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
Ammosova, Tatyana; Platonov, Maxim; Ivanov, Andrei et al. (2014) 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription. Br J Pharmacol 171:5059-75
Shabman, Reed S; Jabado, Omar J; Mire, Chad E et al. (2014) Deep sequencing identifies noncanonical editing of Ebola and Marburg virus RNAs in infected cells. MBio 5:e02011
Basler, Christopher F (2014) New hope in the search for Ebola virus treatments. Immunity 41:515-7
Johnson, Joshua C; Martinez, Osvaldo; Honko, Anna N et al. (2014) Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells. Antiviral Res 107:102-9
Xu, Wei; Edwards, Megan R; Borek, Dominika M et al. (2014) Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16:187-200
Kumari, Namita; Iordanskiy, Sergey; Kovalskyy, Dmytro et al. (2014) Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase I?B-? expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription. Antimicrob Agents Chemother 58:6558-71
Basler, Christopher F; Woo, Patrick C Y (2014) Editorial overview: emerging viruses. Curr Opin Virol 5:v-vii
Ilinykh, Philipp A; Tigabu, Bersabeh; Ivanov, Andrey et al. (2014) Role of protein phosphatase 1 in dephosphorylation of Ebola virus VP30 protein and its targeting for the inhibition of viral transcription. J Biol Chem 289:22723-38
Basler, Christopher F (2014) Portrait of a killer: genome of the 2014 EBOV outbreak strain. Cell Host Microbe 16:419-21
Feagins, Alicia R; Basler, Christopher F (2014) The VP40 protein of Marburg virus exhibits impaired budding and increased sensitivity to human tetherin following mouse adaptation. J Virol 88:14440-50