are being used to target 'undruggable' intracellular protein–protein interactions. ALRN-6924, a stapled p53-MDM2 peptide, reached Phase II clinical trials for cancer.
Key Facts
- A peptide with a synthetic hydrocarbon cross-link ('staple') that locks it into an alpha-helical conformation.
- The staple bridges two non-natural amino acids (typically olefin-bearing residues at i and i+4 or i+7 positions) via olefin metathesis.
- Stapling dramatically improves three properties: protease resistance (the rigid helix resists enzymatic cleavage), cell permeability (the hydrocarbon staple increases hydrophobicity, enabling membrane crossing), and target affinity (pre-organizing the helix reduces the entropic penalty of binding).
- Developed by Gregory Verdine's lab at Harvard, stapled peptides are being used to target 'undruggable' intracellular protein–protein interactions.
- ALRN-6924, a stapled p53-MDM2 peptide, reached Phase II clinical trials for cancer.
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