The significant burden that results from dengue virus infection combined with the absence of effective vaccines or drugs makes the development of novel therapeutics a high priority. The goal of our research is to identify and optimize compounds that target essential host factors to further our understanding of host-virus interactions and to validate host targets and ?lead? compounds for further development as potential new classes of anti-viral agents. Our strategy is to target essential host factors by developing selective, covalent cysteine-directed inhibitors. The success of covalent inhibitors has been amply demonstrated by the thirtynine FDA-approved drugs that are highly effective in humans. We recently discovered a substituted quinolone, QL-XII-47, that is a potent inhibitor of the four dengue serotypes (EC90 400nM) at concentrations that are non-cytotoxic. Preliminary data indicate that QL-XII-47 acts via a host factor to inhibit DENV at a point late in viral entry. QL-XII- 47 has exhibited inhibitory activity against a number of other viruses within and beyond the Flavivirus family. We will utilize a combination of medicinal chemistry, chemical biology, chemical proteomics, and virology (1) to understand the structural features required to achieve antiviral activity and to obtain analogs with suitable pharmacological properties to enable in vivo experiments;(2) to examine the target and mechanism of action responsible for the potent antiviral activity of QL-XII-47 and related compounds in vitro;and (3) to examine the spectrum of QL-XII-47?s antiviral activities against additional Biodefense Viruses. The goal of this proposal is to identify covalent inhibitors of essential host-factor targets that exhibit broad antiviral activity in vitro and that are efficacious in a murine model of dengue virus infection. Further development of this agent and elucidation of its molecular target(s) may provide the first host-directed pharmacological approach for treating dengue virus infection. The strategy of developing cysteine-directed covalent inhibitors of host factors may provide a new and general paradigm for developing host-directed agents with the potential to broadly protect against many infectious agents.

Public Health Relevance

Dengue virus is the most widespread mosquito-borne virus in the world today and the cause of significant human disease;however, there currently are no vaccines or specific antiviral therapies to prevent or to treat dengue virus infection. The proposed experiments will develop small molecules that inhibit dengue virus by covalently modifying host factors required for viral replication.

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 #
8566335
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$217,346
Indirect Cost
$67,479
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

Showing the most recent 10 out of 289 publications