Stereochemical effects of all-hydrocarbon tethers in i,i+4 stapled peptides

The stereochemical effects of the hydrocarbon crosslink on the conformation and cellular uptake of i,i+4 stapled peptides were studied. Compared to its S,S-configurated counterpart, the crosslink bearing the R,R-configuration provided a significantly diminished helix stabilizing effect and conferred less efficient cellular uptake on the stapled peptides. These results suggest that the vesicular trafficking pathway employed by cells to take up stapled peptides is sensitive to the extent of helical character in the peptide, with greater helicity conferring increased cellular uptake.

An analysis of stereochemical effects of the hydrocarbon crosslink on the helical stability and cellular uptake of i,i+4 stapled peptides reveals that S,S is superior in both respects to R,R.Figure optionsDownload as PowerPoint slide