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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| Format: | Article |
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MDPI AG
2020-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/15/3465 |
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| author | Guanhui Wu Desiree Tillo Sreejana Ray Ta-Chau Chang John S. Schneekloth Charles Vinson Danzhou Yang |
| author_facet | Guanhui Wu Desiree Tillo Sreejana Ray Ta-Chau Chang John S. Schneekloth Charles Vinson Danzhou Yang |
| author_sort | Guanhui Wu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T18:06:14Z |
| format | Article |
| id | doaj.art-7eb68207c446449ca60c4e9267ad76e0 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T18:06:14Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7eb68207c446449ca60c4e9267ad76e02023-11-20T08:28:44ZengMDPI AGMolecules1420-30492020-07-012515346510.3390/molecules25153465Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding SelectivityGuanhui Wu0Desiree Tillo1Sreejana Ray2Ta-Chau Chang3John S. Schneekloth4Charles Vinson5Danzhou Yang6Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USALaboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAInstitute of Atomic and Molecular Sciences, Academia Sinica, P.O. Box 23-166, Taipei 106, TaiwanChemical Biology Laboratory, National Cancer Institute-Frederick, Frederick, MD 21702, USALaboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USADepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 W Stadium Ave, West Lafayette, IN 47907, USAG-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.https://www.mdpi.com/1420-3049/25/15/3465G-quadruplexG4microarrayligand selectivityBMVCMYC |
| spellingShingle | Guanhui Wu Desiree Tillo Sreejana Ray Ta-Chau Chang John S. Schneekloth Charles Vinson Danzhou Yang Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity Molecules G-quadruplex G4 microarray ligand selectivity BMVC MYC |
| 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 | G-quadruplex G4 microarray ligand selectivity BMVC MYC |
| url | https://www.mdpi.com/1420-3049/25/15/3465 |
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