Date of Award

Spring 5-2020

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry and Molecular Biology

Advisor

Melissa Maginnis

Second Committee Member

Sally Molloy

Third Committee Member

Robert Gundersen

Abstract

JC polyomavirus (JCPyV) persists in up to 90% of the global human population. In healthy individuals, the virus resides within the kidneys resulting in a low-level infection. However, in severely immunocompromised individuals, the virus can migrate to the central nervous system (CNS), causing the demyelinating disease progressive multifocal leukoencephalopathy (PML). Currently, this debilitating disease has no clinical therapeutic options and is almost universally fatal. Specifics of the JCPyV infectious cycle, as well as the limitations of traditional laboratory techniques, have previously hindered the search for antiviral agents with the potential to prevent or treat JCPyV infection. To this end, a new high-throughput, in vitro method to measure JCPyV infectivity, the In-cell Western (ICW) assay, has been adapted to allow for rapid, consistent, and impartial analysis of the antiviral properties of large libraries of drugs and other small compounds. Utilizing this ICW platform, a large-scale drug screen was performed using the National Institute for Health (NIH) Clinical Collection, a library of over 700 drugs and small compounds, to identify drugs and compounds that reduce JCPyV infectivity. Through analysis and characterization of these compounds, heretofore unknown therapeutic agents against JCPyV have been identified, including drugs that target cell surface receptors and biochemical pathways involved in calcium and MAP kinase signaling. These compounds are the focus of further characterization to identify the cell-based mechanism by which they inhibit JCPyV infection. Findings from this study provide new information that significantly advances the field in the development of antiviral compounds to treat or prevent PML.

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