Stapled peptides are synthetic 'mini-proteins' that are locked into their bioactive α-helical secondary structure, so conferring high specificity, high potency and resistance to enzymatic degradation. They target protein-protein interactions (PPIs), opening up a range of targets that were previously considered to be undruggable.
Peptides are an alternative class of drug molecule, which are being used to therapeutically target previously undruggable protein-protein interactions (PPIs). The interacting surfaces of PPIs are shallow/flat, large and non-hydrophobic making them ideal targets for peptides, which are able to mimic a native protein. Peptides are highly selective, but often suffer from poor cell permeability, plasma stability and bioavailability.
Stapling a peptide overcomes these limitations by the formation of a synthetic mini-protein, which is locked into a bioactive α-helical secondary structure by site-specific insertion of a chemical 'brace'. Chemical restriction of conformation in this way improves the pharmacological properties of peptides. Stapled peptides possess:
- Increased potency due to stabilization of favorable binding conditions
- Decreased enzymatic degradation due to blockade of protease active sites
- Improved selectivity for intended target decreasing off-target effects
- Improved affinity on an atomic level without requiring additional interactions
Targeting protein-protein interactions (PPIs) with stapled peptides opens an expanded range of targets for therapeutic intervention, which were previously considered to be undruggable. Transcription factors which were thought to be undruggable have been successfully inhibited by stapled peptides; for example, ALRN-6924 is under clinical development as an anti-cancer drug targeting HDM2/p53. Stapled peptides have also been designed to disrupt enzymes, multidrug resistance efflux pumps and membrane receptor dimers.