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
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
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.
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.