title: Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.
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.
authors.affiliation: SIGA Technologies Inc., 4575 SW Research Way, Corvallis, OR 97333, USA.
authors.forename: Tove C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laquerre
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bailey
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Pevear
authors.forename: Shirley S
authors.initials: SS
authors.lastname: Kickner
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Sperzel
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Jones
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.forename: S
authors.initials: S
authors.lastname: Amanda Lund
authors.forename: Dana L
authors.initials: DL
authors.lastname: Kirkwood-Watts
authors.forename: David S
authors.initials: DS
authors.lastname: King
authors.forename: Amy C
authors.initials: AC
authors.lastname: Shurtleff
authors.forename: Mary C
authors.initials: MC
authors.lastname: Guttieri
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.forename: Maureen
authors.initials: M
authors.lastname: Bleam
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001117:Arenaviridae Infections / Q000188:drug therapy / Q000821:virology; D006477:Arenaviruses, New World / Q000187:drug effects*; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral; D006482:Hemorrhagic Fevers, Viral / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007854:Lead / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C510640:ST 294; C510639:ST 336; D013449:Sulfonamides; D014764:Viral Proteins; D007854:Lead; D014508:Urea