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Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies

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Journal of Chemical Biology

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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Acknowledgment

The authors greatly acknowledge Lynda Millstine’s contribution in editing this manuscript.

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Authors and Affiliations

  1. UPMCParis06—CNRS—ENS, UMR 7203 “Laboratoire des BioMolécules” and FR2769 “Chimie Moléculaire”, Université Pierre et Marie Curie, 4 place Jussieu, 75005, Paris, France

    Laurence Dutot, Pascaline Lécorché, Fabienne Burlina, Rodrigue Marquant, Vanessa Point, Sandrine Sagan, Gérard Chassaing & Solange Lavielle

  2. ENS—CNRS—UPMCParis06, UMR 7203 “Laboratoires des BioMolécules” and “Département de Chimie”, 24, Rue Lhomond, 75005, Paris, France

    Jean-Maurice Mallet

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  1. Laurence Dutot
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  2. Pascaline Lécorché
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  3. Fabienne Burlina
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  4. Rodrigue Marquant
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  5. Vanessa Point
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  9. Solange Lavielle
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Correspondence to Solange Lavielle.

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Laurence Dutot and Pascaline Lécorché contributed equally

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Dutot, L., Lécorché, P., Burlina, F. et al. Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies. J Chem Biol 3, 51–65 (2010). https://doi.org/10.1007/s12154-009-0031-9

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