J. Brad Chaires, PhD


James Graham Brown Foundation Endowed Chair of Cancer Biophysics; Professor of Medicine; Director, Biophysics Core Facility, James Graham Brown Cancer Center

Research Program
Structural Biology

Education
B.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)

Research Interest

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.

Publications
Qu 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 36(17):5482-515, 2008; PMC2553573

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

Yu H, Ren J, Chaires JB, Qu X.  Hydration of drug-DNA complexes: greater water uptake for adriamycin compared to daunomycin.  J Med Chem 51(19):5909-11, 2008; PMC2663378.

Petraccone L, Trent JO, Chaires JB.  The tail of the telomere.  J Am Chem Soc 130(49):16530-2, 2008; PMC2636551.

Holt PA, Ragazzon P, Strekowski L, Chaires JB, Trent JO.  Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform.  Nucleic Acids Res 37(4):1280-7, 2009; PMC2651796
 

Garbett NC, Mekmaysy CS, Helm CW, Jenson AB, Chaires JB.  Differential scanning calorimetry of blood plasma for clinical diagnosis and monitoring.  Exp Mol Pathol 86(3):186-91, 2009

Gray RD, Li J, Chaires JB. Energetics and kinetics of a conformational switch in G-quadruplex DNA.  J Phys Chem B 113(9):2676-83, 2009; PMC2772118.

Chaires JB. Human telomeric G-quadruplex: thermodynamic and kinetic studies of telomeric quadruplex stability.  FEBS J [Epub ahead of print]

Gray RD, Petraccone L, Trent JO, Chaires JB. Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence.  Biochemistry 49(1):179-94, 2010; PMC2803354.

Wheelhouse RT, Chaires JB. Drug binding to DNA x RNA hybrid structures.  Methods Mol Biol 613:55-70, 2010

Garbett NC, Mekmaysy CS, Chaires JB.  Sedimentation velocity ultracentrifugation analysis for hydrodynamic characterization of G-quadruplex structures.  Methods Mol Biol 608:97-120, 2010.

Gray RD, Petraccone L, Buscaglia R, Chaires JB.  2-aminopurine as a probe for quadruplex loop structures.  Methods Mol Biol 608:121-36, 2010

Petraccone L, Garbett N, Chaires JB, Trent JO.  An integrated molecular dynamics and experimental study of higher order human telomeric quadruplexes.  Biopolymers 93(6):533-48, 2010.  doi: 10.1002/bip.21392

Holt PA, Buscaglia R, Trent JO, Chaires JB.  A discovery funnel for nucleic acid binding drug candidates.  Drug Dev Res. 72(2):178-86, 2011

Gray RD, Chaires JB.  Linkage of cation binding and folding in human telomeric quadruplex DNA.  Biophys Chem 159(1):205-9, 2011.  doi: 10.1016/j.bpc.2011.05-012

Garbett NC, Chaires JB.  Thermodynamic studies for drug design and screening.  Expert Opin Drug Discov 7(4):299-314, 2012.  doi: 10.1517/17460441.2012.666235.  Review.

Gray RD, Buscaglia R, Chaires JB.  Populated intermediates in the thermal unfolding of the human telomeric quadruplex.  J Am Chem Soc. 134(40):16834-44, 2012.  doi: 10.1021/ja3-7543z

Buscaglia R, Gray RD, Chaires JB.  Thermodynamic characterization of human telomere quadruplex unfolding.  Biopolymers 99(12):1006-18, 2013.  doi: 10.1002/bip.22247

Zhao G, Zhu Y, Eno CO, Liu Y, Deleeuw L,Burlison JA, Chaires JB, Trent JO, Li C.  Activation of the proapoptotic bcl-2-protein bax by a small molecule induces tumor cell apoptosis.  Mol Cell Biol. 34(7):1198-207, 2014.  doi: 10.1128/MCB.00996-13

Garbett NC, Merchant ML, Helm CW, Jenson AB, Klein JB, Chaires JB.  Detection of cervical cancer biomarker patterns in blood plasma and urine by differential scanning calorimetry and mass spectrometry.  PLoS One. 9(1):e84710, 2014.  doi: 10.1371/journal.pone.0084710.  eCollection 2014

Contact Information

CTR Building
505 South Hancock Street
Louisville, KY 40202

(502) 852-1172



Fax: (502) 852-1153