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. 2010 May;54(5):2152-9.
doi: 10.1128/AAC.01315-09. Epub 2010 Mar 8.

Antiviral activity of a small-molecule inhibitor of filovirus infection

Travis K Warren  1 , Kelly L Warfield, Jay Wells, Sven Enterlein, Mark Smith, Gordon Ruthel, Abdul S Yunus, Michael S Kinch, Michael Goldblatt, M Javad Aman, Sina Bavari
Affiliations

Antiviral activity of a small-molecule inhibitor of filovirus infection

Travis K Warren et al. Antimicrob Agents Chemother. 2010 May.

Abstract

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.

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Figures

FIG. 1.
FIG. 1.
Chemical structure of FGI-103.
FIG. 2.
FIG. 2.
Inhibition of EBOV by FGI-103. Inhibition of a recombinant strain of ZEBOV that expresses GFP (ZEBOV-GFP) was assessed by pretreating Vero E6 cell monolayers with FGI-103 overnight and for 48 h following infection. Viral yield assays using wild-type (WT) ZEBOV, SEBOV, MARV-Ravn, and MARV-Ci67 were similarly conducted by treating cells with FGI-103 both prior to virus infection (MOI of 1) and for 48 h afterward. Supernatant harvested from treatment wells was subjected to a standard viral plaque assay using Vero E6 cells. For all assays, inhibition is expressed relative to medium-only control wells containing equivalent DMSO concentrations. Error bars represent standard deviations associated with four replicates, except for the ZEBOV-GFP assay, which shows results from three replicates.
FIG. 3.
FIG. 3.
FGI-103 protects C57BL/6 mice against EBOV infection. Groups of mice (n = 10) were challenged with a lethal dose (1,000 PFU) of mouse-adapted ZEBOV delivered by i.p. injection, and animal health and survival were monitored for 14 days. (A) FGI-103 was delivered to mice by i.p. injection as a 10-mg/kg dose in sterile saline. Doses were administered 1 h prior to EBOV infection (d0) and again at days 2 and 5 postinfection. Control mice received treatment with the vehicle according to the same dosing regimen. (B) FGI-103 was administered to mice as either a 10- or a 5-mg/kg dose by a single i.p. injection delivered at day 1 postinfection. Survival curves that differ significantly (P ≤ 0.05) from that of the vehicle control treatment are indicated by asterisks.
FIG. 4.
FIG. 4.
Delivery of FGI-103 protects BALB/c mice against MARV infection. Mice were challenged with a mouse-adapted strain of MARV-Ravn by delivery of 1,000 PFU by i.p. injection. Treatment groups (n = 10) were monitored for 14 days. Doses of FGI-103 (10 or 5 mg/kg) were administered via i.p. injection at day 1 postinfection. Survival curves that differ significantly (P ≤ 0.05) from that of the vehicle control treatment are indicated by asterisks.
FIG. 5.
FIG. 5.
FGI-103 reduces the in vitro EBOV load, proinflammatory cytokine responses, and tissue pathology in mice. C57BL/6 mice were infected with a lethal dose of mouse-adapted ZEBOV (1,000 PFU delivered i.p.). Mice were treated with either FGI-103 (⧫) delivered as a single 10-mg/kg dose or with the vehicle (▴) 1 day after infection. Mice (n = 5) were sacrificed at the indicated time points to obtain kidney, liver, spleen, and serum samples. Asterisks denote statistically significant (P ≤ 0.05) differences between the means of vehicle- and FGI-treated mice. (A) Tissue samples were homogenized and subjected to a standard plaque assay using Vero cells. The median values of five samples are displayed. (B) Serum cytokine concentrations were determined using a BD Cytometric Bead Array according to the manufacturer's instructions. Average serum cytokine concentrations are shown, and error bars represent standard deviations. (C and D) Representative images of hematoxylin-and-eosin-stained liver tissue (×600) collected at day 6 postinfection showing mild necrosis and hepatitis in the FGI-103-treated animal (C) with more progressive pathology in the vehicle-treated mouse (D). (E to H) Immunoperoxidase staining of tissue collected at day 6 postinfection showing viral antigen in brown with hematoxylin counterstain. In liver tissue (×600) from FGI-103-treated mice (E), the viral antigen is apparently localized to Kupffer cells, and in that from mice treated with the vehicle (F), the viral antigen is more prevalent and distributed throughout the liver. (G and H) Comparison of viral antigen in spleen tissue (×100) collected from FGI-103-treated animals (G) and vehicle-treated mice (H).
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