G-quadruplex-containing oligodeoxynucleotides as DNA topoisomerase I inhibitors

DNA topoisomerase I was found to be highly abundant in fast-proliferating tumor cells and is a potential target for anticancer therapy. A series of G-quadruplex-containing oligodeoxynucleotides (ODNs) were designed and used as inhibitors of DNA topoisomerase I. It was demonstrated that ODNs with G-q...

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Bibliographic Details
Published in:International journal of biological macromolecules 2022-12, Vol.223 (Pt A), p.281-289
Main Authors: Li, Dawei, Chen, Xiyu, Yan, Rumeng, Jiang, Zeshan, Zhou, Bing, Lv, Bei
Format: Article
Language:English
Subjects:
DNA - chemistry
DNA Topoisomerases, Type I
G-quadruplex
G-Quadruplexes
Inhibitor
Oligodeoxynucleotide
Oligodeoxyribonucleotides - chemistry
Oligodeoxyribonucleotides - pharmacology
Supercoiled DNA relaxation
Topoisomerase I
Topoisomerase I Inhibitors - pharmacology
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Summary:DNA topoisomerase I was found to be highly abundant in fast-proliferating tumor cells and is a potential target for anticancer therapy. A series of G-quadruplex-containing oligodeoxynucleotides (ODNs) were designed and used as inhibitors of DNA topoisomerase I. It was demonstrated that ODNs with G-quadruplexes can efficiently inhibit the supercoiled DNA relaxation reaction catalyzed by DNA topoisomerase I. Compared with the other conformations, the parallel propeller-type G-quadruplex was the most efficient DNA topoisomerase I inhibitor. Further studies revealed that integrating G-quadruplexes with duplexes to form quadruplex-duplex hybrids could significantly improve the inhibition efficiency. In addition, a circular ODN that consists of a G-quadruplex motif and DNA topoisomerase I binding site was synthesized and used as a DNA topoisomerase I inhibitor. The results showed that the particularly designed circular ODN displayed high inhibitory efficiency on the activity of DNA topoisomerase I with an IC50 value of 54.8 nM. Moreover, the circular ODN exhibited excellent thermal stability and nuclease resistance. Considering the low cytotoxicity of DNA-based biopharmaceuticals, the design strategy and results reported in this study may shed new light on nucleic acid-based DNA topoisomerase I inhibitor construction for potential anticancer drugs.
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2022.11.025