Comparison of Oct-2-enyl and Oct-4-enyl Staples for Their Formation and α-Helix Stabilizing Effects

Abstract

The all-hydrocarbon i,i+4 stapling system using an oct-4-enyl crosslink is one of the most widely employed chemical tools to stabilize an α-helical conformation of a short peptide. This crosslinking system has greatly extended our ability to modulate intracellular protein-macromolecule interactions. The helix-inducing property of the i,i+4 staple has shown to be highly dependent on the length and the stereochemistry of the oct-4-enyl crosslink. Here we show that changing the double bond position within the i,i+4 staple has a considerable impact not only on the formation of the crosslink but also on α-helix induction. The data further increases the understanding of the structure-activity relationships of this valuable chemical tool.

An RGD-Containing Peptide Derived from Wild Silkworm Silk Fibroin Promotes Cell Adhesion and Spreading

“…The peptide GSGAGGRGDGGYGSGSS (–RGD–) contains hydrophilic side groups –OH, –NH 2 and –COOH, hence it is easier for peptides with a greater number of –RGD– repeats to form intramolecular hydrogen bonds, leading to a change in molecular conformation into a more stable α-helical structure in (–RGD–) 8 . Many bioactive macromolecules include a high proportion of α-helical structure, and this is often correlated with physicochemical properties [23,24].…”

Regulation of protein–protein interactions using stapled peptides

“…The S 3 -S 7 analog gave improved helicity in comparison to the native sequence; however, it still did not match the helicity shown by the S 5 -S 5 stapled peptide. 57 These results demonstrate that the original oct-4-enyl i, i+4 type staple contains the alkene functionality in the optimal position on the hydrocarbon chain to provide an effective constraint. The i, i+3 all-hydrocarbon staple has also been studied to determine the optimal length of hydrocarbon bridge across one turn of a helix.…”

“…This is due, in part, to the α-methyl-substituent of the alkenyl amino acid inducing the Thorpe-Ingold effect 55,56 on the peptide backbone, as well as the presence of a hydrophobic environment as a result of using nonpolar solvents, which promotes helix formation. 57 Peptides incorporating the α,α-disubstituted amino acid Aib were first described by Karle and Balaram and were shown to adopt 3 10 -helix structures. 25 The α-carbon dimethyl substitution of Aib restricts the torsion angles of the peptide bonds to ϕ=-49° and ψ=-26° in comparison to that of α-helix torsion angles, ϕ=-57° and ψ =-47°.…”

“…57 Linear peptides incorporating a (S)-α-methyl, α-allylglycine (S 3 ) at the i position and (S)-α-methyl, α-heptenylglycine (S 7 ) at the i+4 position provided access to both the oct-2-enyl staple (S 3 -S 7 ) ( Figure 7C) and oct-6-enyl staple (S 7 -S 3 ) ( Figure 7E). Both these peptides failed to undergo RCM to provide the corresponding macrocyclic peptides at room temperature.…”

Macrocyclic α-Helical Peptide Drug Discovery

“…Further investigations of hydrocarbon-stapling chemistry have addressed the specific positioning of the olefin moiety of the cross-linker itself in terms of investigating ring closing metathesis efficiency and helical stabilization. 143 The design of hydrocarbon-stapled peptides requires the synthesis of the a-methyl, a-alkenyl glycines (Figure 9.10) and various chemistry methods have been developed to prepare a,a-dialkyl-amino acids with high enantiomeric purity. 144 Exemplifying one asymmetric synthesis approach as first describing such hydrocarbon-stapling chemistry was that by Verdine and colleagues using a Williams chiral auxiliary to prepare the requisite a,adialkylated-amino acids.…”