Flavivirus RNA Replication: Essential Viral Functions as Targets for Antiviral Therapeutics
MEDIMMUNE INC GAITHERSBURG MD
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The objective of this contract research was to gain a detailed understanding of the molecular events involved in flavivirus RNA replication, with the ultimate aim being the identification of inhibitors of the process. We established yellow fever virus YFV as our study system and assembled all the necessary virologic, molecular biologic, and immunologic reagents for the detailed study of viral RNA replication. Methodologies for detection, identification, and analysis of YFV polypeptides and RNA species were in place. Several YFV protein coding regions were engineered into various surrogate expression systems, and the recombinant proteins thereby produced would have served as important sources of material for functional biochemical studies if not for the premature termination of this contract by the government. An RNA dependent RNA polymerase RDRP activity derived from virus infected cells was identified and extensively characterized. A specific, reproducible, and quantifiable assay for this activity was established. A number of peptide based compounds were designed, synthesized, and tested for inhibition of the RDRP activity in this assay. Preliminary data suggested several were inhibitory. Molecular modeling of peptides was investigated for its utility in assisting in next generation inhibitor design.
- Genetic Engineering and Molecular Biology