The filoviruses, the Ebola and Marburg viruses (EBOVs and MARVs), are NIAID category A priority pathogens which cause highly lethal hemorrhagic fever in humans with fatality rates approaching 90 percent. Identification of therapeutic targets and advancing medical countermeasures for these threats is of high priority. Despite this need, no approved therapeutics are available for filoviral infections. To address this unmet need we propose to develop small molecule therapeutics that specifically target viral innate immune evasion functions and viral transcription. The combination of approaches is expected to yield individual panfilovirus inhibitors with different mechanisms of action, which when combined are expected to act synergistically. Combining inhibitors of viral innate immune evasion with viral transcription inhibitors is particularly appealing, from the point of view of synergy. This is because specific suppression of viral transcription will reduce levels of the IFN-antagonists, while also allowing viral replication to proceed, which is a process that can trigger IFN responses. To achieve these goals, the Center, which consists of a diverse team with extensive experience in filovirus biology, antiviral development and medicinal chemistry, will (1) Develop assays and perform HTS screens to identify and optimize small molecule inhibitors of the EBOV and MARV VP35 IFN-antagonists which function to suppress interferon (IFN)-alpha/beta production in filovirus-infected cells. (2) Develop assays and perform HTS screens to identify and optimize small molecule inhibitors of the filovirus antagonists of IFN-induced Jak-STAT signaling, the EBOV VP24 and MARV VP40 proteins. (3) Develop small molecule inhibitors of EBOV and MARV VP30 dephosphorylation that block viral transcription. (4) Evaluate leads and optimized leads for antiviral activity in cell culture and in animal models, prioritizing those with pan-filoviral potential. The expected outcome of this work is the development of inhibitors of filovirus replication that target viral IFN-antagonists and VP30 dephosphorylation and independently display pan-filovirus efficacy in mouse and guinea pig model. We further expect that these therapeutics will exhibit synergistic activities in vivo.

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 #
8641483
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Beanan, Maureen J
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$3,211,769
Indirect Cost
$387,115
Name
Icahn School of Medicine at Mount Sinai
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Esposito, Anthony M; Cheung, Pamela; Swartz, Talia H et al. (2016) A high throughput Cre-lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry. Virology 490:6-16
Pleet, Michelle L; Mathiesen, Allison; DeMarino, Catherine et al. (2016) Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction. Front Microbiol 7:1765
Leung, Daisy W; Amarasinghe, Gaya K (2016) When your cap matters: structural insights into self vs non-self recognition of 5' RNA by immunomodulatory host proteins. Curr Opin Struct Biol 36:133-41
Baer, Alan; Shafagati, Nazly; Benedict, Ashwini et al. (2016) Protein Phosphatase-1 regulates Rift Valley fever virus replication. Antiviral Res 127:79-89
Edwards, Megan R; Liu, Gai; Mire, Chad E et al. (2016) Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins. Cell Rep 14:1632-40
Rialdi, Alex; Campisi, Laura; Zhao, Nan et al. (2016) Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352:aad7993
Chatterjee, Srirupa; Basler, Christopher F; Amarasinghe, Gaya K et al. (2016) Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses. J Mol Biol 428:3467-82
Basler, Christopher F (2015) Innate immune evasion by filoviruses. Virology 479-480:122-30
Messaoudi, Ilhem; Basler, Christopher F (2015) Immunological features underlying viral hemorrhagic fevers. Curr Opin Immunol 36:38-46
Edwards, Megan R; Pietzsch, Colette; Vausselin, Thibaut et al. (2015) High-Throughput Minigenome System for Identifying Small-Molecule Inhibitors of Ebola Virus Replication. ACS Infect Dis 1:380-7

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