In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications.

Abegg, D., Gasparini, G., Hoch, D. G., Shuster, A., Bartolami, E., Matile, S., Adibekian, A., Strained cyclic disulfides enable cellular uptake by reacting with the transferrin receptor, <<JOURNAL OF THE AMERICAN CHEMICAL SOCIETY>>, 2017; 139 (1): 231-238. [doi:10.1021/jacs.6b09643] [http://hdl.handle.net/10807/170782]

Strained cyclic disulfides enable cellular uptake by reacting with the transferrin receptor

Gasparini, Giulio;
2017

Abstract

In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure efficient cellular uptake and intracellular distribution of fully unprotected peptides. We apply this new delivery method to induce apoptotic response in cancer cells using long (up to 20mer) BH3 domain peptides. Moreover, to understand the molecular mechanism of the cellular uptake, we perform chemical proteomics experiments and identify the direct molecular targets of the asparagusic acid tag. Our findings document covalent bond formation between the asparagusic acid moiety and the cysteines 556 and 558 on the surface of the transferrin receptor resulting in subsequent endocytic uptake of the payload. We believe that the small size, low cellular toxicity and the efficient transferrin receptor-mediated uptake render the AspA tag highly attractive for various life science applications.
2017
Inglese
Abegg, D., Gasparini, G., Hoch, D. G., Shuster, A., Bartolami, E., Matile, S., Adibekian, A., Strained cyclic disulfides enable cellular uptake by reacting with the transferrin receptor, <<JOURNAL OF THE AMERICAN CHEMICAL SOCIETY>>, 2017; 139 (1): 231-238. [doi:10.1021/jacs.6b09643] [http://hdl.handle.net/10807/170782]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/170782
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