Characterization of clinically used oral antiseptics as quadruplex-binding ligands

Nucleic Acids Research
David R CalabreseJohn S Schneekloth

Abstract

Approaches to characterize the nucleic acid-binding properties of drugs and druglike small molecules are crucial to understanding the behavior of these compounds in cellular systems. Here, we use a Small Molecule Microarray (SMM) profiling approach to identify the preferential interaction between chlorhexidine, a widely used oral antiseptic, and the G-quadruplex (G4) structure in the KRAS oncogene promoter. The interaction of chlorhexidine and related drugs to the KRAS G4 is evaluated using multiple biophysical methods, including thermal melt, fluorescence titration and surface plasmon resonance (SPR) assays. Chlorhexidine has a specific low micromolar binding interaction with the G4, while related drugs have weaker and/or less specific interactions. Through NMR experiments and docking studies, we propose a plausible binding mode driven by both aromatic stacking and groove binding interactions. Additionally, cancer cell lines harbouring oncogenic mutations in the KRAS gene exhibit increased sensitivity to chlorhexidine. Treatment of breast cancer cells with chlorhexidine decreases KRAS protein levels, while a KRAS gene transiently expressed by a promoter lacking a G4 is not affected. This work confirms that known ligands bind b...Continue Reading

References

Nov 1, 1978·Antimicrobial Agents and Chemotherapy·M R MoodyP H Wiernik
May 8, 1997·Nature·J M GottesfeldP B Dervan
Dec 7, 2000·Molecular Cell·S JanssenU K Laemmli
Nov 13, 2003·Angewandte Chemie·Jochen WiesnerMartin Schlitzer
Sep 16, 2005·Journal of Applied Microbiology·P Gilbert, L E Moore
Apr 25, 2006·Journal of Endodontics·Matthias Zehnder
Oct 3, 2006·Nucleic Acids Research·Sarah BurgeStephen Neidle
Feb 27, 2007·Nature Chemical Biology·Sunita KumariShankar Balasubramanian
Nov 6, 2007·Toxicology in Vitro : an International Journal Published in Association with BIBRA·M GiannelliA Tani
Jan 10, 2008·Journal of Medicinal Chemistry·Anthony M GiannettiMichelle F Browner
Mar 26, 2008·Chemical Reviews·Jason R Thomas, Paul J Hergenrother
Apr 2, 2011·Nature Reviews. Drug Discovery·Shankar BalasubramanianStephen Neidle
Dec 22, 2011·ACS Chemical Biology·Lirui Guan, Matthew D Disney
Mar 17, 2012·Bioorganic & Medicinal Chemistry Letters·Khondaker M RahmanDavid E Thurston
Jul 14, 2012·Organic & Biomolecular Chemistry·Sebastian MüllerShankar Balasubramanian
Sep 29, 2012·Current Pharmaceutical Design·Dáimel Castillo-GonzálezMiguel-Angel Cabrera-Pérez
Jun 12, 2013·PloS One·Wataru YoshidaKazunori Ikebukuro
Oct 11, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Joanna BidzinskaMarco Folini
Jan 24, 2014·Journal of the American Chemical Society·Prashansa AgrawalDanzhou Yang
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lesley A Mathews GrinerCraig J Thomas
May 13, 2014·Bioorganic & Medicinal Chemistry Letters·Stephan A Ohnmacht, Stephen Neidle
May 14, 2014·Journal of the American Chemical Society·Joanna Sztuba-SolinskaJohn S Schneekloth
Sep 23, 2014·Biochimica Et Biophysica Acta·Prachi AgarwalaSouvik Maiti
Dec 3, 2014·Nucleic Acids Research·Dengguo WeiStephen Neidle
Apr 17, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Frank McCormick
Sep 30, 2015·Nature·John A HoweTerry Roemer
Feb 4, 2016·Journal of Medicinal Chemistry·Stephen Neidle
Apr 26, 2016·Methods : a Companion to Methods in Enzymology·Fardokht A Abulwerdi, John S Schneekloth
Jun 2, 2016·Nature Communications·Wang-Yong YangMatthew D Disney
Jul 14, 2016·Journal of the American Chemical Society·Yousuke KatsudaMotonari Uesugi
Aug 28, 2016·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Li-Na Wen, Meng-Xia Xie

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Citations

May 21, 2019·Nucleic Acids Research·Ashok NuthanakantiSeergazhi G Srivatsan
Sep 6, 2019·Current Topics in Medicinal Chemistry·Hai-Zhou WuYan Cheng
Jan 17, 2019·MedChemComm·Sara N JourneyJohn S Schneekloth
Jan 9, 2019·ACS Chemical Biology·Fardokht A AbulwerdiStuart F J Le Grice

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Methods Mentioned

BETA
GTPase
circular dichroism
Fluorescence
NMR
chip
Assay
transfection
fluorescence titration assay
surface plasmon resonance
thermal melt

Software Mentioned

WaterLOGSY
MestReNova
GraphPad Prism
PocketFinder
ICM

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