Dynamics of enteroviral polyprotein cleavages and implications for antiviral drug development
Abstract/Contents
- Abstract
- Enteroviruses are a group of positive stranded RNA viruses that primarily infect the enteric tract, but many species have also been associated with neurological complications, especially acute flaccid myelitis. While poliovirus, the most well studied member of this group, is on its way to eradication, there are other Enteroviruses currently circulating and causing disease, and outbreaks of vaccine associated polio still occur. Therefore, novel treatments are needed. Unfortunately, antiviral treatment is often thwarted by the emergence of drug resistant variants due to the high mutation rates of RNA viruses. One potential avenue for overcoming the problem of resistance is to choose targets that produce dominant inhibitors when interacting with the antiviral drug. Previous work in the lab showed that viral proteases that cleave themselves from the viral polyprotein obligately intra-molecularly can produce such dominant inhibitors by causing uncleaved viral precursor proteins to accumulate. In this work, I explore the potential for enteroviral proteases to produce dominant inhibitors. Chapter 1 summarizes relevant background information, including enterovirus biology, polyprotein processing, and the concept of dominant drug targets. In chapter 2, I identify intra-molecular cleavages in the poliovirus, EV-A71, and EV-D68 polyprotein processing cascades. In chapter 3, I determine the efficacy of existing antivirals for intra- vs inter- molecular cleavages, demonstrating that some antivirals can very effectively inhibit even rapid intra-molecular cleavages. In chapter 4, I show that blocking 2A protease cleavage in multiple enterovirus species can lead to suppression of wildtype viral growth in mixed populations, supporting the hypothesis that inhibiting 2A cleavage could lead to the production of dominant inhibitors. In chapter 5, I attempt to identify the mechanism by which 2A mutant genomes exert a dominance phenotype over more fit wildtype viral genomes. Finally, in chapter 6, I discuss remaining open questions and new research directions stemming from this work. The findings detailed here not only contribute to our understanding of basic enterovirus biology, but also illustrate a paradigm through which novel antiviral treatment approaches can be developed.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Doherty, Jennifer Suzanne |
|---|---|
| Degree supervisor | Kirkegaard, Karla |
| Thesis advisor | Kirkegaard, Karla |
| Thesis advisor | Carette, Jan |
| Thesis advisor | Fire, Andrew |
| Thesis advisor | Sherlock, Gavin |
| Degree committee member | Carette, Jan |
| Degree committee member | Fire, Andrew |
| Degree committee member | Sherlock, Gavin |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Genetics |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jennifer Doherty. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/gx407mb0202 |
Access conditions
- Copyright
- © 2023 by Jennifer Suzanne Doherty
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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