Dengue virus (DENV) is the most important mosquito-bome viral disease affecting humans today. An estimated 100 million people are infected with dengue virus annually, leading to dengue fever and dengue hemorrhagic fever (DHF). Since there are an estimated 2.5 billion people living in areas at risk for epidemic transmission and since both the number of DENV infections and the proportion of infections resulting in DHF have escalated in the past 20 years, the absence of anti-DENV therapeutics or an anti-DENV vaccine is a growing public health concern. We recently discovered two independent series of inhibitors of DV entry based on disubstituted pyrimidine and alpha-ketocyanohydrazone scaffolds, both of which appear to block the fusion step of virus entry. Here, we propose to utilize a combination of focused medicinal chemistry, biochemistry, and virology to understand the structure-activity relationships governing the anti-DENV activity of these compounds as well as their mechanism of action.

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 #
8617035
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
$210,785
Indirect Cost
$65,442
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
Böcking, Till; Aguet, François; Rapoport, Iris et al. (2014) Key interactions for clathrin coat stability. Structure 22:819-29
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
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
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
Vetter, Michael L; Zhang, Zijuan; Liu, Shuai et al. (2014) Fluorescent visualization of Src by using dasatinib-BODIPY. Chembiochem 15:1317-24
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
Morin, Benjamin; Whelan, Sean P J (2014) Sensitivity of the polymerase of vesicular stomatitis virus to 2' substitutions in the template and nucleotide triphosphate during initiation and elongation. J Biol Chem 289:9961-9

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