Peptides make more attractive medicines than proteins or nucleic acids. They have evolved in nature to take on highly specific functions, work with great potency and are far smaller than recombinant proteins and antibodies. But they are inherently unstable chains. As soon as a job is done, they are degraded quickly by proteases—a factor that has tended to limit their utility as pharmaceuticals. “The catch-22 is you want the peptide for its biological activity, but you don't want the peptide for its pharmacological vulnerability,” says Loren Walensky, assistant professor of pediatrics at Harvard Medical School, in Boston, and a member of Aileron's scientific advisory board. Exposure of their amide bonds renders peptides susceptible to proteolytic breakdown, and their polarity makes cell penetration difficult. “The major problem in the discovery of peptide-based drugs has been the ability to get robust cell penetration,” says Gregory Verdine, professor of chemistry at Cambridge-based Harvard University and chairman of Aileron's scientific advisory board. “We're not the first to stabilize helices.”
Stapled peptides are locked into an α-helical—and, thus, a biologically active—conformation. To achieve this, hydrocarbon cross-links are added between two non-natural amino acid residues inserted at each end of the target peptide sequence. A ruthenium-catalyzed olefin metathesis reaction generates the hydrocarbon linkages that impart structural stability to the stapled peptide and render it resistant to proteolytic breakdown. The method is general in its scope. “You can apply this to any peptide that is naturally inclined to be helical,” says Walensky.
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