There remains a clear unmet need for filovirus-specific therapeutics. We previously identified as potential antiviral targets filoviral innate immune evasion proteins;the Ebola virus (EBOV) VP35 (eVP35) and Marburg virus (MARV) VP35 (mVP35), the EBOV VP24 and the MARV VP40 proteins. We demonstrated that eVP35 and mVP35 impair IFNapha/beta production by targeting RIG-l-like receptor (RLR) signaling pathways. We further defined the molecular, biochemical and structural bases for these inhibitory functions. Validating VP35s as therapeutic targets, we also found that EBOVs impaired for VP35 IFN-antagonist function fail to cause disease in any animal model tested. VP35 inhibitors should therefore have therapeutic benefit. We also demonstrated that the EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins inhibit Jak-STAT signaling triggered by IFN-alpha/beta and IFN-gamma, thereby blocking their antiviral effects. Further, our mVP40 data Implicate its IFN antagonist function as a virulence determinant in mice. These IFN Inhibitory functions likely contribute to the Ineffectiveness of IFNs as anti-filoviral therapies. Drugs that Inhibit eVP24 or mVP40 IFN-antagonist functions should augment the antiviral effects of therapeutically-administered IFNs or IFNs produced during the course of infection. Such inhibitors should also synergize with inhibitors of VP35 which will trigger production of IFN-alpha/beta specifically In Infected cells. Here, we capitalize on an established, highly productive collaboration (between the Basler and Amarasinghe labs) and our previous identification of these proteins as potential therapeutic targets to develop assays for high throughput screening for inhibitors of filoviral IFN-antagonist functions. The assays will be provided to Project 2, who will perform high throughput screens and identify and optimize leads. Leads identified by Project 2 will be passed to Project 1 to validate binding, determine the functional and structural basis for their action, define structure-based optimization strategies, and assess pan-filoviral potential by testing their impact on the function of IFN-antagonists from all EBOV species and MARV clades. These assessments will inform the optimization of leads through medicinal chemistry, which will be performed by Project 2.

Public Health Relevance

Ebola and Marburg filoviruses cause a highly lethal hemorrhagic fever and are of concern as potential bioweapons. This project will develop inhibitors targeting the filovirus Innate Immune evasion functions as anti-Ebola and Marburg virus therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109664-01
Application #
8642738
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$711,891
Indirect Cost
$85,804
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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