Although there is great concern over emerging viruses and viruses on the NIAID category A-C priority pathogen lists, there are relatively few prophylactics or therapeutics for these viruses, and most which do exist are highly pathogen-specific or have undesirable side effects or other disadvantages. We have developed a radically new and very broad-spectrum antiviral therapeutic/prophylactic that has the potential to revolutionize the treatment of viral infections, including those due to emerging, category A-C, and common clinical pathogens. Our dsRNA (double-stranded RNA) activated caspase (DAC) approach selectively induces apoptosis in cells containing any viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have previously created a DAC and shown that it is nontoxic and effective against 10 different viruses in 10 mammalian cell types. We have also demonstrated that it is nontoxic in mice and rescues mice from a lethal H1N1 influenza challenge. A large number of viruses on the category A-C lists belong to the arenavirus, bunyavirus, and flavivirus families, virus families against which we have not previously tested DAC. Therefore, the experimental focus of this proposal is to test DAC against representative members of these virus families.
The specific aims are to: 1. Demonstrate efficacy in multiple mammalian cell types against representative members of the arenavirus, bunyavirus, and flavivirus families. 2. Perform DAC pharmacokinetic analyses and assess DAC immunogenicity in vivo. 3. Demonstrate antiviral efficacy in a lethal mouse model using the best challenge virus from the in vitro trials. Success in these aims should demonstrate the potential of DAC to treat arenaviruses, bunyaviruses, and flaviviruses and pave the way for further trials with additional viruses and animal models. This work should greatly advance DAC toward ultimate utility as a safe, broad-spectrum therapeutic/prophylactic for NIAID priority and emerging viral pathogens, filling a large gap in existing therapeutics and directly supporting NERCE's mission.

Public Health Relevance

Success in the proposed work should greatly advance DAC toward ultimate utility as a safe, broad-spectrum therapeutic/prophylactic for NIAID priority viral pathogens, filling a large gap in existing therapeutics and directly supporting NERCE's mission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057159-10
Application #
8617037
Study Section
Special Emphasis Panel (ZAI1-DDS-M (J1))
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$172,903
Indirect Cost
$53,681
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Carocci, Margot; Hinshaw, Stephen M; Rodgers, Mary A et al. (2015) The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob Agents Chemother 59:85-95
Lu, Xi; Skurnik, David; Pozzi, Clarissa et al. (2014) A Poly-N-acetylglucosamine-Shiga toxin broad-spectrum conjugate vaccine for Shiga toxin-producing Escherichia coli. MBio 5:e00974-14
Brauburger, Kristina; Boehmann, Yannik; Tsuda, Yoshimi et al. (2014) Analysis of the highly diverse gene borders in Ebola virus reveals a distinct mechanism of transcriptional regulation. J Virol 88:12558-71
Derbyshire, Emily R; Min, Jaeki; Guiguemde, W Armand et al. (2014) Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrob Agents Chemother 58:1516-22
Böcking, Till; Aguet, François; Rapoport, Iris et al. (2014) Key interactions for clathrin coat stability. Structure 22:819-29
Gorla, Suresh Kumar; McNair, Nina N; Yang, Guangyi et al. (2014) Validation of IMP dehydrogenase inhibitors in a mouse model of cryptosporidiosis. Antimicrob Agents Chemother 58:1603-14
Gavrish, Ekaterina; Shrestha, Binu; Chen, Chao et al. (2014) In vitro and in vivo activities of HPi1, a selective antimicrobial against Helicobacter pylori. Antimicrob Agents Chemother 58:3255-60
Chamoun-Emanuelli, Ana M; Pécheur, Eve-Isabelle; Chen, Zhilei (2014) Benzhydrylpiperazine compounds inhibit cholesterol-dependent cellular entry of hepatitis C virus. Antiviral Res 109:141-8
Vetter, Michael L; Zhang, Zijuan; Liu, Shuai et al. (2014) Fluorescent visualization of Src by using dasatinib-BODIPY. Chembiochem 15:1317-24
Starkey, Melissa; Lepine, Francois; Maura, Damien et al. (2014) Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. PLoS Pathog 10:e1004321

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