Viral hemorrhagic fevers represent a serious public health problem, with recurring outbreaks of hemorrhagic fever occurring in all parts of the world. Some of the most severe hemorrhagic fevers are caused by arenaviruses, of which Lassa fever virus (LFV) infects the greatest number of people. There are currently no vaccines available against Lassa fever, and avenues of treatment for infection by LFV are limited due to the lack of availability of sustainable neutralizing antibodies against the virus. In addition, the severity of the illness has resulted in arenaviruses being classified as Category A pathogens with devastating applications as biological weapons. A key facet of this proposal is to obtain training in the field of virology in contemporary techniques associated with purification and characterization of viruses and the immune responses that result from infection. The investigator's expertise resides in the field of small molecules and their uses in bacteria for inhibition of protein-protein and protein-DNA interactions. This project will expand this expertise into the field of virology, and enable the acquisition of key laboratory skills as the foundation for a career in virology and infectious disease. The experimental aims of this project are twofold. First, we will optimize candidate small molecule inhibitors of LFV binding and entry into cells. Using high-throughput screening of a series of combinatorial chemical libraries in a cell-based reporter assay, we will find specific inhibitors of the interaction between LFV and cellular entry factors as a precursor to viral entry. Second, we will express, purify, and characterize the soluble form of the LFV glycoprotein, which is critical for the entry and fusion of the virus into the cell, and explore the effects of the small molecule inhibitors isolated in Aim 1 on the GP itself, identifying sites of interaction between the glycoprotein and the small molecule and determining key structural targets for inhibition of arenaviral entry and fusion. From this, we can begin to formulate new therapeutic strategies that prevent fatality as a result of Lassa fever. New therapeutic strategies for LFV infection will provide a significant public health benefit, as the economics and availability of current therapies do not provide a viable option for treatment of Lassa fever in underdeveloped areas. By exploring the mechanisms of infection, as well as small molecules as an avenue for development of a drug to block LFV-receptor attachment and viral entry, we hope to develop a universally applicable anti-viral therapy that can be readily deployed to treat arenavirus infection in case of large scale outbreaks or bioterrorism. ? ? ?
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| Lee, Andrew M; Pasquato, Antonella; Kunz, Stefan (2011) Novel approaches in anti-arenaviral drug development. Virology 411:163-9 |
| Whitby, Landon R; Lee, Andrew M; Kunz, Stefan et al. (2009) Characterization of lassa virus cell entry inhibitors: determination of the active enantiomer by asymmetric synthesis. Bioorg Med Chem Lett 19:3771-4 |
