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

Giulio Gasparini, Daniel Abegg, Dominic G. Hoch, Anton Shuster, Eline Bartolami, Stefan Matile, Alexander Adibekian

Risultato della ricerca: Contributo in rivistaArticolo in rivista

57 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)231-238
Numero di pagine8
RivistaJournal of the American Chemical Society
Volume139
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Apoptosis
  • Binding Sites
  • Disulfides
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Receptors, Transferrin
  • Structure-Activity Relationship
  • Thiophenes

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