Emerging avian influenza viruses pose an increasing threat to domestic poultry and human health. The influenza virus hemagglutinin (HA) is an attractive drug target because they are essential for viral entry, and indispensable for virus replication. We hypothesize that fusion inhibitors currently under development in this program will be potent against diverse virus strains, especially HPAI viruses.
Specific aims to further develop these inhibitors are:
Aim 1. Identify fusion inhibitors that are potent against diverse strains of H5N1 influenza viruses. Our preliminary studies have identified a group of lead compounds that have EC50 values in single digit nanomoles across diverse influenza virus strains including H5N3 (vaccine strain), H3N2, H1N1 and type B. To identify potential candidates for preclinical and eventual clinical studies against HPAI H5N1 viruses, we propose to develop a library of analogs based on the initial lead. We propose to measure the inhibitory potencies of candidate compounds against diverse strains of H5N1 influenza viruses. Lead compounds identified from these studies will be advanced to preclinical studies as a component of Program 10.
Aim 2. Determine the mechanisms of action of HA protein inhibitors.Our preliminary data indicate that the fusion nhibitors we have developed alter the structure of HA. For compounds identified in Aim 1 that are potent against H5N1 viruses, we will determine which step of virus entry is blocked using biological and biochemical assays. To map the binding sites of compounds, we will co-crystallize the HA protein with bound inhibitor, and we will also generate and characterize resistant variants. Recombinant HA will be treated with different proteases in order to map the conformationally sensitive regions.
Aim 3. Determine if drug combinations that nclude HA inhibitors provide advantages over existing single-agent therapies in protecting against disease and avoiding drug resistance. A widespread use of HA inhibitors could result in the emergence of drugesistant viruses, similar to the acquisition of drug resistance that has been observed for neuraminidase (NA) and M2 inhibitors. We hypothesize that the use of HA inhibitors in combination with existing NA and/or M2 nhibitors will help counteract drug resistance and decrease the severity of infectious disease.
Emerging avian influenza viruses pose an increasing threat to both domestic poultry and human health. The aims of the proposed project are to develop drugs that may be beneficial in the treatment of influenza.
|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|
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