David N. Frick
Ph.D., The Johns Hopkins University
My lab mainly studies the biochemistry of viral proteins and small molecules that interact with them. Our main interest, presently, is in targeting a helicase encoded by the hepatitis C virus (HCV). Helicases are motor proteins that separate DNA and RNA duplexes and dislodge proteins bound to nucleic acids in reactions fueled by ATP hydrolysis. We also study other helicases from related viruses and human cells, and other viral proteins such as polymerases, proteases and capsid proteins. The goal of most projects in the lab is either to understand how these proteins help copy viral genomes or to understand how small molecule drugs block virus growth by directly interfering with these important enzymes.
|A molecular model of a fluorescent NS3 helicase inhibitor bound to the protein overlaid on a picture of human cells infected with HCV. The human cells also contain the helicase inhibitor, which is visualized in the cytoplasm using fluorescence microscopy.|
Techniques used in our lab:
- Recombinant DNA technology
- Protein purification
- Steady state and transient state kinetics
- Tissue Culture
- Fluorescence Microscopy
- Quantitative RT-PCR
- High throughput screening
- Absorbance spectroscopy
- Fluorescence spectroscopy
- TR-FRET, alpha-screen and FP assays
- Molecular Modeling
Li, K., Frankowski, K. J., Belon, C. A., Neuenswander, B., Ndjomou, J., Hanson, A. M., Shanahan, M. A., Schoenen, F. J., Blagg, B. S., Aube, J., and Frick, D. N. (2012) Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline, J. Med. Chem. 55, 3319-3330.
Mousseau, G., Kota, S., Takahashi, V., Frick, D. N., and Strosberg, A. D. (2011) Dimerization-driven interaction of hepatitis c virus core protein with NS3 helicase, J. Gen. Virol. 92, 101-111.
Belon, C. A., and Frick, D. N. (2011) NS3 Helicase inhibitors, in Hepatitis C: Antiviral Drug Discovery and Development (He, Y., and Tan, S. L., Eds.) pp 327-356, Caister Academic Press.
Peng, L. F., Schaefer, E. A., Maloof, N., Skaff, A., Berical, A., Belon, C. A., Heck, J. A., Lin, W., Frick, D. N., Allen, T. M., Miziorko, H. M., Schreiber, S. L., and Chung, R. T. (2011) Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme a synthase, J. Infect. Dis. 204, 609-616.
Belon, C. A., High, Y. D., Lin, T. I., Pauwels, F., and Frick, D. N. (2010) Mechanism and specificity of a symmetrical benzimidazolephenylcarboxamide helicase inhibitor, Biochemistry 49, 1822-1832.
Frick, D. N., Ginzburg, O., and Lam, A. M. (2010) A method to simultaneously monitor hepatitis C virus NS3 helicase and protease activities, Methods Mol. Biol. 587, 223-233.
Lemon, S. M., McKeating, J. A., Pietschmann, T., Frick, D. N., Glenn, J. S., Tellinghuisen, T. L., Symons, J., and Furman, P. A. (2010) Development of novel therapies for hepatitis C, Antiviral Res. 86, 79-92.
Lam, A. M., Murakami, E., Espiritu, C., Steuer, H. M., Niu, C., Keilman, M., Bao, H., Zennou, V., Bourne, N., Julander, J. G., Morrey, J. D., Smee, D. F., Frick, D. N., Heck, J. A., Wang, P., Nagarathnam, D., Ross, B. S., Sofia, M. J., Otto, M. J., and Furman, P. A. (2010) PSI-7851, a pronucleotide of beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a potent and pan-genotype inhibitor of hepatitis C virus replication, Antimicrob. Agents Chemother. 54, 3187-3196.
Heck, J. A., Meng, X., and Frick, D. N. (2009) Cyclophilin B stimulates RNA synthesis by the HCV RNA dependent RNA polymerase, Biochem. Pharmacol. 77, 1173-1180.
Belon, C. A., and Frick, D. N. (2009) Fuel specificity of the hepatitis C virus NS3 helicase, J. Mol. Biol. 388, 851-864.
Belon, C. A., and Frick, D. N. (2009) Helicase inhibitors as specifically targeted antiviral therapy for hepatitis C, Future Virol 4, 277-293.