title: Preferential uptake of L- versus D-amino acid cell-penetrating peptides in a cell type-dependent manner.
abstract: 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.
authors.affiliation: Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
authors.forename: Wouter P R
authors.initials: WP
authors.lastname: Verdurmen
authors.forename: Petra H
authors.initials: PH
authors.lastname: Bovee-Geurts
authors.forename: Parvesh
authors.initials: P
authors.lastname: Wadhwani
authors.forename: Anne S
authors.initials: AS
authors.lastname: Ulrich
authors.forename: Mattias
authors.initials: M
authors.lastname: Hällbrink
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Roland
authors.initials: R
authors.lastname: Brock
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D057846:Cell-Penetrating Peptides; D006497:Heparan Sulfate; D009569:Nitric Oxide