A novel inhibitor of dengue virus replication that targets the capsid protein.
Dengue viruses (DENV) infect 50 to 100 million people worldwide per year, of which 500,000 develop severe life-threatening disease. This mosquito-borne illness is endemic in most tropical and subtropical countries and has spread significantly over the last decade. While there are several promising vaccine candidates in clinical trials, there are currently no approved vaccines or therapeutics available for treatment of dengue infection. Here, we describe a novel small-molecule compound, ST-148, that is a potent inhibitor of all four serotypes of DENV in vitro. ST-148 significantly reduced viremia and viral load in vital organs and tended to lower cytokine levels in the plasma in a nonlethal model of DENV infection in AG129 mice. Compound resistance mapped to the DENV capsid (C) gene, and a direct interaction of ST-148 with C protein is suggested by alterations of the intrinsic fluorescence of the protein in the presence of compound. Thus, ST-148 appears to interact with the DENV C protein and inhibits a distinct step(s) of the viral replication cycle.
SIGA Technologies, Inc., Corvallis, Oregon, USA. cbyrd@siga.com
Chelsea M
CM
Byrd
Dongcheng
D
Dai
Douglas W
DW
Grosenbach
Aklile
A
Berhanu
Kevin F
KF
Jones
Kara B
KB
Cardwell
Christine
C
Schneider
Kristin A
KA
Wineinger
Jessica M
JM
Page
Chris
C
Harver
Eric
E
Stavale
Shanthakumar
S
Tyavanagimatt
Melialani A
MA
Stone
Ralf
R
Bartenschlager
Pietro
P
Scaturro
Dennis E
DE
Hruby
Robert
R
Jordan
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003715:Dengue / Q000188:drug therapy* / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D004926:Escherichia coli / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D019562:Viral Load / Q000187:drug effects; D010948:Viral Plaque Assay; D014766:Viremia / Q000188:drug therapy* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D036022:Capsid Proteins; D006575:Heterocyclic Compounds, 3-Ring; D011994:Recombinant Proteins; C581551:ST-148; D013830:Thiadiazoles