Daniel A. Engel
- PhD, Yale University
- Professor, Microbiology, Immunology, and Cancer Biology
- Phone: 434-924-8633
- Email: firstname.lastname@example.org
Drug discovery and molecular biology of influenza virus and dengue virus.
Drug Discovery and Molecular Biology of Influenza Virus and Dengue Virus
Treatment of two major viral diseases, influenza and dengue fever, would benefit from new pharmaceuticals. 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.
We are developing new approaches to identifying chemical inhibitors for influenza and dengue virus. 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. Finally, we are studying the enzymology and structure of the dengue virus protease in order to design specific chemical inhibitors that will block virus replication by inhibiting viral protease activity.
- Chen J, Morral N, Engel D. Transcription releases protein VII from adenovirus chromatin. Virology. 2007;369(2): 411-22. PMID: 17888479
- 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
- Rao M, Casimiro M, Lisanti M, D'Amico M, Wang C, Shirley L, Leader J, Liu M, Stallcup M, Engel D, Murphy D, Pestell R. Inhibition of cyclin D1 gene transcription by Brg-1. Cell cycle (Georgetown, Tex.). 2008;7(5): 647-55. PMID: 18239461
- 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
- Hagan K, Reedy C, Uchimoto M, Basu D, Engel D, Landers J. An integrated, valveless system for microfluidic purification and reverse transcription-PCR amplification of RNA for detection of infectious agents. Lab on a chip. 2010;11(5): 957-61. PMID: 21152489
- 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
- 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
- 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
- Schaack J, Qiao L, Walkiewicz M, Stonehouse M, Engel D, Vazquez-Torres A, Nordeen S, Shao J, Moorhead J. Insertion of CTCF-binding sites into a first-generation adenovirus vector reduces the innate inflammatory response and prolongs transgene expression. Virology. 2011;412(1): 136-45. PMID: 21272906
- 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