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Issue 3, 2019
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Click to enter: activation of oligo-arginine cell-penetrating peptides by bioorthogonal tetrazine ligations

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Abstract

Cell-penetrating peptides are able to transport a wide variety of cargo across cell membranes. Although promising, they are not often considered for therapeutic purposes as they lack controllable activity and cell selectivity. We have developed an activation strategy based on a split octa-arginine cell-penetrating peptide (CPP) that can be activated by means of bioorthogonal ligation. To this end we prepared two non-penetrating tetra-arginine halves, functionalized either with a tetrazine or with a complementary bicyclo[6.1.0]nonyne (BCN) group. We demonstrate that an active octa-arginine can be reconstituted in situ upon mixing the complementary split peptides. The resulting activated peptide is taken up as efficiently as the well-established cell-penetrating peptide octa-arginine. The activation of the oligo-arginines can also be achieved using trans-cyclooctene (TCO) as a ligation partner, while norbornene appears too kinetically slow for use in situ. We further show that this strategy can be applied successfully to transport a large protein into living cells. Our results validate a promising first step in achieving control over cell penetration and to use CPPs for therapeutic approaches.

Graphical abstract: Click to enter: activation of oligo-arginine cell-penetrating peptides by bioorthogonal tetrazine ligations

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Supplementary files

Article information


Submitted
03 Oct 2018
Accepted
24 Oct 2018
First published
24 Oct 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 701-705
Article type
Edge Article

Click to enter: activation of oligo-arginine cell-penetrating peptides by bioorthogonal tetrazine ligations

S. A. Bode, S. B. P. E. Timmermans, S. Eising, S. P. W. van Gemert, Kimberly M. Bonger and D. W. P. M. Löwik, Chem. Sci., 2019, 10, 701
DOI: 10.1039/C8SC04394A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

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    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
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    [Original citation] - Published by the PCCP Owner Societies.
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    [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
  • For reproduction of material from all other RSC journals:
    [Original citation] - Published by The Royal Society of Chemistry.

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