Influenza A and B viruses cause a highly contagious respiratory disease in humans. Influenza A viruses, which have been isolated from a wide variety of avian and mammalian species, are responsible for pandemics that have caused high mortality rates. Avian H5N1 influenza A viruses, which have spread from Asia to Europe and Africa, are prime candidates for causing the next pandemic. The current antivirals against influenza A virus target either the M2 ion channel protein (amantadine/rimantadine) or the neuraminidase (NA) (oseltamivir/zamanivir). Many of the human isolates of H5N1 viruses are already resistant to amantadine, and H5N1 viruses that are partially, or completely, resistant to oseltamivir have recently been reported, highlighting the need for new antivirals. Our goal is to target a different, highly conserved influenza A virus-encoded protein, the NS1 protein, for drug development. The NS1 protein of influenza A virus will be designated as the NS1A protein to distinguish it from the NS1 protein encoded by influenza B virus, which will be designated as the NS1B protein. Influenza B viruses appear to infect only humans: We will target two functions of the NS1A protein that are crucial for virus replication: (1) double- stranded RNA (dsRNA)-binding by its N-terminal RNA-binding domain;and (2) binding by its effector domain of a cellular protein required for the 3'end processing of cellular pre-mRNAs (the 30-kDa subunit of the cleavage and polyadenylation factor, or CPSF30). The NS1B protein also has a dsRNA-binding function that we will target. We have already obtained strong evidence that these NS1 binding sites are valid new targets for drug development and have identified key features of their three-dimensional structure by X-ray crystallography and nuclear magnetic resonance (NMR) methods. We will now proceed to identify, assay and develop small organic ligand inhibitors for these three NS1 domains. This project is based on a strong and ongoing collaboration between virology efforts in the Krug laboratory at the University of Texas at Austin (UT-Austin) and structural biology efforts in the Montelione laboratory at Rutgers University. This effort will be augmented by the participation of Drs. Robertus, Ellington and Anslyn at UT-Austin and by the facilities of the Texas Institute for Drug and Diagnostics Development. In addition, the Paessler laboratory at the University of Texas Medical Branch will carry out animal experiments to test our inhibitory compounds.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-CCH-M (M2))
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Krafft, Amy
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University of Texas Austin
Schools of Arts and Sciences
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Aramini, James M; Hamilton, Keith; Ma, Li-Chung et al. (2014) (19)F NMR reveals multiple conformations at the dimer interface of the nonstructural protein 1 effector domain from influenza A virus. Structure 22:515-525
Barman, Sanmitra; You, Lei; Chen, Ran et al. (2014) Exploring naphthyl-carbohydrazides as inhibitors of influenza A viruses. Eur J Med Chem 71:81-90
Cho, Eun Jeong; Xia, Shuangluo; Ma, Li-Chung et al. (2012) Identification of influenza virus inhibitors targeting NS1A utilizing fluorescence polarization-based high-throughput assay. J Biomol Screen 17:448-59
You, Lei; Cho, Eun Jeong; Leavitt, John et al. (2011) Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors. Bioorg Med Chem Lett 21:3007-11
Jasheway, Karl; Pruet, Jeffrey; Anslyn, Eric V et al. (2011) Structure-based design of ricin inhibitors. Toxins (Basel) 3:1233-48
Aramini, James M; Ma, Li-Chung; Zhou, Ligang et al. (2011) Dimer interface of the effector domain of non-structural protein 1 from influenza A virus: an interface with multiple functions. J Biol Chem 286:26050-60
Ubhi, Devinder; Kavanagh, Kathryn L; Monzingo, Arthur F et al. (2011) Structure of Candida albicans methionine synthase determined by employing surface residue mutagenesis. Arch Biochem Biophys 513:19-26
Xia, Shuangluo; Robertus, Jon D (2010) X-ray structures of NS1 effector domain mutants. Arch Biochem Biophys 494:198-204
Das, Kalyan; Aramini, James M; Ma, Li-Chung et al. (2010) Structures of influenza A proteins and insights into antiviral drug targets. Nat Struct Mol Biol 17:530-8
Bai, Yan; Monzingo, Arthur F; Robertus, Jon D (2009) The X-ray structure of ricin A chain with a novel inhibitor. Arch Biochem Biophys 483:23-8

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