Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis

Jie Zhou, Xuewen Du, Cristina Berciu, Steven J. Del Signore, Xiaoyi Chen, Natsuko Yamagata, Avital A. Rodal, Daniela Nicastro, Bing Xu

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Most of the peptides used for promoting cellular uptake bear positive charges. In our previous study, we reported an example of taurine (bearing negative charges in physiological conditions) promoting cellular uptake of D-peptides. Taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide. Particularly, intracellular carboxylesterase (CES) instructs the D-peptide to self-assemble and to form nanofibers, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide, as supported by that the addition of CES inhibitors partially impaired cellular uptake of this molecule in mammalian cell lines. Using dynamin 1, 2, and 3 triple knockout (TKO) mouse fibroblasts, we demonstrated that cells took up this molecule via macropinocytosis and dynamin-dependent endocytosis. Imaging of Drosophila larval blood cells derived from endocytic mutants confirmed the involvement of multiple endocytosis pathways. Electron microscopy (EM) indicated that the precursors can form aggregates on the cell surface to facilitate the cellular uptake via macropinocytosis. EM also revealed significantly increased numbers of vesicles in the cytosol. This work provides new insights into the cellular uptake of taurine derivative for intracellular delivery and self-assembly of D-peptides. Zhou et al. demonstrate that taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide via multiple endocytosis pathways for intracellular carboxylesterase (CES)-instructed self-assembly, which largely disfavors efflux and further enhances the intracellular accumulation of the D-peptide.

Original languageEnglish (US)
Pages (from-to)648-658
Number of pages11
JournalMolecular Therapy
Volume26
Issue number2
DOIs
StatePublished - Feb 7 2018

Keywords

  • TEM
  • endocytosis
  • enzymes
  • esterase
  • macropinocytosis
  • peptides
  • self-assembly
  • taurine

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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