Eric C. Long

Professor & Associate Chair Biological Chemistry and Nucleic Acid Chemistry B.S., Albright College, 1984 Ph.D., University of Virginia, 1988 Fellow of the Jane Coffin Childs Memorial Fund for Medical Research, Columbia University and the California Institute of Technology, 1989-91. Affiliate Member, IU Cancer Center Phone: (317) 274-6888 Email: long@chem.iupui.edu Research Publications

Japan Society for the Promotion of Science, Invitation Fellowship, 2004; Indiana University Trustees Teaching Award, 2002, 2001; Purdue School of Science Teaching Award, 1999; Indiana University Teaching Excellence Recognition Award, 1999, 1997; Purdue Research Foundation Summer Faculty Fellow, 1992.

-- Research Lab --

Research

Intense interest in the design, synthesis and study of DNA and RNA binding agents is based on the ability of such compounds to act as anticancer drugs, nucleic acid structural probes, and models to understand the fundamental molecular recognition of these vital biopolymers. In this general area, our laboratory is engaged in two main research directions: (1) the synthesis and investigation of metal complexes with peptide-based ligands, i.e., "metallopeptides" and (2) the development and application of a high-throughput (HT), high-resolution (HR) strategy to rapidly determine the structures of DNA-bound ligands.

In the first area, we synthesize peptide ligands derived from the basic Gly-Gly-His tripeptide, e.g., Arg-Gly-His or Lys-Gly-His, etc., to generate metallopeptides of Cu²⁺, Ni²⁺, or Co³⁺ that contain the same chemical functional groups, such as guanidinium, amino, and amide moieties, employed by proteins or anti-tumor natural products for the selective recognition of DNA and RNA (see: Long, 1999 and Long & Claussen, 2003). In these systems, the metal center imparts nucleic acid cleavage activity and a well-defined 3-dimensional structure to the peptide that otherwise lacks these attributes. Our goal is to understand how amino acids within the three-dimensional constraints imposed by a metal center can be used to selectively and efficiently target nucleic acids, information central to increasing our understanding of drug- and protein-nucleic acid recognition phenomena. Further insight derived from these studies, such as particular spatial arrangements of chemical functional groups, and the differential activities of the diastereomeric metallopeptides that are often formed, could be used in the future rational design of DNA-interactive agents.

In our second area of current research, in collaboration with Prof. Millie Georgiadis, Department of Biochemistry & Molecular Biology, we are developing a high-throughput, high-resolution (HT-HR) strategy to expedite the investigation of DNA binding compounds. In this strategy, we make use of high-throughput screens to determine the precise site-selectivity of an unknown DNA binding agent followed by a host-guest crystallization approach to determine high-resolution information. As we determined for the minor groove binding compound netropsin shown below (see: Goodwin et al., 2005), host-guest crystallization generates a protein-oligonucleotide complex that provides an open "scaffolding" within the crystal lattice formed for a potential DNA binding ligand. Importantly, this strategy can yield detailed information about a DNA binding compound within days of the onset of study because crystallization is rapid while, typically, such investigations require months, or even years to generate useful high resolution data. In conjunction with this project we are synthesizing libraries of DNA binding compounds that can be screened for particular properties of biomedical relevance though our HT-HR strategy.

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Recent Publications

K. D. Goodwin, M. A. Lewis, E. C. Long and M. M. Georgiadis "The crystal structure of DNA-bound Co(III)•bleomycin B2: Insights on intercalation and minor groove binding" Proceedings of the National Academy of Sciences, U.S.A, 2008, 105, in press.

M. J. Murcia, D. L. Shaw, C. A. Naumann and E. C. Long "Fluorescence correlation spectroscopy of CdSe/ZnS quantum dot bioimaging probes with ultra-thin biocompatible coatings" Optics Communications, 2008, 281, 1771-1780.

Y. Jin, M. A. Lewis, N. H. Gokhale, E. C. Long and J. A. Cowan "Influence of sterochemistry and redox potentials on the single- and double-strand DNA cleavage efficiency of Cu(II)• and Ni(II)•Lys-Gly-His-derived ATCUN metallopeptides" Journal of the American Chemical Society, 2007, 129, 8353-8361.

F. A. Tanious, W. Laine, P. Peixoto, C. Bailly, K. D. Goodwin, M. A. Lewis, E. C. Long, M. M. Georgiadis, R. R. Tidwell and W. D. Wilson "Unusually strong binding to the DNA minor groove by a highly twisted benzimidazole-diphenylether: Induced fit and bound water" Biochemistry, 2007, 46, 6944-6956.

H. Hamada, Y. Abe, R. Nagane, Y.-Y. Fang, M. A. Lewis, E. C. Long and M. Chikira "DNA-fiber EPR investigation of the influence of amino-terminal residue stereochemistry on the DNA binding orientation of Cu(II)•Gly-Gly-His-derived metallopeptides" Journal of Inorganic Biochemistry, 2007, 101, 1529-1536.

K. D. Goodwin, M. A. Lewis, F. A. Tanious, R. R. Tidwell, W. D. Wilson, M. M. Georgiadis and E. C. Long "A high-throughput, high-resolution strategy for the study of site-selective DNA binding agents: Analysis of a 'highly twisted' benzimidazole-diamidine" Journal of the American Chemical Society 2006, 128, 7846-7854.

Y.-Y. Fang, K. B. Lipkowitz and E. C. Long "Molecular dynamics simulations of the orientation of Ni(II)•Gly-Gly-His and Ni(II)•Arg-Gly-His metallopeptide-DNA Association" Journal of Chemical Theory & Computation 2006, 2, 1453-1463.

Y.-Y. Fang, C. A. Claussen, K. B. Lipkowitz and E. C. Long "Diastereoselective DNA cleavage recognition by Ni(II)•Gly-Gly-His-derived metallopeptides" Journal of the American Chemical Society 2006, 128, 3198-3207.

M. A. Lewis and E. C. Long "Fluorescent intercalator displacement analyses of DNA binding by the peptide-derived natural products netropsin, actinomycin, and bleomycin" Bioorganic & Medicinal Chemistry 2006, 14, 3481-3490.

M. J. Murcia, D. L. Shaw, H. Woodruff, C. A. Naumann, B. A. Young and E. C. Long "Facile sonochemical synthesis of highly luminescent ZnS-shelled CdSe quantum dots" Chemistry of Materials 2006, 18, 2219-2225.

K. D. Goodwin E. C. Long, E. C. and M. M. Georgiadis "A host-guest approach for determining drug-DNA interactions: An example using netropsin" Nucleic Acids Research 2005, 33, 4106-4116.

Y.-Y. Fang, B. D. Ray, C. A. Claussen, K. B. Lipkowitz and E. C. Long "Ni(II)•Arg-Gly-His-DNA interactions: Investigation into the basis for minor groove binding and recognition" Journal of the American Chemical Society 2004, 126, 5403-5412.

J. Van Dijk, C. Lafont, M. L. W. Knetsch, J. Derancourt, D. J. Manstein, E. C. Long and P. Chaussepied "Conformational changes in actin-myosin isoforms probed by Ni(II)•Gly-Gly-His reactivity" Journal of Muscle Research & Cell Motility 2004, 25, 527-537.

E. C. Long and C. A. Claussen "DNA and RNA recognition and modification by Gly-Gly-His-derived metallopeptides" in: DNA and RNA Binders: From Small Molecules to Drugs, M. Demeunynck, C. Bailly and W. D. Wilson, Eds., Wiley-VCH, 2003, pp 88-125.

S. Verma, S. G. Srivatsan, C. A. Claussen and E. C. Long "DNA strand scission by a Cu(I)•adenylated polymeric template: Preliminary mechanistic and recycling studies" Bioorganic & Medicinal Chemistry Letters 2003, 13, 2501-2504.

Representative Publications prior to 2000

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