A DNA-binding artificial ion channel selectively inhibits cancer cell growth

Peptidomimetics, synthetic molecules designed to mimic the structure and function of peptides, offer promising avenues for therapeutic applications. These molecules can be engineered to interact with biological systems in specific ways, such as targeting DNA structures or forming transmembrane channels.

One area of particular interest is their potential to treat cancer by stabilizing G-quadruplex (G4) DNA structures, which play a crucial role in regulating oncogene expression. Traditional treatments face limitations in effectively targeting these structures, creating a need for innovative peptidomimetic solutions.

A recent study introduced a novel thiazole-based peptidomimetic, TBP2, which forms self-assembling ion channels, significantly impacting cellular functions, particularly in cancer cells.

Confocal microscopy on Giant Unilamellar Vesicles (GUVs, prepared with Vesicle Prep Pro) and cervical carcinoma HeLa cells revealed that TBP2 effectively embeds within the GUVs, cell membranes, and cell nuclei.

Patch-clamp experiments on GUVs conducted with the Port-a-Patch system demonstrated that TBP2 efficiently facilitated the transport of sodium and potassium ions across the GUV membrane, confirming TBP2’s capability to form functional ion channels with high conductance (~0.6 nS for Na+ and ~0.68 nS for K+).

Importantly, TBP2 was shown to selectively bind to and stabilize G-quadruplex (G4) structures (particularly the c-MYC22 G4) in several cancer cell lines, triggering cancer cell death. Intriguingly, TBP2 did not inhibit the growth of normal kidney epithelial (NKE) and HEK293T cells up to 100 µM and exhibited selective cytotoxicity towards cancer cells.

Overall, this study highlighted TBP2 as a potent synthetic peptidomimetic that not only transports ions effectively but also interacts with DNA structures to regulate gene expression. This dual functionality opens new avenues for developing peptidomimetics with therapeutic applications, particularly in targeting cancer cells through ion transport and G-quadruplex stabilization.

Find the full article here: https://www.nature.com/articles/s41467-024-49534-0

Learn more about automated preparation of solvent-free GUVs with the Vesicle Prep Pro: https://www.nanion.de/products/vesicle-prep-pro/

Discover patch clamp solutions from Nanion: https://www.nanion.de/product-categories/automated-patch-clamp/