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

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...

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Autores principales: Wu, Guanhui, Tillo, Desiree, Ray, Sreejana, Chang, Ta-Chau, Schneekloth, John S., Vinson, Charles, Yang, Danzhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436161/
https://www.ncbi.nlm.nih.gov/pubmed/32751510
http://dx.doi.org/10.3390/molecules25153465
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author Wu, Guanhui
Tillo, Desiree
Ray, Sreejana
Chang, Ta-Chau
Schneekloth, John S.
Vinson, Charles
Yang, Danzhou
author_facet Wu, Guanhui
Tillo, Desiree
Ray, Sreejana
Chang, Ta-Chau
Schneekloth, John S.
Vinson, Charles
Yang, Danzhou
author_sort Wu, Guanhui
collection PubMed
description 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′-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.
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spelling pubmed-74361612020-08-24 Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity Wu, Guanhui Tillo, Desiree Ray, Sreejana Chang, Ta-Chau Schneekloth, John S. Vinson, Charles Yang, Danzhou Molecules Article 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′-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. MDPI 2020-07-30 /pmc/articles/PMC7436161/ /pubmed/32751510 http://dx.doi.org/10.3390/molecules25153465 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Guanhui
Tillo, Desiree
Ray, Sreejana
Chang, Ta-Chau
Schneekloth, John S.
Vinson, Charles
Yang, Danzhou
Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title_full Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title_fullStr Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title_full_unstemmed Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title_short Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
title_sort custom g4 microarrays reveal selective g-quadruplex recognition of small molecule bmvc: a large-scale assessment of ligand binding selectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436161/
https://www.ncbi.nlm.nih.gov/pubmed/32751510
http://dx.doi.org/10.3390/molecules25153465
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