Preferential uptake of L- versus D-amino acid cell-penetrating peptides in a cell type-dependent manner

Chem Biol. 2011 Aug 26;18(8):1000-10. doi: 10.1016/j.chembiol.2011.06.006.


The use of protease-resistant D-peptides is a prominent strategy for overcoming proteolytic sensitivity in the use of cell-penetrating peptides (CPPs) as delivery vectors. So far, no major differences have been reported for the uptake of L- and D-peptides. Here we report that cationic L-CPPs are taken up more efficiently than their D-counterparts in MC57 fibrosarcoma and HeLa cells but not in Jurkat T leukemia cells. Reduced uptake of D-peptides co-occurred with persistent binding to heparan sulfates (HS) at the plasma membrane. In vitro binding studies of L- and D-peptides with HS indicated similar binding affinities. Our results identify two key events in the uptake of CPPs: binding to HS chains and the initiation of internalization. Only the second event depends on the chirality of the CPP. This knowledge may be exploited for a stereochemistry-dependent preferential targeting of cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / metabolism
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell-Penetrating Peptides / chemistry*
  • Cell-Penetrating Peptides / metabolism*
  • Heparitin Sulfate / metabolism
  • Humans
  • Nitric Oxide / metabolism
  • Stereoisomerism


  • Amino Acids
  • Cell-Penetrating Peptides
  • Nitric Oxide
  • Heparitin Sulfate