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.

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.
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.
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.
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.
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.
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.