Neurotropic alphaviruses such as western, eastern, and Venezuelan equine encephalitis viruses are transmitted by mosquitoes, cause serious and potentially fatal central nervous system infections in humans, and are considered NIAID Category B Priority Pathogens due to their potential misuse as bioterrorism agents. Although vaccine development is in progress for several alphaviruses, there is an urgent and pressing need for broadly active antiviral agents against these virulent pathogens. Studies with experimental alphavirus encephalitis in mice have shown that while neurons are damaged directly by virus, uninfected neurons are also damaged via bystander mechanisms that involve altered homeostatic and neuroprotective functions of microglial cells or astrocytes. Thus, we hypothesize that combination therapy that directly targets virus replication and enhances neuroprotective responses will provide synergistic benefit in viral encephalitis. To identify and develop new antivirals to test this hypothesis, we recently screened a chemically defined small molecule library and identified a thieno[3,2-b]pyrrole compound that has potent activity against neurotropic alphaviruses in culture. Furthermore, a limited structure-activity relationship analysis with twenty structurally related analogs identified six additional compounds with enhanced in vitro activity. In addition, to explore the innovative use of natural products as a source for novel antivirals, we analyzed a series of extracts derived from marine actinomycetes and identified several that contained potent activity against alphaviruses. We are currently positioned to rapidly and efficiently move candidate antivirals through preclinical development, and we have assembled a team of experienced investigators with diverse expertise in the fields of virology, neurology, pathology, physiology, and medicinal chemistry to accomplish this task. The long-term goals of this highly collaborative project are to develop effective and broadly active therapies for encephalitis caused by neurotropic alphaviruses and related arboviruses.
The specific aims of this proposal are: (1) targeted chemical modification of lead antiviral compounds, based on the initial structure-activity relationship analysis, to enhance potency, reduce toxicity, improve solubility and metabolic stability, and optimize membrane permeability;(2) identify molecular target(s) responsible for their antiviral activity;(3) analyze the in vivo pharmacokinetics and efficacy of candidate antivirals, including combination treatment with neuroprotective agents;and (4) isolate and characterize novel compounds with antiviral activity derived from marine microbes.

Public Health Relevance

This study will examine the use of combination therapies to treat central nervous system infections caused by potentially deadly viruses that are transmitted by insects. This novel treatment approach is designed to provide enhanced benefit over treatment with individual drugs, and is directly relevant to public health as there are currently no effective medications to treat the frequently devastating diseases caused by these viruses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-FDS-M (M1))
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Tseng, Christopher K
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Barraza, Scott J; Delekta, Philip C; Sindac, Janice A et al. (2015) Discovery of anthranilamides as a novel class of inhibitors of neurotropic alphavirus replication. Bioorg Med Chem 23:1569-87
Blakely, Pennelope K; Delekta, Phillip C; Miller, David J et al. (2015) Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development. J Neurovirol 21:43-55
Delekta, Phillip C; Dobry, Craig J; Sindac, Janice A et al. (2014) Novel indole-2-carboxamide compounds are potent broad-spectrum antivirals active against western equine encephalitis virus in vivo. J Virol 88:11199-214
Sindac, Janice A; Barraza, Scott J; Dobry, Craig J et al. (2013) Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication. J Med Chem 56:9222-41
Sindac, Janice A; Yestrepsky, Bryan D; Barraza, Scott J et al. (2012) Novel inhibitors of neurotropic alphavirus replication that improve host survival in a mouse model of acute viral encephalitis. J Med Chem 55:3535-45