Stabilization of human telomeric RNA G-quadruplex by the water-compatible optically pure and biologically-active metallohelices

Jaroslav Malina,Peter Scott,Viktor Brabec

doi:10.1038/s41598-020-71429-5

Jaroslav Malina, Peter Scott + Show 1 more

Open Access

https://doi.org/10.1038/s41598-020-71429-5

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Abstract

RNA G-quadruplexes have been suggested to play key roles in fundamental biological processes and are linked to human diseases. Thus, they also represent good potential therapeutic targets. Here, we describe, using the methods of molecular biophysics, interactions of a series of biologically-active supramolecular cationic metallohelices with human telomeric RNA G-quadruplex. We demonstrate that the investigated metallohelices bind with a high affinity to human telomeric RNA G-quadruplex and that their binding selectivity considerably differs depending on the dimensions and overall shape of the metallohelices. Additionally, the investigated metallohelices inhibit DNA synthesis on the RNA template containing four repeats of the human telomeric sequence by stabilizing the RNA G-quadruplex structure. Collectively, the results of this study suggest that stabilization of RNA sequences capable of G-quadruplex formation by metallohelices investigated in this work might contribute to the mechanism of their biological activity.

Highlights

RNA G-quadruplexes have been suggested to play key roles in fundamental biological processes and are linked to human diseases
The binding affinities of 5a–h towards telomeric RNA quadruplex (TERRA) G-quadruplex were evaluated by using the fluorescent intercalator displacement (FID) assay
The addition of metallohelices resulted in a decrease in the fluorescence intensity due to the displacement of bound thiazole orange (TO), where the percent fluorescence reduction is directly related to the extent of binding

Summary

Introduction

RNA G-quadruplexes have been suggested to play key roles in fundamental biological processes and are linked to human diseases. We demonstrate by using FRET melting assays, FID assays, gel electrophoresis and other methods that 5a–h are able to recognize and stabilize human telomeric RNA (TERRA) G-quadruplex.

Results

Conclusion