Frick, David
Member
Milwaukee Institute for Drug Discovery (MIDD)
Professor of Chemistry and Biochemistry
Website
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.
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.