Lassa fever virus (LASV) is endemic in West Africa and causes human hemorrhagic fever with high fatality rate in certain circumstances. Because of its extreme virulent nature, lack of effective treatment modality, and ease of transmission, LASV is classified in the Category A Pathogen list by the CDC and therefore can only be manipulated in the Biosafety level 4 (BSL-4) facilities. Ribavirin is the only known compound thatshows some beneficial effect against LASV infection if it is administered early in the course of infection. However, because the illness is insidious and usually begins with non-specific flu-like symptoms, most patients are not accurately diagnosed early enough for this treatment. It is therefore necessary to identify additional pro-drugs and more effective compounds against LASV infection. We have recently established anon-hazardous replicon system for studying LASV viral RNA synthesis in a conventional BSL-2 laboratory. We propose here to utilize this reporter-based system to develop a robust and convenient high-throughput assay to search for novel anti-LASV compounds that specifically target viral RNA synthesis.
Aim 1 : we will establish and validate the high throughput screening method by using ribavirin as an anti-viral agent.
Aim 2 : we will perform an initial screen against a library of 1280 compounds with documented pharmacological activities. Primary hits will be screened by a secondary biological assay. Our long-term goal is to screen against a library of ~100,000 compounds for unknown compounds with potent antiviral activity. These studies may yield potential pro-drug candidates for further development. These know or unknown compounds will likely be effective against LASV and perhaps also other pathogenic arenaviruses that cancause deadly hemorrhagic fevers in humans. They may also provide invaluable tools for studying arenavirus biology.
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