Scott Singleton is an associate professor of Medicinal Chemistry and Natural Products in the UNC Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill. Prior to his appointment to the faculty of UNC in 2003, Dr. Singleton was an assistant professor in the Departments of Chemistry and Biochemistry and Cell Biology at Rice University (1996-2003). Dr. Singleton’s areas of research interest lie at the interface of chemistry and biology, and his NIH-sponsored research program endeavors to understand the molecular basis for the evolution of drug resistance in pathogenic microorganisms. Seeking new opportunities for the development of integrated, multidisciplinary knowledge and technologies, Dr. Singleton has led efforts to develop and adapt methods of organic chemistry and synthetic biology to provide new molecular tools - both biologically active small molecules and innovative platforms - for hypothesis-driven biological research and pharmaceutical discovery. Dr. Singleton is also an award-winning teacher of organic chemistry and medicinal chemistry for undergraduate, graduate, and professional students. Dr. Singleton holds a BA in chemistry and in biology from Trinity University (San Antonio, Texax) and a PhD in organic chemistry from the California Institute of Technology. Following his doctoral research with Professor Peter B. Dervan at Caltech, Dr. Singleton was an NSF postdoctoral fellow with Professor Stephen J. Benkovic at Penn State.

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Research Interests:
Bio-Organic and Biophysical Chemical Investigations of the Mechanisms DNA Repair, Directed Evolution of Novel Enzymes, Development of Alternate Strategies for Targeting Drug-Resistant Pathogenic Microorganisms

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Independent Research

Published (reverse chronological order)

1. Lee, A.M., Wigle, T.J., and Singleton, S.F.*, “Two-Tiered High-Throughput Screening-Compatible Assay for Inhibitors of RecA Activities,” Analytical Biochemistry (in press).
2.  Wigle, T.J., and Singleton, S.F.*, “Directed Molecular Screening for RecA ATPase Inhibitors,” Bioorganic & Medicinal Chemistry Letters, DOI 10.1016/j.bmcl.2007.04.013 (2007).
3. Cline, D.J., Holt, S.L., and Singleton, S.F.*, “Inhibition of Escherichia coli RecA by a Rationally Redesigned Helical Peptide,” Organic & Biomolecular Chemistry, DOI DOI: 10.1039/B703159A (2007).
4. Singleton, S.F.*, Roca, A.I., Lee, A.M., and Xiao, J., “Probing the Structures of RecA-DNA Filaments. Advantages of a Flurescent Guanine Analog,” Tetrahedron 63: 3553-3566 (2007).
5. Lee, A.M., Xiao, J., and Singleton, S.F.*, “Origins of Sequence Selectivity in Homologous Genetic Recombination:  Insights from Rapid Kinetic Probing of RecA-mediated DNA Strand Exchange,” Journal of Molecular Biology 360: 343-359 (2006).
6. Xiao, J., Lee, A.M., and Singleton, S.F.*, “Direct evaluation of a kinetic model for RecA-mediated DNA strand exchange:  Importance of nucleic acid dynamics and entropy during homologous genetic recombination,” ChemBioChem 7: 1265-1278 (2006).
7. Lee, A.M. and Singleton, S.F.*, “Intersubunit Electrostatic Complementarity in the RecA Nucleoprotein Filament Regulates Nucleotide Substrate Specificity and Conformational Activation,” Biochemistry 45: 4514-4529 (2006).
8. Wigle, T.J., Lee, A.M., and Singleton, S.F.*, “Conformationally Selective Binding of Nucleotide Analogs to Escherichia coli RecA:  A Ligand-Based Analysis of the RecA ATP-Binding Site,” to Biochemistry 45: 4502-4513 (2006).
9. Xiao, J., Lee, A.M., and Singleton, S.F.*, “Construction and Evaluation of a Kinetic Scheme for RecA-mediated DNA Strand Exchange,” Biopolymers 81: 473-496 (2006).
10. Lee, A.M., and Singleton, S.F., “A Molecular Target for Suppression of the evolution of Antibiotic Resistance: Inhibition of the Escherichia coli RecA Protein by N⁶-(1-Naphthyl)-ADP,” Journal of Medicinal Chemistry, 48: 5408-5411 (2005).
11. Lee, A.M., and Singleton, S.F., “Inhibition of the Escherichia coli RecA protein: zinc(II), copper(II) and mercury(II) trap RecA as inactive aggregates,” Journal of Inorganic Biochemistry, 98: 1981-1986 (2004).
12. Roca, A.I., and Singleton, S.F., “Direct Evaluation of a Mechanism of Activation of the RecA Nucleoprotein Filament,” Journal of the American Chemical Society, 125: 15366-15375 (2003).
13. Singleton, S.F., Simonette, R.A., Sharma, N.C., and Roca, A.I., “Intein-Mediated Affinity-Fusion Purification of the Escherichia coli RecA Protein,” Protein Expression & Purification, 26: 476-488 (2002).
14. Xiao, J., and Singleton, S.F., “Elucidating a Key Intermediate in Homologous DNA Strand Exchange:  Structural Characterization of the RecA·Triple-Stranded-DNA Complex Using Fluorescence Resonance Energy Transfer,” Journal of Molecular Biology, 320: 529-558 (2002).
15. Singleton, S.F., and Xiao, J., “The Stretched DNA Geometry of Recombination and Repair Nucleoprotein Filaments,” Biopolymers (Nucleic Acid Science), 61: 145-158 (2002).
16. Peng, Z.-H., Sharma, V., Singleton, S.F., and Gershon, P.D., “Synthesis and Application of a Chain-Terminating Dinucleotide mRNA Cap Analog,” Organic Letters, 4: 161-164 (2002).
17. Singleton, S.F., Shan, F., Kanan, M.W., McIntosh, C.M., Stearman, C.J., Helm, J.S., and Webb, K.J., “Facile Synthesis of a Fluorescent Deoxycytidine Analogue Suitable for Probing the RecA Nucleoprotein Filament,” Organic Letters, 3: 3919-3922 (2001).
18. Berger, M.D., Lee, A.M., Simonette, R.A., Jackson, B.E., Roca, A.I., and Singleton, S.F., “Design and Evaluation of a Tryptophanless RecA Protein with wild type Activity,” Biochemical and Biophysical Research Communications, 286: 1195-1203 (2001).

 In preparation.

1. Wigle, T.J. and Singleton, S.F., “Toward Functionally Selective Inhibitors of RecA from Pathogenic Bacteria,” for ChemBioChem.
2. Singleton, S.F., Lee, A.L., and Benkovic, S.J., "Tuning the Catalytic Activity of Escherichia coli Dihydrofolate Reductase Using Chemical Denaturants and Viscogens," for Biochemistry.
3. Sharma, N.C., Simonette, R.A., and Singleton, S.F., “A Semi-synthetic Genetic Circuit for the Selection of Rare, Site-specific Proteases from Gigascale Libraries,” for Protein Engineering.
4. Wigle, T.J., Zeng, B.-B., and Singleton, “Bismuth-dithiol Inhibition of the Escherichia coli RecA Protein,” for Journal of Inorganic Biochemistry.
5. Sharma, N.C., and Singleton, S.F., “Rapid Activity Screens for Human Viral Proteases in Escherichia coli,” for Protein Engineering.
6. Cline, D.J., Kamilaris, A., and Singleton, S.F., “Modulation of the Helical Stabilities of Peptide Inhibitors of Escherichia coli RecA,” for Journal of the American Chemical Society.
7. Hadimani, M.B., Guntas, D., Lee, A.M., and Singleton, S.F., “Cyclo-Sal Pronucleotides of AZT: Antibacterial Agents that Bypass Drug Resistance,” for Bioorganic and Medicinal Chemistry.

Undergraduate, Graduate and Postdoctoral Research

Published (reverse chronological order).

1. Cannon, W.R., Singleton, S.F., and Benkovic, S.J., “A Perspective on Biological Catalysis,” Nature Structural Biology, 3: 821-833 (1996).
2. Wagner, C.R., Huang, Z., Singleton, S.F., and Benkovic, S.J., “The Molecular Basis for Non-Additive Mutational Effects in Escherichia coli Dihydrofolate Reductase,” Biochemistry, 34: 15671-15680 (1995).
3. Plum, G.E., Pilch, D.S., Singleton, S.F., and Breslauer, K.J., “Nucleic Acid Hybridization: Triplex Stability and Energetics,” Annual Reviews of Biophysics and Biomolecular Structure, 24: 319–350 (1995).
4. Singleton, S.F., and Dervan, P.B., “Temperature Dependence of the Energetics of Oligonucleotide-Directed Triple Helix Formation at a Single DNA Site,” Journal of the American Chemical Society, 116: 10376–10382 (1994).
5. Singleton, S.F., and Dervan, P.B., “Equilibrium Association Constants for Oligonucleotide-Directed Triple Helix Formation at Single DNA Sites:   Linkage to Cation Valence and Concentration,” Biochemistry, 32: 13171–13179 (1993).
6. Singleton, S.F., and Dervan, P.B., “Influence of pH on the Equilibrium Association Constants for Oligodeoxyribonucleotide-Directed Triple Helix Formation at Single DNA Sites,” Biochemistry, 31: 10995–11003 (1992).
7. Singleton, S.F., and Dervan, P.B., “Thermodynamics of Oligonucleotide-Directed Triple Helix Formation:  An Analysis Using Quantitative Affinity Cleavage Titration,” Journal of the American Chemical Society, 114: 6957–6965 (1992).
8. Plum, G.E., Park, Y.-W., Singleton, S.F., and Dervan, P.B., “Thermodynamic Characterization of the Stability and the Melting Behavior of a DNA Triplex:  A Spectroscopic and Calorimetric Study,” Proceedings of the National Academy of Sciences U.S.A., 87: 9436–9440 (1990).
9. Plummer, B.F., and Singleton, S.F., “An Analysis of the Electronic Transitions of Aceanthrylene,” Journal of Physical Chemistry, 94: 7363–7366 (1990).
10. Plummer, B.F., and Singleton, S.F., “Triplets, Biradicals, Radical Ions, and the Heavy-Atom Solvent Effect in the Photodimerization of Aceanthrylene,” Journal of Physical Chemistry , 93: 5515–5520 (1989).
11. Plummer, B.F., and Singleton, S.F., “The Photodimerization of Aceanthrylene,” Tetrahedron Letters , 28: 4801–4804 (1987).