Cell-Penetrating Peptide-Bismuth Bicycles

Cell-penetrating peptides (CPPs) play a significant role in the delivery of cargos into human cells. We report the first CPPs based on peptide-bismuth bicycles, which can be readily obtained from commercially available peptide precursors, making them accessible for a wide range of applications. These CPPs enter mammalian cells as demonstrated by live-cell microscopy using fluorescently labelled peptides. We report efficient sequences that demonstrate increased cellular uptake compared to conventional CPPs like the TAT peptide (derived from the transactivating transcriptional activator of human immunodeficiency virus 1) or octaarginine (R8), 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. This has allowed us to confirm the presence of bismuth in cells after exposure to our CPPs. Mechanistic studies indicated an energy-dependent endocytic cellular uptake sensitive to inhibition by rottlerin, most likely involving macropinocytosis.

 

Comments:

Wow, that's fascinating! The use of peptide-bismuth bicycles as cell-penetrating peptides (CPPs) sounds innovative. Creating CPPs from commercially available peptide precursors for various applications opens up exciting possibilities. It's impressive that these peptides demonstrate increased cellular uptake compared to conventional ones like TAT peptide and octaarginine, especially with only three positive charges.

The utilization of live-cell microscopy with fluorescently labeled peptides for visualization adds a dynamic aspect to understanding their mechanisms. The substantial increase in cellular uptake due to bicyclization triggered by bismuth(III) is quite noteworthy.

Additionally, employing inductive coupled plasma mass spectrometry (ICP-MS) to analyze cell lysates for confirming bismuth presence after exposure to CPPs seems like a robust method. This innovative approach might provide deeper insights into cellular uptake mechanisms and peptide localization within cells.

The revelation about the energy-dependent endocytic cellular uptake, possibly involving macropinocytosis and sensitivity to rottlerin inhibition, offers a glimpse into the mechanism behind the enhanced uptake of these peptides.

Overall, this research seems promising in advancing our understanding of CPPs and their potential in cellular delivery systems. The combination of innovative techniques and the utilization of bismuth(III) for enhancing cellular uptake opens avenues for further exploration and application in various biomedical fields.

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Cat.No.	Product Name	Information
S7862	Rottlerin	Rottlerin (Mallotoxin, NSC 56346, NSC 94525), a natural compound purified from Mallotus Philippinensis, is a specific Protein kinase inhibitor with IC50 of 3 μM, 6 μM and 5.3 μM for PKCδ(from baculovirus-infected Sf9 insect cells), PKCδ(from porcine spleen) and CaM kinase III, respectively. Rottlerin also inhibits PKCα, PKCγ, PKCβ, PKCη, CKII and PKA with IC50 of 30 μM, 40 μM, 42 μM, 82 μM, 30 μM and 78 μM, respectively.

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PKC