Treatment of Dengue Virus Infection with Repurposed Pharmaceuticals that Inhibit Cellular Autophagy
Abstract
Dengue virus infection is responsible for 50 to 100 million infections per year worldwide and has plagued US military personnel for decades. Its incidence and severity are increasing due to the widening geographic range of the mosquitos that transmit it, and it is no longer limited to tropical climates. US military personnel are especially at risk due to their frequent geographical changes in deployment because the severity of the symptoms associated with dengue virus infections increases with subsequent exposure to new types of virus. There are currently no vaccines or treatments for dengue virus infection, and the development of new medicines is costly and time-consuming. The research proposed here is to take advantage of new computational approaches to search databases of existing pharmaceuticals and other compounds whose effects on humans are known that inhibit dengue virus. Dengue virus growth relies on the cellular autophagy pathway, and it is known that autophagy can be inhibited in the short term, at least in mice, without harm. The query compound will be spautin-1 (specific and potent autophagy inhibitor), which is, as its name implies, the most effective small-molecule inhibitor of autophagy found to date. It is also a potent inhibitor of dengue virus infection. Compounds will be identified computationally and tested for their inhibition of dengue virus in mice. One such compound has already been identified. Inhibitors will be subsequently studied for their mechanism of action and ability to block dengue pathogenesis in mice. One reason to target host processes to treat viral infections is to decrease the frequency of drug resistance, and this hypothesis will be tested directly. Successful completion of this project should result in the identification of one or more Food and Drug Administration-approved compounds ready to be tested in clinical trials for their efficacy against dengue virus infection in military and civilian populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610074
Entities
People
- Karla Kirkegaard
Organizations
- Stanford University
- United States Army