Arthropod-borne flaviviruses, and especially dengue viruses, cause a wide range of important human diseases for which there are no specific therapies. To address this critical shortfall in preparedness to confront these emerging and re-emerging viruses we have established a program to investigate host factors as targets of anti-dengue therapy. We have discovered many novel drug targets using functional genomics and en masse biochemical approaches. Among these are the 3'-5' exonucleases of the DnaQ/DEDDh superfamily of enzymes: EXD2, WRN and ERI3 (PRNPIP)). These enzymes are highly related to virally encoded exonucleases in SARS coronavirus and Lassa fever virus suggesting that the DnaQ/DEDDh superfamily of enzymes is widely used by pathogenic viruses and thus inhibitors of these enzymes could have broad spectrum of activity. We propose to characterize these enzymes in detail and to identify compounds that inhibit their activity and dengue infection. This will be achieved by 1) Developing in vitro assays for EXD2, WRN and ERI3 and 2) developing in vivo (yeast-based) assays to screen inhibitors of EXD2, WRN and ERI3. Significance to public health. Flaviviruses, and especially dengue virus, are an emerging threat to public health in the US, a current risk to our armed forces and other citizens deployed around the world, and a major problem globally. At this time there is little that can be done to prevent or treat the majority of flaviviral infections and therefore development of anti-flaviviral drugs is of crucial importance.

Public Health Relevance

Mosquito transmitted dengue viruses, cause a wide range of important human diseases for which there are no specific therapies. To address this critical shortfall in preparedness to confront these emerging and re-emerging viruses we propose to carry out work that will set the foundation for the discovery of new compounds that inhibit cellular enzymes that these viruses need to grow.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837
Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749
Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236

Showing the most recent 10 out of 387 publications