![]() Walensky discovered that the peptides side-stepped the membrane diffusion issue by crossing the membrane through active endosomal uptake, which deposited the peptides inside of the cell. In collaboration with Edward Taylor of Princeton University, Loren Walensky, who was then a post-doc in Verdine's lab, subsequently demonstrated that stapling BH3 peptides enabled the synthetic peptides to retain their α-helical conformation, further demonstrating that these peptides were taken up by cancer cells and bound their physiologic BCL-2 family targets, which correlated with the induction of cell death. 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. Grubbs and Helen Blackwell in the late 1990s, who used the Grubbs catalyst to cross-link O-allylserine residues in a covalent bond. This variation of olefin metathesis and its application to stapled peptides was developed by Nobel laureate Robert H. ![]() Staples synthesized using ring-closing metathesis (RCM) are common. R isomers shown, but S enantiomers may also be used. Olefin terminated, non-natural amino acids used to as building blocks to form stapled peptides. Various strategies have been employed for constraining α-helices, including the non-covalent and covalent stabilization techniques however, the all-hydrocarbon covalent link, termed a peptide staple, has been shown to have improved stability and cell penetrability, making this stabilization strategy particularly relevant for clinical applications. This approach can increase target affinity, increase cell penetration, and protect against proteolytic degradation. Introducing a synthetic brace (staple) helps to lock a peptide in a specific conformation, reducing conformational entropy. PPIs are frequently misregulated in disease, provides the long-running impetus to create alpha-helical peptides to inhibit disease-state PPIs for clinical applications, as well as for basic science applications. 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. Furthermore, small peptides (such as single alpha-helices or α-Helices) can lose helicity in solution due to entropic factors, which diminishes binding affinity. Additionally, protein and peptides are often subject to proteolytic degradation if they do enter the cell. ![]() Meanwhile, the protein therapeutics that lack these issues are bedeviled by another problem, poor cell penetration due to an insufficient ability to diffuse across the cell membrane. 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. The two primary classes of therapeutics are small molecules and protein therapeutics.
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