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bioRxiv · 10.1101/2021.04.07.438780

Towards customized studies of G-quadruplex DNA structures in live cells

Prasad, B.·Doimo, M.·Andreasson, M.·L Hote, V.·Chorell, E.·Wanrooij, S.
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Abstract

G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of how, when, and why G4 DNA structures form in vivo are largely missing leaving a knowledge gap that requires tailored chemical biology studies in relevant live-cell model systems. Towards this end, we developed a synthetic platform centered around one of the most effective and selective G4 stabilizing compounds, Phen-DC3. We used a structure-based design to equip Phen-DC3 with an amine in a position that does not interfere with G4 interactions. To evaluate the power of the approach, we next used this reactive handle to conjugate a BODIPY fluorophore and a cell-penetrating peptide to Phen-DC3. The BODIPY conjugation generated a fluorescent derivative with retained G4 selectivity, G4 stabilization, and cellular effects that revealed the localization and function of Phen-DC3 in human cells. On the other hand, the cell-penetrating peptide conjugation, while retaining G4 selectivity and stabilization, increased nuclear localization and cellular effects, showcasing the potential of this approach to modulate and direct cellular uptake e.g. as delivery vehicles. The developed platform can thus generate tailored biochemical tools for the studies of G4 biology to uncover molecular details and therapeutic approaches.

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Prasad, B., Doimo, M., Andreasson, M., L Hote, V., Chorell, E., Wanrooij, S.. 2021-04-07. Towards customized studies of G-quadruplex DNA structures in live cells. https://doi.org/10.1101/2021.04.07.438780

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