Cell-Penetrating Peptide–Bismuth Bicycles

02 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Cell-penetrating peptides (CPPs) play a significant role in the delivery of cargos into human cells for a wide range of therapeutic and diagnostic applications. We disclose the first CPPs based on peptide–bismuth bicycles, which can be readily obtained from commercially available peptide precursors, making them highly accessible for a wide range of applications. These CPPs enter mammalian cells with high efficiency as demonstrated by live-cell microscopy using fluorescently labelled peptides. We report highly efficient sequences that demonstrate comparable cellular uptake to conventional CPPs, despite requiring only three positive charges. Bicyclization triggered by the presence of bismuth(III) increases cellular uptake by more than one order of magnitude. Through the analysis of cell lysates using inductive coupled plasma mass spectrometry (ICP-MS), we have introduced an alternative approach to examine the cellular uptake of CPPs without the use of fluorescent dyes. This has allowed us to confirm the presence of bismuth in cells after exposure to our CPPs.


Mass spectrometry

Supplementary materials

Supporting Information
Supplementary figures, schemes and tables. Full description of experiments and compound characterisation.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.