Publication 263

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  1. Abegg, D.; Gasparini, G.; Hoch, D.; Shuster, A.; Bartolami, E.; Matile, S.; Adibekian, A. “Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor” J. Am. Chem. Soc. 2017, 139, 231-238

In this study, we demonstrate that appendage of a single asparagusic acid residue (AspA tag) is sufficient to ensure effi-cient celullar 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, in order to under-stand 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 aspar-agusic acid moiety and the cysteines 556 and C558 on the surface of the transferrin receptor resulting in subsequent en-docytic 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.

DOI: 10.1021/jacs.6b09643 

open archive unige:90971 • pdf