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 broadly to G4 structures, while other drugs and druglike compounds can have more selective interactions that may be biologically relevant.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Calabrese DR,Zlotkowski K,Alden S,Hewitt WM,Connelly CM,Wilson RM,Gaikwad S,Chen L,Guha R,Thomas CJ,Mock BA,Schneekloth JS Jrdoi
10.1093/nar/gky084subject
Has Abstractpub_date
2018-04-06 00:00:00pages
2722-2732issue
6eissn
0305-1048issn
1362-4962pii
4898060journal_volume
46pub_type
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