|
|
 |
Florida Faculty and Professional Staff
Timothy Tellinghuisen
Assistant Professor
Department of Infectology
TSRI - 2005
Education
B.S. - University of Massachusetts at Lowell (1992)
M.S. - University of Massachusetts at Lowell (1994)
Ph.D. - Purdue University (2000)
Post-Doctoral Training - The Rockefeller University (2005)
Research Focus
Hepatitis C virus (HCV) is a significant human pathogen and a problem of global importance, with estimates placing nearly 3% of the world’s population as chronically infected. Long-term viral replication in these individuals leads to significant liver disease, including cirrhosis and hepatocellular carcinoma. The current regimen of non-specific HCV therapeutics is poorly tolerated and ineffective in many patients, emphasizing the need for effective specific anti-viral drugs. Extensive structural and functional characterization of the HCV protease/helicase (NS3) and RNA dependent RNA polymerase (NS5B) has led to the development of new classes of potent small molecule inhibitors of HCV replication. Despite these advances, the high mutation rate inherent in RNA virus replication, and the subsequent evolution of drug resistance, dictates the development of new anti-virals for multi-drug ‘cocktail’ therapy. In contrast to NS3 and NS5B, studies on the NS5A protein, another replicase complex component, have lagged behind. NS5A remains enigmatic, with no known function in HCV replication. Our research has therefore invested heavily in the characterization of the NS5A protein. Through the use of biochemical and genetic methodology we have defined the NS5A protein as an absolutely required metalloprotein component of the HCV RNA replication machinery. Our recent crystal structure of the amino-terminal domain of NS5A has provided us a glimpse of the potential membrane, protein, and RNA interactions of NS5A in the viral replicase complex. Our long-term goal is to understand, at the molecular level, the assembly, composition, and functions of the HCV RNA replication machinery. Better understanding of the NS5A protein properties, interactions and functions will provide a more complete view of the replicase complex and potentially fuel new anti-viral drug design.
Selected References
Tellinghuisen, T.L., Marcotrigiano, J., Gorbalenya, A.E. and Rice, C.M. The Hepatitis C Virus NS5A Protein is a Zinc Metalloprotein. J. Biol. Chem. 279,47:48576-87, 2004.
Tellinghuisen, T.L., Marcotrigiano, J. and Rice, C.M. Structure of the Zinc-Binding Domain of an Essential Component of the Hepatitis C Virus Replicase. Nature. 435: 374-79, 2005.
Lindenbach, B.D., Evans, M.J., Syder, A., Woelk, B., McKeating, J.A., Tellinghuisen, T.L. and Rice, C.M. Complete Replication of Hepatitis C Virus in Cell Culture. Science. 309: 623-26, 2005.
|
|
|
|
