The CDC and NIAID have classified Ebola virus (EBOV) and Marburg virus (MARV) as Category A priority pathogens. EBOV and MARV cause severe and often fatal hemorrhagic fever in humans and nonhuman primates with case fatality rates up to 90% for some species or strains such as EBOV Zaire and MARV strain Angola. There are presently no approved active or passive therapeutic modalities for EBOV infections resulting from a natural outbreak, laboratory accident, or deliberate misuse. Therefore, identification of effective small molecule inhibitors of filoviral IFN-antagonists and of VP30 function that can be developed into drugs would be of high significance. The goal of this Center Is to develop small molecule anti-filoviral therapeutics that target filoviralinterferon (IFN) antagonist functions and VP30 function. Fundamental to this effort will be the testing of candidate compounds for antiviral activity against EBOV and MARV in cell culture and in animal models. Such testing must be performed at Biosafety Level 4 / Animal Biosafety level 4 (BSL- 4/ABSL-4) in accordance with Select Agent rules. The BSL4 core will first evaluate the antiviral activity of compounds identified by Projects 2 and 3 in cell culture. Lead inhibitors will be further evaluated In the mouse and guinea pig models of EBOV or MARV Infections to identify the best preclinical development candidates. Therefore, Core B will provide the proof of concept for the antiviral activities of hit compounds isolated In Projects 2 and 3. Moreover, Core B has an Important role in the hit to lead optimization. Its efforts together with the efforts from Projects 1, 2 and 3 will provide the relationships between analog structure and four key features - anti-filovirus activity, In vitro ADME including potential oral bioavailability, in vivo efficacy and safety. Further, an understanding of the MOA, as outlined in Projects 1 and 3, will be very Important In the design and future development of these first-in-class inhibitors by, for example, alleviating concerns about target-based toxicity.

Public Health Relevance

The proposed research is relevant to public health because It is aimed at development of a drug which will target the Interaction of a viral protein with a host enzyme and which is likely to be active against all species of filoviruses. The proposed research is relevant to the NIH mission that pertains to a reduced vulnerability of the population to biothreat agents, including hemorrhagic fever viruses.

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 #
8642744
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
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
$517,441
Indirect Cost
$62,368
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Knoverek, Catherine R; Amarasinghe, Gaya K; Bowman, Gregory R (2018) Advanced Methods for Accessing Protein Shape-Shifting Present New Therapeutic Opportunities. Trends Biochem Sci :
Ivanov, Andrey; Lin, Xionghao; Ammosova, Tatiana et al. (2018) HIV-1 Tat phosphorylation on Ser-16 residue modulates HIV-1 transcription. Retrovirology 15:39
Chanthamontri, C Ken; Jordan, David; Wang, Wenjie et al. (2018) Ebola Viral Protein 35 N-terminus is a Parallel Tetramer. Biochemistry :
Dashti, Hesam; Wedell, Jonathan R; Westler, William M et al. (2018) Applications of Parametrized NMR Spin Systems of Small Molecules. Anal Chem 90:10646-10649
Fink, Susan L; Vojtech, Lucia; Wagoner, Jessica et al. (2018) The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep 8:8989
Tigabu, Bersabeh; Ramanathan, Palaniappan; Ivanov, Andrey et al. (2018) PHOSPHORYLATED VP30 OF MARBURG VIRUS IS A REPRESSOR OF TRANSCRIPTION. J Virol :
Su, Zhaoming; Wu, Chao; Shi, Liuqing et al. (2018) Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly. Cell 172:966-978.e12
Luthra, Priya; Liang, Jue; Pietzsch, Colette A et al. (2018) A high throughput screen identifies benzoquinoline compounds as inhibitors of Ebola virus replication. Antiviral Res 150:193-201
Duehr, James; Wohlbold, Teddy John; Oestereich, Lisa et al. (2017) Novel Cross-Reactive Monoclonal Antibodies against Ebolavirus Glycoproteins Show Protection in a Murine Challenge Model. J Virol 91:
Lin, Xionghao; Kumari, Namita; DeMarino, Catherine et al. (2017) Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03. Oncotarget 8:76749-76769

Showing the most recent 10 out of 47 publications