A switchable stapled peptide

Abstract

The O-N acyl transfer reaction has gained significant popularity in peptide and medicinal chemistry. This reaction has been successfully applied to the synthesis of difficult sequence-containing peptides, cyclic peptides, epimerization-free fragment coupling and more recently, to switchable peptide polymers. Herein, we describe a related strategy to facilitate the synthesis and purification of a hydrophobic stapled peptide. The staple consists of a serine linked through an amide bond formed from its carboxylic acid function and the side chain amino group of diaminopropionic acid and through an ester bond formed from its amino group and the side chain carboxylic acid function of aspartic acid. The α-amino group of serine was protonated during purification. Interestingly, when the peptide was placed at physiological pH, the free amino group initiated the O-N shift reducing the staple length by one atom, leading to a more hydrophobic stapled peptide.

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

“…In these applications, the isoacyl motif was inserted into the thioester segment, C‐terminal segment, or the peptide hydrazide that served as a thioester precursor . One recent application was also reported for a side‐chain stapled peptide, in which the isoacyl motif was inserted as part of the cross‐linker placed between the i and i +4 positions …”

“…[85] One recent applicationw as also reported for as ide-chain stapled peptide, in which the isoacyl motif was inserted as part of the cross-linker placed between the i and i+ +4p ositions. [86]…”