Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity

Author:

Wu, Guanhui [ORCID]

Tillo, Desiree [ORCID]

Ray, Sreejana

Chang, Ta-Chau [ORCID]

Schneekloth,Jay

Vinson, Charles

Yang, Danzhou [ORCID]
Author Address

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USA., Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Institute of Atomic and Molecular Sciences, Academia Sinica, P.O. Box 23-166, Taipei 106, Taiwan., Chemical Biology Laboratory, National Cancer Institute-Frederick, Frederick, MD 21702, USA., Purdue Center for Cancer Research, West Lafayette, IN 47906, USA., Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.,

Abstract:

G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3 39;-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition.

See More

Author Address