Identification and characterization of potent small ...
|Title||Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses|
|Author(s)||T. C. Bolken, S. Laquerre, Y. M. Zhang, Trina R. Bailey, D. C. Pevear, S. S. Kickner, L. E. Sperzel, K. F. Jones, T. K. Warren, S. A. Lund, D. L. Kirkwood Watts, D. S. King, A. C. Shurtleff, M. C. Guttieri, Y. J. Deng, M. Bleam, D. E. Hruby|
|Abstract||Category A arenaviruses as defined by the National Institute of Allergy and Infectious Diseases (NIAID) are human pathogens that could be weaponized by bioterrorists. Many of these deadly viruses require biosafety level-4 (BSL-4) containment for all laboratory work, which limits traditional laboratory high-throughput screening (HTS) for identification of small molecule inhibitors. For those reasons, a related BSL-2 New World arenavirus, Tacaribe virus, 67-78% identical to Junin virus at the amino acid level, was used in a HTS campaign where approximately 400,000 small molecule compounds were screened in a Tacaribe virus-induced cytopathic effect (CPE) assay. Compounds identified in this screen showed antiviral activity and specificity against not only Tacaribe virus, but also the Category A New World arenaviruses (Junin, Machupo, and Guanarito). Drug resistant variants were isolated, suggesting that these compounds act through inhibition of a viral protein, the viral glycoprotein (GP2), and not through cellular toxicity mechanisms. A lead compound, ST-294, has been chosen for drug development. This potent and selective compound, with good bioavailability, demonstrated protective anti-viral efficacy in a Tacaribe mouse challenge model. This series of compounds represent a new class of inhibitors that may warrant further development for potential inclusion in a strategic stockpile..|
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