Daniel A. Engel
- PhD, Yale University
- Professor, Microbiology, Immunology, and Cancer Biology
- Phone: 434-924-8633
- Email: email@example.com
Drug Discovery and Molecular Biology of Pathogenic RNA viruses: Influenza, Dengue and Ebola.
Drug Discovery and Molecular Biology of Pathogenic RNA viruses: Influenza, Dengue and Ebola
Influenza, dengue fever, and Ebola hemorrhagic fever are diseases caused by highly pathogenic RNA viruses which have proven difficult to target for drug discovery. For influenza, the yearly "seasonal" vaccine does not keep up with the constant genetic drift of the virus, or with new pandemic strains. For dengue virus, there are no vaccines or drugs available despite approximately 100 million cases per year worldwide. Ebola virus remains unchallenged by pharmaceuticals.
We are developing new approaches to identifying chemical inhibitors for these three viruses. One approach is "chemical-genetic", and it employs the budding yeast Saccharomyces cerevisiae as a test tube. We genetically modify yeast to express specific viral proteins such as the NS1 protein from influenza virus. This expression system is then used to screen for new chemical compounds that can inhibit the function of the viral protein in the yeast cell. Next, the inhibitors are tested for their ability to block virus replication in mammalian cell culture. Their mechanisms of action are studied using a combination of molecular, genetic, medicinal chemistry and structural biology methods.
In the case of the influenza NS1 protein, which normally blocks the host cell's interferon system, our inhibitors restore both interferon signaling and the host cell's ability to prevent virus replication. It is hoped that these antiviral compounds will be useful clinically and also as probes of biological function. We are using similar chemical-genetic approaches to target cellular "host factors" that are required for dengue virus replication. We are also studying the enzymology and structure of the dengue virus protease, which is critically required for viral infection, in order to design specific chemical inhibitors that will block virus replication by inhibiting viral protease activity.
- Dziubańska P, Derewenda U, Ellena J, Engel D, Derewenda Z. The structure of the C-terminal domain of the Zaire ebolavirus nucleoprotein. Acta crystallographica. Section D, Biological crystallography. 2014;70 2420-9. PMID: 25195755 | PMCID: PMC4157450
- The influenza virus NS1 protein as a therapeutic target. Antiviral research. 2013;99(3): 409-416. PMID: 23796981
- Suomalainen M, Luisoni S, Boucke K, Bianchi S, Engel D, Greber U. A direct and versatile assay measuring membrane penetration of adenovirus in single cells. Journal of virology. 2013. PMID: 24027314 | PMCID: PMC3807902
- Gupta A, Jha S, Engel D, Ornelles D, Dutta A. Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Oncogene. 2012. PMID: 23178490 | PMCID: PMC3955737
- Frieman M, Basu D, Matthews K, Taylor J, Jones G, Pickles R, Baric R, Engel D. Yeast based small molecule screen for inhibitors of SARS-CoV. PloS one. 2011;6(12): e28479. PMID: 22164298 | PMCID: PMC3229576
- Jablonski J, Basu D, Engel D, Geysen H. Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. Bioorganic & medicinal chemistry. 2011;20(1): 487-97. PMID: 22099257 | PMCID: NIHMS333169
- Walkiewicz M, Basu D, Jablonski J, Geysen H, Engel D. Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner. The Journal of general virology. 2010;92 60-70. PMID: 20881091 | PMCID: PMC3052532
- Walkiewicz M, Morral N, Engel D. Accurate single-day titration of adenovirus vectors based on equivalence of protein VII nuclear dots and infectious particles. Journal of virological methods. 2009;159(2): 251-8. PMID: 19406166 | PMCID: PMC2774845
- Basu D, Walkiewicz M, Frieman M, Baric R, Auble D, Engel D. Novel influenza virus NS1 antagonists block replication and restore innate immune function. Journal of virology. 2008;83(4): 1881-91. PMID: 19052087 | PMCID: PMC2643796
- Johnson J, Osheim Y, Xue Y, Emanuel M, Lewis P, Bankovich A, Beyer A, Engel D. Adenovirus protein VII condenses DNA, represses transcription, and associates with transcriptional activator E1A. Journal of virology. 2004;78(12): 6459-68. PMID: 15163739 | PMCID: PMC416553