Infection by flaviviruses such as dengue, yellow fever, and West Nile is a major medical and socioeconomic problem worldwide, yet effective antiviral therapeutics to treat flavivirus infection are not currently available. As such, it is imperative that potent, selective, and cost-effective antiviral compounds be identified. The overall goal of this project is the discovery of novel inhibitors of the flavivirus RNA methyltransferase (MTase) enzyme that can serve as effective broad-spectrum chemotherapeutic agents for the treatment of flavivirus infection. The MTase enzyme generates the cap structure at the 5' end of viral RNAs that is required for efficient translation of the viral genome and is essential for viral growth. We have designed and successfully implemented a simple and rapid in vitro high-throughput assay to identify compounds that interfere with RNA cap binding by the MTase. Our initial validation screen of molecule libraries at the National Screening Laboratory (NSRB) has identified a number of compounds as MTase inhibitors. In this project, we propose to expand on these results with the goal of identifying and optimizing a chemically diverse set of MTase cap-binding inhibitors in order to identify lead compounds for drug development.
Specific Aim 1 : We will perform additional HTS and will biochemically determine the inhibition constants and antiviral activity for additional hit compounds.
Specific Aim 2 : Using the resulting information, we will employ an integrated array of in silico molecular modeling techniques to identify structurally related small molecule compounds which based on our structural knowledge of the RNA cap binding site and in silico analysis will have improved affinity and cross selectivity for flavivirus MTase proteins and acceptable drug-like characteristics. We will also employ medicinal chemistry to design and synthesize derivatives when necessary to improve physiochemical properties.
Specific Aim 3 : The best inhibitors (in terms of breadth, potency and drug-like characteristics) will be tested for antiviral activity in cell culture and for the potential for emergence of resistance Inhibitors. Inhibitory effects for lead compounds will be determined against West Nile virus in an existing mouse model. This project takes advantage of an ongoing collaboration that brings together the expertise (virology and computational biology) of the lead investigators and will result in the rapid and efficient identification of inhibitors of flavivirus replication with the ultimate goal of describing lead compounds with drug-like properties suitable for preclinical development for the treatment flavivirus infection. This research Project fits within the RMRCE Integrated Research Focus on Viral Therapeutics, and will interact directly with RPs 3.1 and 3.8 and utilize the resources of Core C.

Public Health Relevance

Mosquito-borne hemorrhagic-fever resulting from flavivirus infection causes significant human morbidity and mortality throughout the world, yet there are currently no effective therapeutics to treat infected patients. The goal of this project is to utilize biochemical and rational drug design methodologies to identify and characterize broadly active antiviral compounds targeting the conserved flaviviral methyltransferase.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Colorado State University-Fort Collins
Fort Collins
United States
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Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99
Wang, Hong; Siddharthan, Venkatraman; Hall, Jeffery O et al. (2014) Autonomic deficit not the cause of death in West Nile virus neurological disease. Clin Auton Res 24:15-23
Scharton, Dionna; Bailey, Kevin W; Vest, Zachary et al. (2014) Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. Antiviral Res 104:84-92
Shives, Katherine D; Beatman, Erica L; Chamanian, Mastooreh et al. (2014) West nile virus-induced activation of mammalian target of rapamycin complex 1 supports viral growth and viral protein expression. J Virol 88:9458-71
Calvert, Amanda E; Dixon, Kandice L; Delorey, Mark J et al. (2014) Development of a small animal peripheral challenge model of Japanese encephalitis virus using interferon deficient AG129 mice and the SA14-14-2 vaccine virus strain. Vaccine 32:258-64
Richert, Laura E; Rynda-Apple, Agnieszka; Harmsen, Ann L et al. (2014) CD11cýýý cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice. Eur J Immunol 44:397-408
Soffler, Carl; Bosco-Lauth, Angela M; Aboellail, Tawfik A et al. (2014) Pathogenesis of percutaneous infection of goats with Burkholderia pseudomallei: clinical, pathologic, and immunological responses in chronic melioidosis. Int J Exp Pathol 95:101-19
Porta, Jason; Jose, Joyce; Roehrig, John T et al. (2014) Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies. J Virol 88:9616-23
Jones-Carson, Jessica; Zweifel, Adrienne E; Tapscott, Timothy et al. (2014) Nitric oxide from IFN?-primed macrophages modulates the antimicrobial activity of ?-lactams against the intracellular pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella. PLoS Negl Trop Dis 8:e3079
Phillips, Aaron T; Schountz, Tony; Toth, Ann M et al. (2014) Liposome-antigen-nucleic acid complexes protect mice from lethal challenge with western and eastern equine encephalitis viruses. J Virol 88:1771-80

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