DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA-targeted drugs is that the fundamental molecular mechanisms that govern sequence and structural-selective ligand binding to DNA are poorly understood. The rational design of new DNA-targeted drugs requires a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of specificity. The long-range goal of the proposed research is to understand the molecular mechanism of intercalation reactions, with emphasis on the energetic basis of their sequence and structural selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Research in the next funding period will focus on innovative studies designed to clarify the mechanisms that govern structural and sequence selective ligand binding to nucleic acids.
Specific aims i nclude: 1. Use and refinement of a highthroughput competition dialysis assay for the identification and characterization of structural selective ligand binding to nucleic acids. 2. Characterization of ligand binding to DNA:RNA hybrid structures. 3. Characterization of regional-selective drug binding by a novel calorimetric """"""""bootprinting"""""""" method. The results of these studies will: 1. Provide a definitive taxonomy of structural selective ligand binding to nucleic acids, along with a description of the energetic basis of that structural selectivity, 2. Provide fundamental information to guide the rational design of compounds targeted to DNA:RNA hybrid structures, a target of enormous biological significance. 3. Provide a new tool for the quantitative study of drug-DNA interaction in long (genomic) pieces of DNA.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Fu, Yali
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University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
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Del Villar-Guerra, Rafael; Trent, John O; Chaires, Jonathan B (2018) G-Quadruplex Secondary Structure Obtained from Circular Dichroism Spectroscopy. Angew Chem Int Ed Engl 57:7171-7175
Del Villar-Guerra, Rafael; Gray, Robert D; Chaires, Jonathan B (2017) Characterization of Quadruplex DNA Structure by Circular Dichroism. Curr Protoc Nucleic Acid Chem 68:17.8.1-17.8.16
Bon?ina, MatjaĆŸ; Vesnaver, Gorazd; Chaires, Jonathan Brad et al. (2016) Unraveling the Thermodynamics of the Folding and Interconversion of Human Telomere G-Quadruplexes. Angew Chem Int Ed Engl 55:10340-4
Chaires, Jonathan B; Dean, William L; Le, Huy T et al. (2015) Hydrodynamic Models of G-Quadruplex Structures. Methods Enzymol 562:287-304
Chaires, Jonathan B (2015) A small molecule--DNA binding landscape. Biopolymers 103:473-9
Zhao, Huaying; Ghirlando, Rodolfo; Alfonso, Carlos et al. (2015) A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation. PLoS One 10:e0126420
Le, Huy T; Dean, William L; Buscaglia, Robert et al. (2014) An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation. J Phys Chem B 118:5390-405
Gray, Robert D; Trent, John O; Chaires, Jonathan B (2014) Folding and unfolding pathways of the human telomeric G-quadruplex. J Mol Biol 426:1629-50
Chaires, Jonathan B; Trent, John O; Gray, Robert D et al. (2014) An improved model for the hTERT promoter quadruplex. PLoS One 9:e115580
Buscaglia, Robert; Miller, M Clarke; Dean, William L et al. (2013) Polyethylene glycol binding alters human telomere G-quadruplex structure by conformational selection. Nucleic Acids Res 41:7934-46

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