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Cell-surface thiols affect cell entry of disulfide-conjugated peptides

Soline Aubry^*,, Fabienne Burlina^*,, Edmond Dupont, Diane Delaroche^*,, Alain Joliot, Solange Lavielle^*,, Gérard Chassaing^*, and Sandrine Sagan^*,,1

^* UPMC Université Paris 06, UMR 7613, Synthesis, Structure, and Function of Bioactive Molecules, Paris, France;

CNRS, UMR 7613, Synthesis, Structure, and Function of Bioactive Molecules, Paris, France; and

Ecole Normale Supérieure, CNRS UMR 8542, Homeoprotein Cell Biology, Paris, France

¹ Correspondence: UPMC, Case courier 182, 4 place Jussieu, 75005 Paris, France. E-mail: sandrine.sagan{at}upmc.fr

Cell-penetrating peptides (CPPs) can cross the cell membrane and are widely used to deliver bioactive cargoes inside cells. The cargo and the CPP are often conjugated through a disulfide bridge with the common acceptation that this linker is stable in the extracellular biological medium and should not perturb the internalization process. However, with the use of thiol-specific reagents combined with mass spectrometry (as a quantitative method to measure intracellular concentrations of peptides) and confocal microscopy (as a qualitative method to visualize internalized peptides) analyses, we could show that, depending on the peptide sequence, thiol/disulfide exchange reactions could happen at the cell surface. These exchange reactions lead to the reduction of disulfide conjugates. In addition, it was observed that not only disulfide- but also thiol-containing peptides could cross-react with cell-surface thiols. The peptides cross-linked by thiol-containing membrane proteins were either trapped in the membrane or further internalized. Therefore, a new route of cellular uptake was unveiled that is not restricted to CPPs: a protein kinase C peptide inhibitor that is not cell permeant could cross cell membranes when an activated cysteine (with a 3-nitro-2-pyridinesulfenyl moiety) was introduced in its sequence.—Aubry, S., Burlina, F., Dupont, E., Delaroche, D., Joliot, A., Lavielle, S., Chassaing, G., Sagan, S. Cell-surface thiols affect cell entry of disulfide-conjugated peptides.

Key Words: CPP • redox potential • MALDI-TOF MS

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				C.-Y. Jiao, D. Delaroche, F. Burlina, I. D. Alves, G. Chassaing, and S. Sagan Translocation and Endocytosis for Cell-penetrating Peptide Internalization J. Biol. Chem., December 4, 2009; 284(49): 33957 - 33965. [Abstract] [Full Text] [PDF]