|
James Graham Brown Foundation Endowed Chair of Cancer Biophysics; Professor of Medicine; Director, Biophysics Core Facility, James Graham Brown Cancer Center
Research ProgramStructural Biology
Research Interests
Physical biochemistry, drug-DNA interactions, high-throughput screening
My research interests are in the physical biochemistry of nucleic acids and their interactions. We use spectroscopic and calorimetric methods to measure the thermodynamics of nucleic acid binding interactions and to study the stability of nucleic acid structures. Small molecules that bind selectively to particular nucleic acid structures (triplexes, quadruplexes) are of particular current interest. In addition, we are actively interested in the development of enabling biophysical technologies for the rapid screening of drug-nucleic acid interactions. A novel competition dialysis assay was invented to screen small molecule libraries against an array of defined nucleic acid sequences and structures. This technology will enable us to better define nucleic acids as molecular targets for small molecule therapeutics.
EducationB.A., University of California at Santa Cruz, Biology, 1972
Ph.D., University of Connecticut, Biophysics, 1978
Postdoctoral Fellow, Yale University, Biophysical Chemistry, 1978-1981
Research and Professional Experience
1979-1981
Department of Medicine, Yale University, NIH Postdoctoral Fellow
1982
Full Member of Graduate Faculty, Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS
1982-1986
Assistant Professor, Department of Biochemistry, University of Mississippi Medical Center, Jackson
1986-1990
Associate Professor, Department of Biochemistry, University of Mississippi Medical Center, Jackson
1987
Tenured, Department of Biochemistry, University of Mississippi Medical Center, Jackson
1989-1990
Visiting Scientist, Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry
1990-2004
Professor, Department of Biochemistry, University of Mississippi Medical Center, Jackson
2000-present
Professor, Joint Appointment, Department of Chemistry, University of Mississippi, Oxford
2004-present
James Graham Brown Endowed Professor of Biophysics, Division of Hematology-Oncology, University of Louisville, Louisville, KY
2004-present
Professor with tenure, Department of Medicine, University of Louisville
2004-present
Senior Scientist, James Graham Brown Cancer Center, University of Louisville
Selected Awards and Professional Honors
1968
President's Scholar, University of California
1989-1990
Alexander von Humboldt Fellow
1991-1992
Member, National Science Foundation Advisory Panel for the Biophysics Program
1996
Basic Science Teacher Award, University of Mississippi School of Dentistry
1997-2001
Chartered Reviewer, NIH, Molecular and Cellular Biophysics Study Section
2000
Outstanding Chemist, Mississippi Section of the American Chemical Society
2000, 2003
Member, National Cancer Institute Program Project Grant Site Visit Team
2000
Member, Committee of Visitors for the Biomolecular Structure and Function and Biomolecular Processes Clusters, Division of Molecular and Cellular Biosciences, National Science Foundation
2004
Chairperson, NIH Bioengineering Research Partnership Review Panel ZRG1 BST-A(50)
PublicationsQu X, Chaires JB. Analysis of drug-DNA binding data. in: Numerical Computer Methods, Part C, Method in Enzymology, Vol. 321, (L Brand, MJ Johnson, eds.), Academic Press, Inc., pp. 353-69, 2000
Haq I, Jenkins T, Chowdhry BZ, Jinsong Ren, Chaires JB. Parsing the free energy of drug-DNA interactions. In: Energetics of Biological Macromolecules, Part C, Methods in Enzymology, Vol. 323, (MJ Johnson, GK Ackers, eds.), Academic Press, Inc., pp. 373-405, 2000
Ren J, Chaires JB. Preferential binding of 3,3’-diethyloxadicarbocyanine to triplex DNA. J Am Chem Soc (Communication) 122:424-5, 2000
Ren J, Bailly C, Chaires JB. NB-506, an indolcarbazole topoisomerase I inhibitor, binds preferentially to triplex DNA. FEBS Lett 470:355-9, 2000
Ren J, Jenkins TC, Chaires JB. Energetics of intercalation reactions. Biochemistry 39:8439-47, 2000
Qu X, Trent JO, Fokt I, Priebe W, Chaires JB. Allosteric, chiral-selective drug binding to DNA. Proc Natl Acad Sci USA 97:12032-7, 2000
Bailly C, Goossens JF, Laine W, Anizon F, Prudhomme M, Ren J, Chaires JB. Formaldehyde cross-linking of a 2’-aminoglucose Rebeccamycin derivative to both A-T and G-C base pairs in DNA. J Medic Chem 43:4711-20, 2000
Dignam JJ, Qu X, Chaires JB. Equilibrium unfolding of Bombyx mori glycyl-tRNA synthetase. J Biol Chem 276:4028-37, 2001
Chaires JB. Analysis and interpretation of ligand-DNA binding isotherms. In: Drug-Nucleic Acid Interactions, Methods in Enzymology, Vol. 340, (JB Chaires, MJ Waring, eds.), Academic Press, Inc., pp. 3-22, 2001
Ren J, Chaires JB. Rapid screening of structurally selective ligand binding to nucleic acids. Ibid., pp. 99-108
Priebe W, Fokt I, Przewloka T, Chaires JB, Portugal J, Trent JO. Exploiting the anthracycline scaffold for designing DNA targeting agents. Ibid., pp. 529-55
Ren J, Qu X, Dattagupta N, Chaires JB. Molecular recognition of a RNA:DNA hybrid structure. J Am Chem Soc 123:6742-3, 2001
Murr MM, Harting MT, Guelev V, Ren J, Chaires JB, Iverson BL. An octakis-intercalating molecule. Bioorganic Medicinal Chem 9:1141-8, 2001
Alberti P, Ren J, Teulade-Fichou MP, Guittat L, Riou JF, Chaires JB, Helene C, Vigneron JP, Lehn JM, Mergny JL. Interaction of an acridine dimer with DNA quadruplex structures. J Biomolec Struct Dynam 19:505-13, 2001
Carrasco C, Vezin H, Wilson WD, Ren J, Chaires JB, Bailly C. DNA binding properties of the indolocarbazole antitumor drug NB-506. AntiCancer Drug Design 16:99-107, 2002
Ren J, Qu X, Trent JO, Chaires JB. Tiny telomere DNA. Nucleic Acids Res 30:2307-15, 2002
Carrasco C, Rosu F, Gabelica V, Houssier C, De Pauw E, Garbay-Jaureguiberry C, Roques B, Wilson WD, Chaires JB, Waring MJ, Bailly C. Tight binding of the antitumor drug ditercalinium to quadruplex DNA. Chem Bio Chem 3:100-6, 2002
Chaires JB. A competition dialysis assay for the study of structure-selective ligand binding to nucleic acids. In: Current Protocols in Nucleic Acid Chemistry (SL Beaucage, DE Bergstrom, GD Glick, RA Jones, eds), John Wiley & Sons, Inc., New York, Unit 8.3, 2002
Bishop GR, Chaires JB. Characterization of DNA structures by circular dichroism. Ibid, Unit 7.12.
Chaires JB. Energetics of anthracycline-DNA interactions. In: Small Molecule DNA and RNA Binders: From Synthesis to Nucleic Acid Complexes (M Demeunynck, C Bailly, WD Wilson, eds.) Wiley-VCH Verlag GmbH, Weinheim, pp. 461-81, 2003
Reynisson J, Schuster GB, Howerton SB, Williams LD, Barnett RN, Cleveland CL, Landman U, Harrit N, Chaires JB. The intercalation of trioxatriangulenium ion (TOTA+) in DNA: binding, electron transfer, x-ray crystallography, and electronic structure. J Am Chem Soc 125:2072-83, 2003
Murphy PM, Phillips VA, Jennings SA, Garbett NC, Chaires JB, Jenkins TC, Wheelhouse RT. Biarylpyrimidines: a new class of ligand for high-order DNA recognition. Chem Commun 10:1160-1, 2003
Dignam JD, Nada S, Chaires JB. Thermodynamic characterization of the binding of nucleotides to glycyl-tRNA synthetase. Biochemistry 42:5333-40, 2003
Chaires JB, Ren J, Henary M, Zegrocka O, Bishop GR, Strekowski L. Triplex selective 2-(2-naphthyl)quinoline compounds: origins of affinity and new design principles. J Am Chem Soc 125:7272-83, 2003
Qu X, Ren J, Riccelli PV, Benight AS, Chaires JB. Enthalpy/entropy compensation: Influence of DNA flanking sequence on the binding of 7-amino actinomycin D to its primary binding site in short DNA duplexes. Biochemistry 42:11960-7, 2003
Leng F, Chaires JB, Waring MJ. Energetics of echinomycin binding to DNA. Nucleic Acids Res 31:6191-6, 2003
Chaires JB, Ren J, Hamelberg D, Kumar A, Pandya V, Boykin DW, Wilson WD. Structural selectivity of aromatic diamidines. J Med Chem 47:5729-42, 2004
Mergny JL, Li J, Lacroix L, Amrane S, Chaires JB. Thermal difference spectra: a specific signature for nucleic acid structures. Nucleic Acids Res 33:e138, 2005
Xing F, Song G, Ren J, Chaires JB, Qu X. Molecular recognition of nucleic acids: coralyne binds strongly to poly(A). FEBS Lett 579:5035-9, 2005
Li J, Correia JJ, Wang L, Trent JO, Chaires JB. Not so crystal clear: the structure of the human telomere G-quadruplex in solution differs from that present in a crystal. Nucleic Acids Res 33:4649-59, 2005
Chaires JB. Competition dialysis: an assay to measure the structural selectivity of drug-nucleic acid interactions. Curr Med Chem Anti-Canc Agents 5:339-52, 2005 [Review]
Song G, Xing F, Qu X, Chaires JB, Ren J. Oxazine 170 induces DNA:RNA:DNA triplex formation. J Med Chem 48:3471-3, 2005
Portugal J, Cashman DJ, Trent JO, Ferrer-Miralles N, Przewloka T, Fokt I, Priebe W, Chaires JB. A new bisintercalating anthracycline with picomolar DNA binding affinity. J Med Chem 48(26):8209-19, 2005
Chaires JB. A thermodynamic signature for drug-DNA binding mode. Arch Biochem Biophys 453(1):26-31, 2006
Shi X, Chaires JB. Sequence- and structural-selective nucleic acid binding revealed by the melting of mixtures. Nucleic Acids Res 34(2):e14, 2006
Grant L, Sun J, Xu H, Subramony SH, Chaires JB, Hebert MD. Rational selection of small molecules that increase transcription through the GAA repeats found in Friedreich's ataxia. FEBS Lett 580(22):5399-405, 2006
Wheelhouse RT, Jennings SA, Phillips VA, Pletsas D, Murphy PM, Garbett NC, Chaires JB, Jenkins TC. Design, synthesis, and evaluation of novel biarylpyrimidines: a new class of ligand for unusual nucleic acid structures. J Med Chem 49(17):5187-98, 2006
Nagarajan M, Morrell A, Antony S, Kohlhagen G, Agama K, Pommier Y, Ragazzon PA, Garbett NC, Chaires JB, Hollingshead M, Cushman M. Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors. J Med Chem 49(17):5129-40, 2006
Spink CH, Garbett N, Chaires JB. Enthalpies of DNA melting in the presence of osmolytes. Biophys Chem 126(1-3):176-85, 2007
Bishop GR, Ren J, Polander BC, Jeanfreau BD, Trent JO, Chaires JB. Energetic basis of molecular recognition in a DNA aptamer. Biophys Chem 126(1-3):165-75, 2007
Freyer MW, Buscaglia R, Cashman D, Hyslop S, Wilson WD, Chaires JB, Lewis EA. Binding of netropsin to several DNA constructs: evidence for at least two different 1:1 complexes formed from an -AATT-containing ds-DNA construct and a single minor groove binding ligand. Biophys Chem 126(1-3):186-96, 2007
Antonacci C, Chaires JB, Sheardy RD. Biophysical characterization of the human telomeric (TTAGGG)(4) repeat in a potassium solution. Biochemistry 2007 Mar 24; [Epub ahead of print]
Dignam JD, Qu X, Ren J, Chaires JB. Daunomycin binding to detergent micelles: a model system for evaluating the hydrophobic contribution to drug-DNA interactions. J Phys Chem B 111(39):11576-84, 2007
Ragazzon PA, Garbett NC, Chaires JB. Competition dialysis: a method for the study of structural selective nucleic acid binding. Methods 42(2):173-82, 2007 [Review]
Garbett NC, Ragazzon PA, Chaires JB. Circular dichroism to determine binding mode and affinity of ligand-DNA interactions. Nat Protoc 2(12):3166-72, 2007.
Garbett NC, Miller JJ, Jenson AB, Chaires JB. Calorimetric analysis of the plasma proteome. Semin Nephrol 27(6):621-6, 2007 [Review]
Garbett NC, Miller JJ, Jenson AB, Miller DM, Chaires JB. Interrogation of the plasma proteome with differential scanning calorimetry. Clin Chem 53(11):2012-4, 2007
Ragazzon P, Chaires JB. Use of competition dialysis in the discovery of G-quadruplex selective ligands. Methods 43(4):313-23, 2007
Lane AN, Chaires JB, Gray RD, Trent JO. Stability and kinetics of G-quadruplex structures. Nucleic Acids Res. 2008 Aug 21. [Epub ahead of print]
Holt PA, Chaires JB, Trent JO. Molecular docking of intercalators and groove-binders to nucleic acids using Autodock and Surflex. J Chem Inf Model. 2008 Jul 22. [Epub ahead of print]
Chaires JB. Calorimetry and thermodynamics in drug design. Annu Rev Biophys 37:135-51, 2008 [Review]
Gray RD, Chaires JB. Kinetics and mechanism of K+- and Na+-induced folding of models of human telomeric DNA into G-quadruplex structures. Nucleic Acids Res 36(12):4191-203, 2008
Chaires JB, Mergny JL. Targeting DNA. Biochimie 90(7):973-5, 2008
Mekmaysy CS, Petraccone L, Garbett NC, Ragazzon PA, Gray R, Trent JO, Chaires JB. Effect of O6-methylguanine on the stability of G-quadruplex DNA. J Am Chem Soc 130(21):6710-1, 2008
Chaires JB. Allostery: DNA does it, too. ACS Chem Biol 3(4):207-9, 2008
Garbett NC, Chaires JB. Binding: a polemic and rough guide. Methods Cell Biol 84:3-23, 2008
Garbett NC, Miller JJ, Jenson AB, Chaires JB. Calorimetry outside the box: a new window into the plasma proteome. Biophys J 94(4):1377-83, 2008
Contact InfoCTR Building
505 South Hancock Street
Louisville, KY 40202
Phone: (502) 852-1172
Fax: (502) 852-1153
|
|