Stapled peptide

The design of small molecule inhibitors of protein-protein interactions has been impeded by issues such as the general lack of small-molecule starting points for drug design, the typical flatness of the interface, the difficulty of distinguishing real from artifactual binding, and the size and character of typical small-molecule libraries.

Furthermore, small peptides (such as single alpha-helices or α-helices) can lose helicity in solution due to entropic factors, which diminishes binding affinity.

[5] α-Helices are the most common protein secondary structure and play a key role in mediating many protein–protein interactions (PPIs) by serving as recognition motifs.

[10] In 2000, Gregory Verdine and colleagues reported the first synthesis of an all-hydrocarbon cross-link for peptide α-helix stabilization, combining the principles of RCM with α,α-disubstitution of the amino acid chiral carbon and on-resin peptide synthesis.

[21][22] In 2013, Aileron Therapeutics, which was co-founded by Verdine, Walensky and Taylor, completed the first stapled peptide clinical trial with their growth-hormone-releasing hormone agonist ALRN-5281.

A cartoon depiction of a stapled peptide. The red coloring depicts a helix, and the green coloring denotes the hydrocarbon staple. Rendering based on PDB 4MZK ​. [ 1 ]
Olefin terminated, non-natural amino acids used to as building blocks to form stapled peptides. R isomers shown, but S enantiomers may also be used. [ 8 ]