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  • Title: Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.
    Author: Bolken TC, Laquerre S, Zhang Y, Bailey TR, Pevear DC, Kickner SS, Sperzel LE, Jones KF, Warren TK, Amanda Lund S, Kirkwood-Watts DL, King DS, Shurtleff AC, Guttieri MC, Deng Y, Bleam M, Hruby DE.
    Journal: Antiviral Res; 2006 Feb; 69(2):86-97. PubMed ID: 16343651.
    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 Junín 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 (Junín, 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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