The overall goal of this project is to identify new therapies that target influenza virus replication. The global health burden of annual influenza epidemics coupled with the emergence of highly pathogenic strains of influenza virus has highlighted the urgent need for new effective treatments A primary concern with the current drugs (amantadines and neuraminidase inhibitors) used to treat influenza is the development of resistance mutations that negate therapeutic benefit. Published evidence suggests that targeting the influenza virus RNA dependent RNA polymerase (RdRp) is a rational approach for antiviral therapy. The RdRp is responsible for a number of functions including 5'cap recognition, endonuclease activity, replication, transcription, and polyadenylation. Recently, cryo-EM reconstitution studies identified branchedribonucleoproteins (RNPs) structures as putative replication interhiediates and suggested a mechanism for viral replication by a second polymerase activity on the RNP template . The second polymerase activity is believed to be a function ofthe polymerase complex. Clearly, the RdRp provides multiple functional domains that could be targets for antiviral drug therapy. Previous studies showed that mutations in the conserved regions of PB1 subunit of the polymerase complex produce inactive RNA polymerase. We hypothesize that compounds that specifically target the polymerase complex might reduce the frequency of escape mutations, or promote escape mutants that are unfit for replication. We have recently identified potential hit compounds from previous HTS screens that significantly inhibit the influenza virus polymerase activity in an RdRp transient assay. These hit compounds were effective against three different strains of influenza viruses in CPE assays. We propose to characterize these compounds and use high-throughput screening (HTS) of novel small molecule libraries to identify anti-polymerase candidate compounds, chemically optimize them, and establish their effectiveness in an influenza mouse model.

Public Health Relevance

Influenza A viruses continue to emerge from the aquatic avian reservoir and cause seasonal epidemics and infrequent pandemics. Recent experimental evidence by our group and others support the development of novel antivirals targeting the influenza polymerase function.The discovery of molecules that inhibit influenza virus RNA replication is essential to complement the existing drug arsenal, which is proving less effective due t o t h e increasing incidence of mutational resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109680-01
Application #
8650370
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$882,792
Indirect Cost
$33,516
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Mounce, Bryan C; Cesaro, Teresa; Moratorio, Gonzalo et al. (2016) Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses. J Virol 90:9683-9692
Morrison, Clayton R; Plante, Kenneth S; Heise, Mark T (2016) Chikungunya Virus: Current Perspectives on a Reemerging Virus. Microbiol Spectr 4:
McCarthy, Mary K; Morrison, Thomas E (2016) Chronic chikungunya virus musculoskeletal disease: what are the underlying mechanisms? Future Microbiol 11:331-4
Rasmussen, Lynn; White, E Lucile; Bostwick, James R (2016) Acoustic Droplet Ejection Applications for High-Throughput Screening of Infectious Agents. J Lab Autom 21:188-97
Everts, Maaike; Suto, Mark J; Painter, George R et al. (2016) Consortia's critical role in developing medical countermeasures for re-emerging viral infections: a USA perspective. Future Virol 11:187-195
Haese, Nicole N; Broeckel, Rebecca M; Hawman, David W et al. (2016) Animal Models of Chikungunya Virus Infection and Disease. J Infect Dis 214:S482-S487
Broeckel, Rebecca; Haese, Nicole; Messaoudi, Ilhem et al. (2015) Nonhuman Primate Models of Chikungunya Virus Infection and Disease (CHIKV NHP Model). Pathogens 4:662-81
Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin et al. (2015) Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists. J Virol 89:8011-25
Sali, Tina M; Pryke, Kara M; Abraham, Jinu et al. (2015) Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathog 11:e1005324
Mainou, Bernardo A; Ashbrook, Alison W; Smith, Everett Clinton et al. (2015) Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry. J Virol 89:8701-12

Showing the most recent 10 out of 15 publications