Ebola virus (EboV) is readily transmitted and rapidly fatal, and there is no effective vaccine or drug therapy Recent experiments reveal that the physiological trigger for EboV infection is stepwise proteolytic cleavage ol the envelope glycoprotein (GP) by cathepsin L and cathepsin B, two members of a family of endosoma cysteine proteases. Importantly, well-characterized small molecule inhibitors of cathepsin proteases markedly inhibit EboV infection in vitro (>99%). The goal of this proposal is to develop the potential of cathepsir inhibitors as anti-EboV drugs.
Specific Aim #1 : Develop pipeline of small molecules that inhibit EboV GP-dependent infection a. Screen compounds in major classes of cathepsin inhibitors to identify lead compounds with anti- EboV activity. Include inhibitors already under development for other disorders. b. Determine if any of the 198 specific inhibitors of EboV-GP infection identified by high-throughput screen of 40,000 small molecules are cathepsin inhibitors or function synergistically with them. c. Determine anti-EboV activity of promising lead compounds in existing animal models.
Specific Aim #2 : Determine role of cathepsins in EboV infection. a. Use selective inhibitors and knockout-derived cell lines to identify all cathepsins that mediate EboV and Marburg virus infection. b. Identify the cathepsins that mediate infection of host tissues where EboV replication is high. c. Develop BL3-based system to select and analyze EboV variants that are dependent on specific cathepsins and/or are resistant to specific inhibitors.
Specific Aim #3 : Design, synthesize and test second generation EboV inhibitors as part of drug development plan. SA 1-2 will inform the starting point for an iterative lead optimization protocol to identify the most highly selective cathepsin inhibitors that retain potent and broad anti-EboV activity.

Public Health Relevance

Ebola virus causes outbreaks of rapidly fatal hemorrhagic fever. Current therapy is supportive care;there is no EboV anti-viral therapy. The unpredictable onset, ease of transmission, rapidity of progression, high mortality and bio-terrorism potential has created a high level of public concern about Ebola. Therefore, development of an effective anti-Ebola virus therapy is high priority.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057159-09
Application #
8375453
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$526,323
Indirect Cost
$152,340
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Nair, Dhanalakshmi R; Chen, Ji; Monteiro, João M et al. (2017) A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism. J Antibiot (Tokyo) 70:1009-1019
Huang, Nai-Jia; Pishesha, Novalia; Mukherjee, Jean et al. (2017) Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin. Nat Commun 8:423
Mertins, Philipp; Przybylski, Dariusz; Yosef, Nir et al. (2017) An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. Cell Rep 19:2853-2866
de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke et al. (2017) Discovery of host-targeted covalent inhibitors of dengue virus. Antiviral Res 139:171-179
Choo, Min-Kyung; Sano, Yasuyo; Kim, Changhoon et al. (2017) TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects. J Exp Med 214:1297-1311
Zheng, Huiqing; Colvin, Christopher J; Johnson, Benjamin K et al. (2017) Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nat Chem Biol 13:218-225
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Vrentas, Catherine E; Moayeri, Mahtab; Keefer, Andrea B et al. (2016) A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection. J Biol Chem 291:21596-21606
Helenius, Iiro Taneli; Nair, Aisha; Bittar, Humberto E Trejo et al. (2016) Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression. J Biomol Screen 21:363-71
Fink, Avner; Hassan, Musa A; Okan, Nihal A et al. (2016) Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse Chromosome 19. MBio 7:e02243

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