Antiviral activity of a small-molecule inhibitor of filovirus infection.
There exists an urgent need to develop licensed drugs and vaccines for the treatment or prevention of filovirus infections. FGI-103 is a low-molecular-weight compound that was discovered through an in vitro screening assay utilizing a variant of Zaire ebolavirus (ZEBOV) that expresses green fluorescent protein. In vitro analyses demonstrated that FGI-103 also exhibits antiviral activity against wild-type ZEBOV and Sudan ebolavirus, as well as Marburgvirus (MARV) strains Ci67 and Ravn. In vivo administration of FGI-103 as a single intraperitoneal dose of 10 mg/kg delivered 24 h after infection is sufficient to completely protect mice against a lethal challenge with a mouse-adapted strain of either ZEBOV or MARV-Ravn. In a murine model of ZEBOV infection, delivery of FGI-103 reduces viremia and the viral burden in kidney, liver, and spleen tissues and is associated with subdued and delayed proinflammatory cytokine responses and tissue pathology. Taken together, these results identify a promising antiviral therapeutic candidate for the treatment of filovirus infections.
Warren
Travis K
TK
US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
Warfield
Kelly L
KL
Wells
Jay
J
Enterlein
Sven
S
Smith
Mark
M
Ruthel
Gordon
G
Yunus
Abdul S
AS
Kinch
Michael S
MS
Goldblatt
Michael
M
Aman
M Javad
MJ
Bavari
Sina
S
D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics; D005260:Female; D016563:Filoviridae / Q000187:drug effects* / Q000235:genetics; D018702:Filoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000473:pathology / Q000821:virology; D008297:Male; D008379:Marburg Virus Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D029024:Marburgvirus / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D054852:Small Molecule Libraries; D014709:Vero Cells
D000578:Amidines; D000998:Antiviral Agents; D001572:Benzofurans; D016207:Cytokines; C550936:FGI 103; D054852:Small Molecule Libraries; D049452:Green Fluorescent Proteins