Identification and characterization of potent small molecule inhibitor of hemorrhagic fever New World arenaviruses.
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.
Bolken
Tove C
TC
SIGA Technologies Inc., 4575 SW Research Way, Corvallis, OR 97333, USA.
Laquerre
Sylvie
S
Zhang
Yuanming
Y
Bailey
Thomas R
TR
Pevear
Daniel C
DC
Kickner
Shirley S
SS
Sperzel
Lindsey E
LE
Jones
Kevin F
KF
Warren
Travis K
TK
Amanda Lund
S
S
Kirkwood-Watts
Dana L
DL
King
David S
DS
Shurtleff
Amy C
AC
Guttieri
Mary C
MC
Deng
Yijun
Y
Bleam
Maureen
M
Hruby
Dennis E
DE
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
D000998:Antiviral Agents; C510640:ST 294; C510639:ST 336; D013449:Sulfonamides; D014764:Viral Proteins; D007854:Lead; D014508:Urea