Date of Award

7-3-2024

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

First Advisor

Bryan Mounce

Abstract

Enteroviruses cause 10 to 15 million infections annually in the United States, and Coxsackievirus B3 is one of the most commonly reported. Coxsackieviruses may become persistent, characterized as a viral infection that is not cleared from host cells and that generates a continuous infection. Patients who develop persistent CVB3 infection may not respond to the same antivirals as an acute infection, which may be detrimental. Therefore, there is a need for broad-range antiviral drugs to combat acute and persistent CVB3 infection, as there is no well-accepted treatment available. We developed a model system to study persistent CVB3 using a pancreatic ductal cell line PANC-1, and we used Vero-E6 cells to study acute infection. We maintained persistently infected cells in tissue culture for over a year and characterized the infection. In efforts to identify novel antivirals, using the National Institutes of Health’s Developmental Therapeutics Program (DTP), we screened thousands of compounds for antiviral activity against acute and persistent CVB3, and among the top hits was Ro 5-3335. Ro 5-3335 is a 1,4-benzodiazepine nordazepam. It acts as RUNX1-CBFB inhibitor against acute myeloid leukemia. Further, it can inhibit gene expression in HIV-1 at the transcription level through interference with Tat-mediated transactivation. We find that Ro 5-3335 potently inhibits persistent and acute CVB3 infection, likely by affecting a cellular pathway. We also show that Ro 5-3335 is broadly antiviral and inhibits a variety of other human pathogens. This work underscores the importance of targeting persistent and acute infection and highlights the potential for Ro 5-3335 as a broad-acting antiviral molecule. Overall, Ro 5-3335 is a promising antiviral that can be used to target CVB3 at multiple stages of infection.

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