profile-default

David Frick

Professor
Chemistry-Biochemical
 (414) 229-6670
 Chemistry Building 333

Website

http://people.uwm.edu/frickd/

Research Area

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.

NS3 fluorescent inhibitor

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
    • Enzymology
    • 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
    • Biocalorimetry
    • Molecular Modeling

For more information, see our Lab Website and UWM News on our research.

Selected Publications

Corby, M J., Stoneman, M R., Biener, G, Paprocki, J D., Kolli, R, Raicu, Valerica, and Frick, David N. “Quantitative microspectroscopic imaging reveals viral and cellular RNA helicase interactions in live cells.” The Journal of biological chemistry 292.27 (2017): 11165-11177.
Bassetto, M, Leyssen, P, Neyts, J, Yerukhimovich, M M., Frick, David N., and Brancale, A. “Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication.” European journal of medicinal chemistry 123. (2016): 31-47.
Bassetto, M, Ferla, S, Leyssen, P, Neyts, J, Yerukhimovich, M M., Frick, David N., O’Donnell, R, and Brancale, A. “Novel symmetrical phenylenediamines as potential anti-hepatitis C virus agents.” Antiviral chemistry & chemotherapy. (2016).
Bassetto, M, Leyssen, P, Neyts, J, Yerukhimovich, M M., Frick, David N., Courtney-Smith, M, and Brancale, A. “In silico identification, design and synthesis of novel piperazine-based antiviral agents targeting the hepatitis C virus helicase.” European journal of medicinal chemistry 125. (2016): 1115-1131.
Kaushik-Basu, N, Ratmanova, N K., Manvar, D, Belov, D S., Cevik, O, Basu, A, Yerukhimovich, M M., Lukyanenko, E R., Andreev, I A., Belov, G M., Manfroni, G, Cecchetti, V, Frick, David N., Kurkin, A V., Altieri, A, and Barreca, M L. “Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one derivatives as novel selective anti-hepatitis C virus agents.” European journal of medicinal chemistry 122. (2016): 319-25.
Ndjomou, Jean, Corby, M. J., Sweeney, Noreena L., Hanson, Alicia M., Aydin, Cihan, Ali, Akbar, Schiffer, Celia A., Li, Kelin, Frankowski, Kevin J., Schoenen, Frank J., and Frick, David N. “Simultaneously Targeting the NS3 Protease And Helicase Activities For More Effective Hepatitis C Virus Therapy.” ACS Chem. Biol. 10. (2015).
Sweeney, Noreena L., Alicia, Hanson M., Mukherjee, Sourav, Ndjomou, Jean, Geiss, Brian J., Steel, John J., Li, Kelin, Frankowski, Kevin J., Schoenen, Frank J., and Frick, David N. “Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase.” ACS Infect. Dis 1. (2015): 140-148.
Andreev, Ivan A., Manvar, Dinesh, Barreca, Maria Letizia L., Belov, Dmitry S., Basu, Amartya, Sweeney, Noreena L., Ratmanova, Nina R., Lukyanenko, Evgeny R., Manfroni, Giuseppe, Cecchetti, Violetta, Frick, David N., Altieri, Andrea, Kaushik-Basu, Neerja, and Kurkin, Alexander V. “Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold.” European Journal of Medicinal Chemistry 96. (2015): 250-8.
Provazzi, P J., Mukherjee, S, Hanson, A M., Nogueira, M L., Carneiro, B M., Frick, David N., and Rahal, P. “Analysis of the Enzymatic Activity of an NS3 Helicase Genotype 3a Variant Sequence Obtained from a Relapse Patient.” PloS one 10.12 (2015): e0144638.
Mukherjee, Sourav, Weiner, Warren S., Schroeder, Chad E., Simpson, Denise S., Hanson, Alicia M., Sweeney, Noreena L., Marvin, Rachel K., Ndjomou, Jean, Kolli, Rajesh, Isailovic, Dragan, Schoenen, Frank J., and Frick, David N. “Ebselen Inhibits Hepatitis C Virus NS3 Helicase Binding to Nucleic Acid and Prevents Viral Replication.” ACS Chemical Biology 9. (2014): 2393-2403.
Aydin, Cihan, Mukherjee, Sourav, Hanson, Alicia M., Frick, David N., and Schiffer, Celia A. “The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities.” Protein Science 22. (2013): 1786-98.
Shadrick, William R., Mukherjee, Sourav, Hanson, Alicia M., Sweeney, Noreena L., and Frick, David N. “Aurintricarboxylic Acid Modulates the Affinity of Hepatitis C Virus NS3 Helicase for Both Nucleic Acid and ATP.” Biochemistry 52 (36). (2013): 6151–6159.
Hanson, Alicia M., and Frick, David N. “Molecular Beacon based helicase assays on the FLUOstar Omega.” BMG Application Notes. (2013).
Mannan, M. Amin-ul, Shadrick, William R., Biener, Gabriel, Anshu, Ashish, Raicu, Valerica, Frick, David N., and Dey, Madhusudan. “An Ire1-Phk1 Chimera Reveals a Dispensable Role of Autokinase Activity in Endoplasmic Reticulum Stress Response.” J. Mol. Biol. 425. (2013): 2083-99.
Shadrick, William R., Ndjomou, Jean, Mukherjee, Sourav, Hanson, Alicia M., and Frick, David N. “Discovering New Medicines Targeting Helicases: Challenges and Recent Progress.” J Biomol Screen 18. (2013): 761-781.
Kelin, Li, Frankowski, Kevin J., Hanson, Alicia M., Ndjomou, Jean, Shanahan, Matthew A., Mukherjee, Sourav, Kolli, Rajesh, Shadrick, William R., Sweeney, Noreena L., Belon, Craig A., Neuenswander, Ben, Ferguson, Jill, Aubé, Jeff, Schoenen, Frank J., Blagg, Brian S., and Frick, David N. “Hepatitis C Virus NS3 Helicase Inhibitor Discovery.” Probe Reports from the NIH Molecular Libraries Program. (2013).
Sweeney, Noreena L., Shadrick, William W., Mukherjee, Sourav, Li, Kelin, Frankowski, Kevin J., Schoenen, Frank J., and Frick, David N. “Primuline Derivatives That Mimic RNA To Stimulate Hepatitis C Virus NS3 Helicase-Catalyzed ATP Hydrolysis.” J. Biol. Chem. 288. (2013): 19949-19957.
Ndjomou, Jean, Kolli, Rajesh, Mukherjee, Sourav, Shadrick, William R., Hanson, Alicia M., Sweeney, Noreena, Bartczak, Diana, Lin, Kelin, Frankowski, Kevin J., Schoenen, Frank J., and Frick, David N. “Fluorescent primuline derivatives inhibit hepatitis C virus NS3-catalyzed RNA unwinding, peptide hydrolysis and viral replicase formation.” Antiviral Research 96. (2012): 245-255.
Mukherjee, Sourav, Hanson, Alicia M., Shadrick, William R., Ndjomou, Jean, Sweeney, Noreena L., Herandez, John J., Bartczak, Diana, Li, Kevin, Frankowski, Kevin J., Heck, Julie A., Arnold, Alexander E., Schoenen, Frank J., and Frick, David N. “Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays.” Nucleic Acid Research 40.17 (2012): 8607-8621.
Hanson, Alicia M., Hernandez, John J., Shadrick, William R., and Frick, David N. “Identification and Analysis of Inhibitors Targeting the Hepatitis C Virus NS3 Helicase.” Methods in Enzymology 511. (2012): 463-483.
Mastrangelo, Eloise, Pezzullo, Margherita, De Burghgraeve, Tine, Kaptein, Suzanne, Pastorino, Boris, Dallmeier, Kai, de Lamballerie, Xavier, Neyts, Johan, Hanson, Alicia M., Frick, David N., Bolognesi, Martino, and Milani, Mario. “Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug.” Journal of Antimicrobial Chemotherapy 67. (2012): 1884-1894.
Li, Kevin, Frankowski, Kevin J., Belon, Craig A., Neuenswander, Ben, Ndjomou, Jean, Hanson, Hanson M., Shanahan, Matthew A., Schoenen, Frank J., Blagg, Brian S., Aube, Jeff, and Frick, David N. “Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline.” J. Med. Chem. 55. (2012): 3319-3330.
Peng, Lee F., Schaefer, Esperance A., Maloof, Nicole, Skaff, ANdrew, Berical, Andrew, Belon, Craig A., Heck, Julie A., Lin, Wenyu, Frick, David N., Allen, Todd M., Mizorko, Henry M., Schreiber, Stuart L., and Chung, Raymond T. “Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A synthase.” J Infect Dis. 204.4 (2011): 609-616.
Belon, Craig A., and Frick, David N. “Hepatitis C Virus NS3 Helicase inhibitors.” Hepatitis C: Antiviral Drug Discovery and Development. Hepatitis C: Antiviral Drug Discovery and Development: Caister Academic Press, (2011): 237-256.
Mousseau, G S., Takahashi, V, Frick, David N., and Strosberg, A D. “Dimerization-driven interaction of hepatitis C virus core protein with NS3 helicase.” Journal of General Virology 92. (2011): 101-111.
Lam, Angela M., Murakami, Eisuke, Espiritu, Christine, Micolochick Steuer, Holly M., Nui, Congrong, Keilman, Meg, Bao, Haiying, Zennou, Veronique, Bourne, Nigel, Julander,3, Justin G., Morrey, John D., Smee, Donald F., Frick, David N., Heck, Julie A., Wang, Peiyuan, Nagarathnam, Dhanapalan, Ross, Bruce S., Sofia, Michael J., Otto, Michael J., and Furman, Philip A. “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. 54.8 (2010): 3187 – 3196.