CPB 69700 RESEARCH SEMINAR

DEPARTMENT OF COMPARATIVE PATHOBIOLOGY

Michael Owston, DVM, MS, Dipl. ACVP
Graduate Student in Anatomic Pathology

Department of Comparative Pathobiology

Purdue University

“Characterization of flavivirus inhibitors”

Thurs., April 9, 2009

VPTH 112

3:30 pm

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Abstract: The flaviviruses are agents of worldwide importance and include dengue, yellow fever, and West Nile viruses. Despite worldwide vaccination availability, yellow fever virus is still estimated to infect 200,000 people and kill 30,000 people annually. There is no approved vaccine against dengue virus, and it infects 50-100 million and kills 25,000-50,000 annually. Since the introduction of West Nile virus to the USA, over 1,000 human deaths in the USA have been reported. By using a high-throughput screen of more than 30,000 compounds, six antivirals were identified that were effective inhibitors of yellow fever RNA replication. A virus mutant partially resistant to the inhibitory effects of two of these compounds was identified after serial passages of virus in the presence of compound. This virus had a single amino acid substitution in the non-structural protein 4B (NS4B), which has previously been shown to have inhibitory action on the host antiviral response. A mutation in NS5 was also present, but this mutation by itself was shown to not confer resistance. Second generation compounds, based on the structure of the most effective compound, have helped to identify important components of the compounds that enhance their activity. Additionally, preliminary results on the activity of these compounds against West Nile and dengue replication will be presented.