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. 2024 Oct 7;21(10):5255-5260.
doi: 10.1021/acs.molpharmaceut.4c00688. Epub 2024 Sep 2.

Bismuth-Cyclized Cell-Penetrating Peptides

Jeremy L Ritchey  1 , Lindsi Filippi  1 , Davis Ballard  1 , Dehua Pei  1
Affiliations

Bismuth-Cyclized Cell-Penetrating Peptides

Jeremy L Ritchey et al. Mol Pharm. .

Abstract

Intracellular delivery of biological cargos, which would yield new research tools and novel therapeutics, remains an active area of research. A convenient and potentially general approach involves the conjugation of a cell-penetrating peptide to a cargo of interest. However, linear CPPs lack sufficient cytosolic entry efficiency and metabolic stability, while previous backbone cyclized CPPs have several drawbacks including the necessity for chemical synthesis and posttranslational conjugation to peptide/protein cargos and epimerization during cyclization. We report here a new class of bismuth cyclized CPPs with excellent cytosolic entry efficiencies, proteolytic stability, and potential compatibility with genetic encoding and recombinant production.

Keywords: bismuth; cell-penetrating peptides; drug delivery; endosomal escape; peptide cyclization.

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Conflict of interest statement

The authors declare the following financial interest(s): D.P. and J.R. have filed a patent application on the findings of this work (US2023/029093). D.P. is Co-Founder and equity holder of Entrada Therapeutics, Syneron Tech, Permeasis Therapeutics, and Scioto AgriTech.

Figures

Figure 1.
Figure 1.
(A) Structures of Tat and CPP12. (B) Structure and synthesis of BCP16. (C) UPLC chromatograms of BCP16 before (top) and after Bi3+ mediated cyclization (bottom).
Figure 2.
Figure 2.
Proteolytic stability of BCP15–17 (t1/2 = 0.9, 26, and 3.4 h, respectively) in 25% human serum diluted in PBS. Data shown represent the mean and standard deviation of three independent sets of experiments (n = 3).
Figure 3.
Figure 3.
Representative live-cell confocal microscopic images of HeLa cells after treatment with 5 μM CPP12TMR or BCP16TMR for 2 h in the presence of 1% FBS. Scale bar, 5 μm.
Figure 4.
Figure 4.
Inhibition of the Keap1-Nrf2 interaction in HepG2 cells by peptides P1, CPP12-P1, and BCP16-P1 as monitored by the ARE reporter assay. (A) Structure of BCP16-P1. (B) Comparison of the three peptides for their ability to increase the transcriptional activity of Nrf2 in HepG2 cells in a serum-free medium. (C) Same as (B) but in the presence of 10% FBS. Data reported represent the mean ± SD of three biological replicates (n = 3).
Figure 5.
Figure 5.
Effect of CPP12, BCP16, and CBS on the viability of HeLa cells. All values reported are relative to that of vehicle (no peptide, 100%) and represent the mean and standard deviation of three independent sets of experiments (n = 3).
See this image and copyright information in PMC

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