Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies |
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Authors: | Laurence Dutot Pascaline Lécorché Fabienne Burlina Rodrigue Marquant Vanessa Point Sandrine Sagan Gérard Chassaing Jean-Maurice Mallet Solange Lavielle |
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Institution: | 1.UPMCParis06—CNRS—ENS, UMR 7203 “Laboratoire des BioMolécules” and FR2769 “Chimie Moléculaire”,Université Pierre et Marie Curie,Paris,France;2.ENS—CNRS—UPMCParis06, UMR 7203 “Laboratoires des BioMolécules” and “Département de Chimie”,Paris,France |
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Abstract: | Cell-penetrating peptides (CPPs), which are usually short basic peptides, are able to cross cell membranes and convey bioactive
cargoes inside cells. CPPs have been widely used to deliver inside cells peptides, proteins, and oligonucleotides; however,
their entry mechanisms still remain controversial. A major problem concerning CPPs remains their lack of selectivity to target
a specific type of cell and/or an intracellular component. We have previously shown that myristoylation of one of these CPPs
affected the intracellular distribution of the cargo. We report here on the synthesis of glycosylated analogs of the cell-penetrating
peptide (R6/W3): Ac-RRWWRRWRR-NH2. One, two, or three galactose(s), with or without a spacer, were introduced into the sequence of this nonapeptide via a triazole link, the Huisgen reaction being achieved on a solid support. Four of these glycosylated CPPs were coupled via a disulfide bridge to the proapoptotic KLAK peptide, (KLAKLAKKLAKLAK), which alone does not enter into cells. The effect
on cell viability and the uptake efficiency of different glycosylated conjugates were studied on CHO cells and were compared
to those of the nonglycosylated conjugates: (R6/W3)S-S-KLAK and penetratinS-S-KLAK. We show that glycosylation significantly
increases the cell viability of CHO cells compared to the nonglycosylated conjugates and concomitantly decreases the internalization
of the KLAK cargo. These results suggest that glycosylation of CPP may be a key point in targeting specific cells. |
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