Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses

Bolken, Tove′ C.; Laquerre, Sylvie; Zhang, Yuanming; Bailey, Thomas R.; Pevear, Daniel C.; Kickner, Shirley S.; Sperzel, Lindsey E.; Jones, Kevin F.; Warren, Travis K.; Amanda Lund, S.; Kirkwood-Watts, Dana L.; King, David S.; Shurtleff, Amy C.; Guttieri, Mary C.; Deng, Yijun; Bleam, Maureen; Hruby, Dennis E.

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.