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Activity of the Anti-Orthopoxvirus Compound ST-246 Against Vaccinia, Cowpox and Camelpox Viruses in Cell Monolayers and Organotypic Raft Cultures

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Activity of the Anti-Orthopoxvirus Compound ST-246 Against Vaccinia, Cowpox and Camelpox Viruses in Cell Monolayers and Organotypic Raft Cultures Andrei 21/11/07 15:46 Page 1205 Antiviral Therapy 12:1205–1216 Activity of the anti-orthopoxvirus compound ST-246 against vaccinia, cowpox and camelpox viruses in cell monolayers and organotypic raft cultures Sophie Duraffour1,2, Robert Snoeck1, Rita de Vos 3, Joost J van Den Oord3, Jean-Marc Crance 2, Daniel Garin2, Dennis E Hruby4, Robert Jordan4, Erik De Clercq1 and Graciela Andrei1* 1Rega Institute For Medical Research, KU Leuven, Leuven, Belgium 2CRSSA Emile Pardé, Virology Laboratory, La Tronche, France 3Pathology Department, UZ Leuven, Leuven, Belgium 4SIGA Technologies, Inc., Corvallis, Oregon, CA, USA *Corresponding author: Tel: +32 16 33 73 72; Fax: +32 16 33 73 40; E-mail: [email protected] Background: The potential use of variola virus as a biolog- Results: ST-246 inhibited preferentially the production of ical weapon has renewed efforts in the development of extracellular virus compared with intracellular virus antiviral agents against orthopoxviruses. ST-246 [4- production in HEL and PHK cells (for VV) and in PHK cells trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-di (for CMLV). In organotypic epithelial raft cultures, ST-246 oxo-4,6-ethenocycloprop [f]isoindol-2(1H)-yl)-benza- at 20 μg/ml inhibited extracellular VV and CMLV produc- mide] is an anti-orthopoxvirus compound active against tion by 6 logs, whereas intracellular virus yield was several orthopoxviruses including vaccinia virus (VV), reduced by 2 logs. In the case of CPV, both extracellular cowpox virus (CPV), camelpox virus (CMLV), ectromelia and intracellular virus production were completely inhib- virus (ECTV) and variola virus in cell culture. The ited by ST-246 at 20 μg/ml. Histological sections of the compound has been shown to inhibit the release of extra- infected rafts, treated with increasing amounts of drug, cellular virus by targeting the F13L VV protein and to confirmed the antiviral activity of ST-246: the epithelium protect mice from VV, CPV and ECTV orthopoxvirus- was protected and there was no evidence of viral infection. induced disease. Electron microscopic examination confirmed the absence Methods: The antiviral activity of ST-246 was assessed of intracellular enveloped virus forms in VV-, CPV- and against extracellular and intracellular VV, CPV and CMLV CMLV-infected cells treated with 10 μg/ml of ST-246. production in human embryonic lung (HEL) fibroblasts Conclusions: These data indicate that ST-246 is a potent and primary human keratinocyte (PHK) cell monolayers, anti-orthopoxvirus compound; the mode of inhibition is as well as in three-dimensional raft cultures. dependent on the virus and cell type. Introduction Smallpox has been eradicated by a worldwide vaccina- of cytomegalovirus (CMV) retinitis in AIDS patients, is tion campaign in the late 1970s [1]. In today’s popula- permitted for use as an emergency treatment in the case tion, the level of residual immunity is considered to be of a smallpox outbreak. CDV exhibits activity in cell low or non-existent. Currently, the potential release of culture against a wide range of DNA viruses including variola virus (VARV) by bioterrorists and the growing adenoviruses, herpesviruses, hepadnaviruses, polyoma- number of cases of human monkeypox have prompted viruses, papillomaviruses and orthopoxviruses [5]. the development of new antiviral chemotherapies CDV has been shown to block the replication of VARV effective against orthopoxvirus infections [2,3]. and monkeypox virus (MPXV) in cell culture and to A number of new treatments are currently the subject protect mice from lethal challenge of ectromelia virus of active investigations. However, antiviral drugs offer (ECTV), vaccinia virus (VV) or cowpox virus (CPV) a combination of chemical stability and simplicity of [6,7]. However, CDV has to be administered by the delivery that is especially attractive from a public health intravenous route due to its poor bioavailability. The perspective. Currently, only cidofovir (CDV; (S)-1-(3- risk of nephrotoxicity induced by CDV can be reduced hydroxy-2-phosphonylmethoxypropyl)cytosine; by administration of probenecid. CDV analogues and HPMPC; Vistide®) [4], a drug approved for the treatment esters of CDV have been shown to block the replication © 2007 International Medical Press 1359-6535 1205 Andrei 21/11/07 15:46 Page 1206 S Duraffour et al. of VARV, MPXV, CPV and ECTV in vitro [8–10], and Materials and methods when delivered orally protect mice from a lethal chal- lenge with VV, CPV or ECTV [11–14]. CDV and other Cells known nucleotide analogues act by interfering with Human embryonic lung (HEL) fibroblasts (HEL-299; DNA polymerase activity [15]. ATCC CCL-137) were cultured in MEM Earle’s medium A need exists for active compounds with mechanisms (Gibco, Invitrogen Corporation, UK) supplemented with of action different from that of CDV [16]. ST-246 (4- 10% fetal calf serum (FCS), 1% L-glutamine, 1% non- trifluoromethyl-N-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3- essential amino acids, 1% sodium pyruvate and 1% dioxo-4,6-ethenocycloprop[f]isoindol-2(1H)-yl)-benza antibiotic/antimycotic at 37˚C in a 5% CO2 atmosphere. mide) has already been described as an orally bioavail- These HEL cells were used for antiviral assays. Primary able antiviral compound that is active against several human keratinocytes (PHKs) were isolated from orthopoxvirus species, including VV, CPV, camelpox neonatal foreskins and cultured as already described virus (CMLV), MPXV, ECTV, and two strains of VARV, [10]. These PHKs were used for both antiviral assays in in Vero, BSC-40 and human foreskin fibroblasts [17]. monolayers and for organotypic raft cultures. Importantly, ST-246 was found to be active against a CDV-resistant CPV variant. The compound was inac- Compounds tive against unrelated DNA- and RNA-containing The sources of the compounds were as follows: CDV viruses, demonstrating specificity for inhibition of (HPMPC), Gilead Sciences, Foster City, CA; and ST-246, orthopoxvirus replication. ST-246 has been shown to ViroPharma, Inc., Exton, PA. act at the level of extracellular virus production, reducing extracellular VV formation by 10-fold while Viruses having little effect on the production of intracellular The following viral strains were used: vaccinia virus virus [17]. One of the potential targets of the compound (VV), strain Copenhagen-GFP, kindly provided by has been validated as the F13L VV protein, which is one Dr R Drillien (E0345 ISERM, EFS-Alsace, France), of the proteins required for wrapping of intracellular cowpox virus (CPV), strain Brighton, and camelpox virus mature virus to form intracellular enveloped virus (CMLV), strain Iran, kindly provided by Dr H Meyer [18–22]. Orally administered ST-246 protected mice (Bundeswehr Institute of Microbiology, Germany) [24]. from lethal orthopoxvirus challenges and prevented poxvirus-induced disease. Mice acquired protective Antiviral assays immunity and were resistant to subsequent lethal chal- The antiviral activities of the compounds against each lenge [17]. ST-246 was proven to be highly effective in of the viruses listed above were evaluated in HEL and animal models of systemic orthopoxvirus disease, even PHK cells. Both cell lines were cultured in 96-well when treatment was delayed up to 72 h post-viral inoc- microtitre plates. Confluent monolayers were infected ulation and dosing was reduced to once daily [23]. with each virus at a multiplicity of infection (MOI) of Unlike CDV, which targets the viral DNA polymerase, 0.01 in 2% FCS. After 2 h of incubation at 37˚C with ST-246 inhibits virus spread by targeting a protein 5% CO2, residual virus was removed and the infected involved in the release of the virus. cells were further incubated with their respective The present study was conducted to provide a more growth medium containing serial dilutions of the test in-depth view of the antiviral activity of ST-246 against compounds (in duplicate). After 2–3 days for VV and extracellular and intracellular virus production. All CPV or 6 days for CMLV in both HEL and PHK cells, experiments were performed against three the cells were fixed with ethanol and stained with orthopoxviruses, VV strain Copenhagen, CPV strain Giemsa solution. Viral cytopathic effect (CPE) was Brighton, and CMLV strain Iran [24]. The inhibitory recorded, and the 50% inhibitory concentration (IC50) effects of ST-246 were determined on both extracellular was defined as the compound concentration required and intracellular virus production in human embryonic to reduce viral CPE by 50%. The IC50 values of the lung fibroblast and primary human keratinocyte mono- compounds tested against each strain were calculated layers, as well as in a three-dimensional model of as the mean of three independent experiments. organotypic epithelial raft cultures. The raft culture system has been considered as an effective model for Cytotoxicity assays evaluating antiviral compounds against some epithe- The cell toxicities of the compounds were evaluated liotropic viruses such as papilloma, herpes and based upon the inhibition of cell growth. The cells poxviruses [10,25–27]. Finally, infected cells treated were seeded into 96-well microtitre plates at with 10 μg/ml of ST-246 were examined using electron 3.5×103 cells/well/100 μl for HEL cells and at microscopy. The mode of action of this compound is 5×103 cells/well/100 μl for PHK cells. After 1 day also discussed. (HEL cells) or 3 days (PHK cells) of incubation, 100 μl 1206 © 2007 International Medical Press Andrei 21/11/07 15:46 Page 1207 Inhibitory effects of ST-246 on orthopoxvirus replication of medium containing serial dilutions of the test were included for the normal differentiated epithelium compounds were added (in duplicate). After 4 days of (uninfected rafts), viral replication (infected untreated incubation for both cell lines, the cells were trypsinized rafts), and rafts infected and treated with several and the cell number per well was determined with a concentrations of CDV (20, 5, 2, 0.5 and 0.2 μg/ml).
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