John O. Trent, PhD


Associate Professor of Medicine; Wendell Cherry Endowed Chair in Cancer Translational Research; Director, Molecular Modeling Core Facility, James Graham Brown Cancer Center

Research Program
Structural Biology

Education

B.Sc., University of Canterbury, New Zealand, Chemistry, 1988
Ph.D., University of Canterbury, New Zealand, Chemistry, 1992
Postdoc, University of Geneva, Switzerland, Organic Chemistry, 1992-1994

Research and Professional Experience
1994-1996
Postdoctoral Fellowship/Lecturer, CRC Biomolecular Structure Unit, The Institute of Cancer Research, Sutton, Surrey, UK.

1996-1997
Scientific Staff/Lecturer, CRC Biomolecular Structure Unit, The Institute of Cancer Research, Sutton, Surrey, UK.

1997-1999
Research Assistant Professor, Division of Hematology/Oncology, University of Alabama, Birmingham; and Associate Scientist, Comprehensive Cancer Center, University of Alabama

1998-present
Director, Birmingham Veterans Administration Molecular Modeling Shared Facility

1999-present
Assistant Professor, Division of Internal Medicine, Department of Medicine, University of Louisville, KY

1999-present
Associate Scientist, James Graham Brown Cancer Center, University of Louisville


1999-present
Director, James Graham Brown Cancer Center Molecular Modeling Facility, University of Louisville


2000-present
Assistant Professor of Biochemistry & Molecular Biology and Chemistry, University of Louisville

2005-present
Associate Professor of Medicine, University of Louisville

Selected Awards and Professional Honors
1984-1987
Sir James Gear Scholarship

1988
Sir Neil Issac Scholarship

1988-1991
University Grants Committee Post-Graduate Scholarship

1989
Winner, New Zealand Institute of Chemistry Conference Student Paper Competition

1990, 1991
Rochester and Rutherford Scholarship

1991
Judge for the New Zealand Institute of Chemistry Conference Student Paper Competition


2008
Apple Scientific Innovator Award

Research Interest

Structure-based drug design, macromolecular molecular dynamics modeling of proteins, DNA and RNA drug discovery.

My group uses numerous computational techniques to complement experimental approaches aimed at understanding macromolecular interactions. The methods include molecular dynamics, free energy perturbation calculations, and Monte-Carlo methods as applied to real world problems. The combination of modeling techniques with different experimental modalities such as NMR, X-ray diffraction and thermodynamic methods is synergistic, and is the key to understanding structure and function. We have successfully modeled the structure of the nucleolin binding quadruplex, as verified by biophysical studies such as CD (with P. Bates), analytical ultracentrifugation and NMR (with A. Lane). We also have produced detailed rhodopsin-based homology models of the CCR5 and CXCR4 chemokine receptors, embedded in a complete, solvated lipid bilayer, that successfully account for the saturation mutation data obtained by Dr. S. C. Peiper at the Brown Cancer Center (now at Georgia Medical College, Augusta). We have a strong interest in quadruplex structure and as a drug target and collaborate with Dr. J. B. Chaires on the biophysical aspect of this work.

We also have enhanced our drug discovery program by establishing a distributing computing Grid for virtual screening. The Grid development is in collaboration with Dataseam and uses thousands of computer processors in schools across the Commonwealth of Kentucky. It is now routine in my laboratory to screen millions of potential compounds against a cancer target in days. We have successfully screened over 20 cancer targets that are moving into the laboratories for anticancer activity testing.

Publications

Pritchard DG, Trent JO, Li X, Zhang P, Egan ML, Baker JR.  Homology modeling of Group B Streptococcal hyaluronan lyase and characterization of its active site.  Proteins 40(4):675, 2000

Hu Q, Trent JO, Tomaras GD, Wang Z, Murray JL, Conolly SM, Navenot JM, Barry AP, Greenberg ML, Peiper SC.  Identification of ENV determinants in V3 that influence the molecular anatomy of CCR5 utilization.  J Mol Biol 302(2):359-75, 2000

Qu X,
Trent JO, Fokt I, Priebe W, Chaires JB.  From the Cover:  Allosteric, chiral-selective drug binding to DNA.  Proc Natl Acad Sci USA 97(22):12032-7, 2000

Vigneswaran N, Nadarajah J, Knops J, Trent JO, Miller DM, Zacharias W.  Intra- and intermolecular triplex DNA formation in the murine c-myb proto-oncogene promoter is inhibited by mithramycin.  Biol Chem 382(2):329-42, 2001

Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG,
Trent JO, Miller DM, Bates PJ.  Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides.  J Biol Chem 276(46):43221-30, 2001

Basye J, Trent JO, Gao D, Ebbinghaus SW.  Triplex formation by morpholino oligonucleotides in the HER-2/neu promoter requires the pyrimidine motif.  Nucleic Acids Res 29(23):4873-80, 2001

Dapic V, Bates PJ,
Trent JO, Rodger A, Thomas SD, Miller DM.  Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications.  Biochemistry 41(11):3676-85, 2002

Ren J, Qu X,
Trent JO, Chaires JB.  Tiny telomere DNA.  Nucleic Acids Res 30(11):2307-15, 2002

Mitchell TC, Thompson BS,
Trent JO, Casella CR.  A short domain within Bcl-3 is responsible for itslymphocyte survival activity.  Ann N Y Acad Sci 975:132-47, 2002

Dapic V, Abdomerovi V, Marrington R, Peberdy J, Rodger A, Trent JO, Bates PJ.  Biophysical and biological properties of quadruplex oligodeoxyribonucleotides.  Nucleic Acids Res 31(8):2097-107, 2003

Feltzer RE,
Trent JO, Gray RD.  Alkaline proteinase inhibitor of pseudomonas aeruginosa: A mutational and molecular dynamics study of the role of N-terminal residues in the inhibition of pseudomonas alkaline proteinase.  J Biol Chem 278(28):25952-7, 2003

Gyi JI, Gao D, Conn GL,
Trent JO, Brown T, Lane AN.  The solution structure of a DNA·RNA duplex containing 5-propynyl U and C; comparison with 5-Me modifications. Nucleic Acids Res 31(10):2683-93, 2003

Singh S, Powell DW, Rane MJ, Millard TH,
Trent JO, Pierce WM, Klein JB, Machesky LM, McLeish KR.  Identification of the p16-Arc subunit of the Arp2/3 complex as a substrate of MAPK-activated protein kinase- 2 by proteomic analysis.  J Biol Chem 278(80):36410-7, 2003

Trent JO
, Wang ZX, Murray JL, Shao W, Tamamura H, Fujii N, Peiper SC.  Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists.  J Biol Chem 278(47):47136-44, 2003

Leduc AM,
Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AF.  Helix- stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions.  Proc Natl Acad Sci USA 100(20):11273-8, 2003

Galande
AK, Trent JO, Spatola AF.  Understanding base-assisted desulfurization using a variety of disulfide- bridged peptides.  Biopolymers 71(5):534-51, 2003

Jankowski K, Kucia M, Wysoczynski M, Reca R, Zhao D, Trzyna E,
Trent J, Peiper S, Zembala M, Ratajczak J, Houghton P, Janowska-Wieczorek A, Ratajczak MZ.  Both hepatocyte growth factor (HGF) and stromal-derived factor-1 regulate the metastatic behavior of human rhabdomyosarcoma cells, but only HGF enhances their resistance to radiochemotherapy.  Cancer Res 63(22):7926-35, 2003

Tamamura H, Hiramatsu K, Mizumoto M, Ueda S, Kusano S, Terakubo S, Akamatsu M, Yamamoto N,
Trent JO, Wang Z, Peiper SC, Nakashima H, Otaka A, Fujii N.  Enhancement of the T140-based pharmacophores leads to development of more potent and bio-stable CXCR4 antagonists.  Org Biomol Chem 1:3663-9, 2003

Tamamura H, Hiramatsu K, Kusano S, Terakubo S, Yamamoto N,
Trent JO, Wang Z, Peiper SC, Nakashima H, Otaka A, Fujii N.  Synthesis of potent CXCR4 inhibitors possessing low cytotoxicity and improved biostability based on T140 derivatives.  Org Biomol Chem 1(21):3656-62, 2003

Tabb-Massey A, Caffrey JM, Logsden P, Taylor S,
Trent JO, Ellis SR.  Ribosomal proteins Rps0 and Rps21 of Saccharomyces cerevisiae have overlapping functions in the maturation of the 3' end of 18S rRNA.  Nucleic Acids Res 31(23):6798-805, 2003

Zhilina ZV, Ziemba AJ,
Trent JO, Reed MW, Gorn V, Zhou Q, Duan W, Hurley L, Ebbinghaus SW.  Synthesis and evaluation of a triplex-forming oligonucleotide-pyrrolobenzodiazepine conjugate.  Bioconjug Chem 15:1182-92, 2004

Galliera E, Jala VR,
Trent JO, Bonecchi R, Signorelli P, Lefkowitz RJ, Mantovani A, Locati M, Haribabu B.  ß-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6.  J Biol Chem 279(24):25590-7, 2004

Tamamura H, Mizumoto M, Hiramatsu K, Kusano S, Terakubo S, Yamamoto N,
Trent JO, Wang Z, Peiper SC, Nakashima H, Otaka A, Fujii N.  Topochemical exploration of potent compounds using retro-enantiomer libraries of cyclic pentapeptides.  Org Biomol Chem 2(8):1255-7, 2004

Wei Y, Yen TY, Cai J,
Trent JO, Pierce WM, Young WW Jr.  Structural features of the lysosomal hydrolase mannose 6-phosphate uncovering enzyme.  Glycoconj J 22(1-2):13-9, 2005

Tamamura H, Araki T, Ueda S, Wang Z, Oishi S, Esaka A,
Trent JO, Nakashima H, Yamamoto N, Peiper SC, Otaka A, Fujii N.  Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds. J Med Chem 48(9):3280-9, 2005

Booth J, Brown T, Vadhia SJ, Lack O, Jon Cummins W,
Trent JO, Lane AN.  Determining the origin of the stabilization of DNA by 5-aminopropynylation of pyrimidines.  Biochemistry 44(12):4710-9, 2005

Gray RD
, Trent JO.  Contribution of a single-turn alpha-helix to the conformational stability and activity of the alkaline proteinase inhibitor of Pseudomonas aeruginosaBiochemistry 44(7):2469-77, 2005

Tamamura H, Hiramatsu K, Ueda S, Wang Z, Kusano S, Terakubo S,
Trent JO, Peiper SC, Yamamoto N, Nakashima H, Otaka A, Fujii N.  Stereoselective synthesis of [L-Arg-L/D-3-(2-naphthyl)alanine]-type (E)-alkene dipeptide isosteres and its application to the synthesis and biological evaluation of pseudopeptide analogues of the CXCR4 antagonist FC131.  J Med Chem 48(2):380-91, 2005

Hu Q, Napier KB, Trent JO, Wang Z, Taylor S, Griffin GE, Peiper SC, Shattock RJ.  Restricted variable residues in the C-terminal segment of HIV-1 V3 loop regulate the molecular anatomy of CCR5 utilization.  J Mol Biol 350(4):699-712, 2005
 
Klein JB, Barati MT, Wu R, Gozal D, Sachleben LR Jr, Kausar H, Trent JO, Gozal E, Rane MJ.  Akt-mediated valosin-containing protein 97 phosphorylation regulates its association with ubiquitinated proteins.  J Biol Chem 280(36):31870-81, 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(14):4649-59, 2005
 
Galande AK, Bramlett KS, Trent JO, Burris TP, Wittliff JL, Spatola AF.  Potent inhibitors of LXXLL-based protein-protein interactions.  Chembiochem 6(11):1991-8, 2005
 
Tamamura H, Esaka A, Ogawa T, Araki T, Ueda S, Wang Z, Trent JO, Tsutsumi H, Masuno H, Nakashima H, Yamamoto N, Peiper SC, Otaka A, Fujii N.  Structure-activity relationship studies on CXCR4 antagonists having cyclic pentapeptide scaffolds.  Org Biomol Chem 3(24):4392-4, 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
 
Napier KB, Wang ZX, Peiper SC, Trent JO.  CCR5 interactions with the variable 3 loop of gp120.  J Mol Model 13(1):29-41, 2006.
 
Tamamura H, Tsutsumi H, Masuno H, Mizokami S, Hiramatsu K, Wang Z, Trent JO, Nakashima H, Yamamoto N, Peiper SC, Fujii N.  Development of a linear type of low molecular weight CXCR4 antagonists based on T140 analogs.  Org Biomol Chem 4(12):2354-7, 2006
 
Basu S, Jala VR, Mathis S, Rajagopal ST, Del Prete A, Maturu P, Trent JO, Haribabu B.  Critical role for polar residues in coupling leukotriene B4 binding to signal transduction in BLT1.  J Biol Chem 282(13):10005-17, 2007
 
Ueda S, Oishi S, Wang ZX, Araki T, Tamamura H, Cluzeau J, Ohno H, Kusano S, Nakashima H, Trent JO, Peiper SC, Fujii N.  Structure-activity relationships of cyclic peptide-based chemokine receptor CXCR4 antagonists: disclosing the importance of side-chain and backbone functionalities.  J Med Chem 50(2):192-8, 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
 

Walraven JM, Trent JO, Hein DW.  Computational and experimental analyses of mammalian arylamine N-acetyltransferase structure and function.  Drug Metab Dispos 35(6):1001-7, 2007

Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J.  Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth.  Mol Cancer Ther 7(1):110-20, 2008

Walraven JM, Trent JO, Hein DW.  Structure-function analyses of single nucleotide polymorphisms in human N-acetyltransferase 1.  Drug Metab Rev 40(1):169-84, 2008; PMC2265210. Review.

Zarebski A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL.  Mutations in growth factor independent-1 associated with human neutropenia block murine granulopoiesis through colony stimulating factor-1.  Immunity 28(3):370-80, 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

Holt PA, Chaires JB, Trent JO.  Molecular docking of intercalators and groove-binders to nucleic acids using Autodock and Surflex.  J Chem Inf Model 48(8):1602-15, 2008; PMC2755229

Walraven JM, Zang Y, Trent JO, Hein DW.  Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2.  Curr Drug Metab 9(6):471-86, 2008; PMC2507886.  Review

Lane AN, Chaires JB, Gray RD, Trent JO.  Stability and kinetics of G-quadruplex structures.  Nucleic Acids Res 36(17):5482-515, 2008; PMC2553573.  Review

Winner M, Meier J, Zierow S, Rendon BE, Crichlow GV, Riggs R, Bucala R, Leng L, Smith N, Lolis E, Trent JO, Mitchell RA.  A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells.  Cancer Res 68(18):7253-7, 2008; PMC2726006

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

Duan X, Trent JO, Ye H.  Targeting the SUMO E2 conjugating enzyme Ubc9 interaction for anti-cancer drug design.  Anticancer Agents Med Chem 9(1):51-4, 2009. Review

Tamamura H, Tanaka T, Tsutsumi H, Ohashi N, Hiramatsu K, Araki T, Ojida A, Hamachi I, Wang Z, Peiper SC, Trent JO, Ueda S, Oishi S, Fujii N.  Development of chemokine receptor CXCR4 antagonists using bio-mimetic strategy.  Adv Exp Med Biol 611:145-6, 2009

Dailey MM, Hait C, Holt PA, Maguire JM, Meier JB, Miller MC, Petraccone L, Trent JO.  Structure-based drug design: from nucleic acid to membrane protein targets.  Exp Mol Pathol 86(3):141-50, 2009.  Review

Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO.  Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer.  Exp Mol Pathol 86(3):151-64, 2009; PMC2716701. Review

Merk M, Baugh J, Zierow S, Leng L, Pal U, Lee SJ, Ebert AD, Mizue Y, Trent JO, Mitchell R, Nickel W, Kavathas PB, Bernhagen J, Bucala R.  The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor.  J Immunol 182(11):6896-906, 2009

Chernatynskaya AV, Deleeuw L, Trent JO, Brown T, Lane AN.  Structural analysis  of the DNA target site and its interaction with Mbp1.  Org Biomol Chem 7(23):4981-91, 2009

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

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: 10.1002bip.21392


Dailey MM, Miller MC, Bates PJ, Lane AN, Trent JO.  Resolution and characterization of the structural polymorphism of a single quadruplex-forming sequence.  Nucleic Acids Res. 38(14):4877-88, 2010.  doi: 10.1093/nar/gkq166


Cunningham AR, Qamar S, Carrasquer CA, Holt PA, Maguire JM, Cunningham SL, Trent JO.  Mammary carcinogen-protein binding potentials: novel and biological relevant structure-activity relationship model descriptors.  SAR QSAR Environ Res. 21(5-6):463-79, 2010.  doi: 10.1080/1062936X.2010.501818


Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, Trent JO, Chesney J.  A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling.  Oncogene 30(30);3370-80, 2011.  doi: 10.1038/onc.2011.51


Miller MC, Le HT, Dean WL, Holt PA, Chaires JB, Trent JO.  Polymorphism and resolution of oncogene promoter quadruplex-forming sequences.  Org Biomol Chem. 9(22):7633-7, 2011.  doi: 10.1039/c1ob05891f


Telang S, Clem BF, Klarer AC, Clem AL, Trent JO, Bucaala R, Chesney J.  Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation.  J Transl Med. 10:94, 2013.  doi: 10.1186/1479-5876-10-95


Le HT, Miller MC, Buscaglia R, Dean WL, Holt PA, Chaires JB, Trent JO.  Not all G-quadruplexes are created equally: an investigation of the structural polymorphism of the c-Myc G-quadruplex-forming sequence and its interaction with the porphyrin TMPyP4.  Org Biomol Chem. 10(47):9393-404, 2012.  doi: 10.1039/c2ob26504d


Snyder RD, Holt PA, Maguire JM, Trent JO.  Prediction of noncovalent Drug/DNA interaction using computational docking models: studies with over 1350 launched drugs.  Environ Mol Mutagen. 54(8):668-81, 2013.  doi: `10.1002/em.21796


Li J Zheng H, Bates PJ, Malik T, Li XF, Trent JO, Ng CK.  Aptamer imaging with Cu-64 labeled AS1411: preliminary assessment in lung cancer.  Nucl Med Biol. 41(2):179-85, 2014.  doi: 10.1016/j.nucmedbio.2013.10.008


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.0996-13

Contact Information

CTR Building
505 South Hancock Street
Louisville, KY 40202
(502) 852-2194


Fax: (502) 852-4311