Holmstrom Research Project Summary
Viruses are the most numerous biological entities on the planet and can often be extremely pathogenic and globally concerning. For example, the hepatitis C virus (HCV) is a widespread pathogen that infects more than 1 in 50 people worldwide and is responsible for a wide range of progressive hepatotropic diseases. Fortunately, nucleocapsid assembly is a fundamental biochemical process in the viral life cycle that can be targeted by anti-viral agents. For the HCV, nucleocapsid formation is driven by interactions between multiple copies of the multifunctional core protein (HCVcp) and the genomic RNA. Additionally, HCVcp is the most conserved protein of all 10 HCV proteins. For these reasons, the HCVcp represents a promising therapeutic target within the assembly pathway.
However, this approach has not yet been heavily explored because many structural details associated with HCV nucleocapsid formation remain unknown. This research project will help resolve these crucial gaps in knowledge and provide a biophysical description of the HCV assembly pathway by studying the RNA-induced formation of nucleocapsid-like particles (NLPs). Using a wide range of single-molecule fluorescence techniques, including microfluidic mixing, we will identify the molecular mechanisms governing the assembly process. Such models will then be used to identify the mode of action associated with a variety of small molecule, peptide, and nucleic acid aptamer-based agents reported to inhibit various aspects of nucleocapsid assembly.