Novel Broad-Spectrum Flavivirus Inhibitors
At A Glance
Researchers at Colorado State University in collaboration with the University of Northern Colorado have developed a new antiviral therapeutics for treatment of mosquito-borne flavivirus infection, which includes Dengue, West Nile and Yellow Fever.
The novel broad-spectrum anti-flaviviral target was created using a high throughput screening protocol to identify a series of small molecule inhibitory candidates. These inhibitory compounds, as described in a recent Journal of Virology publication, target the enzyme that is responsible for capping the RNA viral genome. In vitro studies indicate the compounds demonstrate good specificity and low toxicity.
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Arthropod-borne virus infections remain a major cause of morbidity and mortality worldwide. More than two billion people are at risk of infection with dengue virus (DEN) and 600 million people at risk of infection with yellow fever virus (YF) (20). Globally, an estimated 50-100 million cases of DEN and 200,000 cases of YF are reported each year, which infections result in approximately 20,000 (DEN) and 30,000 (YF) deaths annually (11). There are currently no clinically useable chemotherapeutic options for the treatment of any flavivirus infection, making it essential that new strategies and targets for the treatment of flavivirus infections be identified.
- Lead compound demonstrates improved activity over Ribavirin
- GTP displacement assay allows for high throughput screening of small molecule compounds
- The RNA capping enzyme is conserved across multiple flaviviruses including dengue, West Nile, and yellow fever viruses
Bullard, KM, et al. “Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323.” PloS One, U.S. National Library of Medicine, 2015, pubmed.ncbi.nlm.nih.gov/26075394/.
J Virol.2012 Jun 6. [Epub ahead of print]J Biomol Screen.2011 Sep;16(8):852-61.J Mol Biol.2009 Feb 6;385(5):1643-54Stahla-Beek, Hillary J, et al. “Identification of a Novel Antiviral Inhibitor of the Flavivirus Guanylyltransferase Enzyme.” Journal of Virology, American Society for Microbiology, Aug. 2012, www.ncbi.nlm.nih.gov/pubmed/22674988#.
Geiss, Brian J, et al. “A High-Throughput Screening Assay for the Identification of Flavivirus NS5 Capping Enzyme GTP-Binding Inhibitors: Implications for Antiviral Drug Development.” Journal of Biomolecular Screening, U.S. National Library of Medicine, Sept. 2011, www.ncbi.nlm.nih.gov/pubmed/21788392#.
Geiss, Brian J, et al. “Analysis of Flavivirus NS5 Methyltransferase Cap Binding.” Journal of Molecular Biology, U.S. National Library of Medicine, 6 Feb. 2009, www.ncbi.nlm.nih.gov/pubmed/19101564#.
Last updated: May 2020