Frick, David
frickd@uwm.eduChemistry Building 333, , , ,

Frick, David

Professor
Chemistry-Biochemical

Education

B.A., Franklin & Marshall College
Ph.D., Johns Hopkins University
Postdoctoral, Harvard Medical School

Website

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

Research Area

My lab mainly studies the biochemistry of viral proteins and small molecules that interact with them in order to discover new antiviral drugs. Our main interest, presently, is in targeting helicases encoded by:

  • The hepatitis C virus (HCV)
  • Dengue virus (DENV)
  • West Nile Virus
  • SARS-CoV-2 (the virus causing COVID-19)

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 helicases from human cells, and other viral proteins as drug targets including 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

Selected Publications

Virdi, R S., Bavisotto, R V., Hopper, N C., Vuksanovic, N, Melkonian, T R., Silvaggi, Nicholas R., and Frick, David N. “Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3.” SLAS discovery : advancing life sciences R & D 25.10 (2020): 1162-1170.
Frick, David N., Virdi, R S., Vuksanovic, N, Dahal, N, and Silvaggi, Nicholas R. “Molecular Basis for ADP-Ribose Binding to the Mac1 Domain of SARS-CoV-2 nsp3.” Biochemistry 59.28 (2020): 2608-2615.
Ray, A, and Frick, David N. “Fluorescent probe displacement assays reveal unique nucleic acid binding properties of human nudix enzymes.” Analytical biochemistry 595. (2020): 113622.
Corby, M J., Raicu, Valerica, and Frick, David N. “New Techniques to Study Intracellular Receptors in Living Cells: Insights Into RIG-I-Like Receptor Signaling.” Advances in experimental medicine and biology 1111. (2019): 219-240.
Yerukhimovich, M M., Marohnic, C C., and Frick, David N. “Role of the Conserved DECH-Box Cysteine in Coupling Hepatitis C Virus Helicase-Catalyzed ATP Hydrolysis to RNA Unwinding.” Biochemistry 57.43 (2018): 6247-6255.
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.