Suppressing antiviral resistance via 'dominant drug targets'
Abstract/Contents
- Abstract
- The emergence of drug resistance can compromise or eliminate the success of pharmaceutical treatments, especially when the genes that encode these drug targets display high mutation rates. One method for suppressing resistance, multi-drug therapy, is not currently applicable to diseases for which the need for treatment is immediate yet only one drug, or more often none, is available. This thesis documents the efficacy of a new paradigm in which a single compound directed against a 'dominant drug target" of an RNA virus suppresses the emergence of drug resistance in cultured cells and in mice. This approach is based on the principle that viral mutations that confer increased fitness, such as drug resistance, arise during intracellular replication. Thus, new drug-resistant viral genomes cannot express their phenotypes in the absence of drug-susceptible genomes until they complete a single infectious cycle. For the targets of most anti-viral compounds drug-resistant genomes can nevertheless be readily selected. However, for V-073, a compound that targets the highly oligomeric poliovirus capsid, no outgrowth of drug-resistant viruses was observed in cultured cells or in mice presumably due to the formation of chimeric structures that contain both drug-susceptible and drug-resistant subunits. The general principle that pharmaceutical targeting of oligomeric structures can suppress drug resistance is applicable to any situation in which drug-resistant genomes are first expressed in the presence of drug-susceptible genomes and their products. Examples include tumor variants that arise by error-prone gene amplification, DNA and RNA viruses, and any pathogens that secrete products into a common milieu. Reduction of the numbers of compounds needed for treatment will be of significant benefit medically and economically, but will require revision of decision-making processes during drug development.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Tanner, Elizabeth Jane | |
|---|---|---|
| Associated with | Stanford University, Department of Genetics. | |
| Primary advisor | Kirkegaard, Karla | |
| Thesis advisor | Kirkegaard, Karla | |
| Thesis advisor | Fire, Andrew Zachary | |
| Thesis advisor | Sherlock, Gavin | |
| Thesis advisor | Stearns, Tim | |
| Advisor | Fire, Andrew Zachary | |
| Advisor | Sherlock, Gavin | |
| Advisor | Stearns, Tim |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Elizabeth Jane Tanner. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Elizabeth Jane Tanner
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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