Efficacy of Therapeutic Intervention with an Oral Ether Lipid Analogue of Cidofovir (CMX001) in a Lethal Mousepox Model

Parker, Scott; Oberle, Christina; Touchette, Erin; Buller, R. Mark

doi:10.1016/j.antiviral.2008.01.132

Cited by 9 publications

(15 citation statements)

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“…In the ECTV/mousepox model, we and others have evaluated successful, delayed dosings with CMX001 and ST-246 (39,40). Further evaluation of dosing regimens would be a logical next step in evaluating drug efficacy against MPXV in C57BL/6 stat1 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…At day of infection (T ϭ 0), mice were anesthetized by intraperitoneal injection of 9 mg/ml ketamine HCl and 1 mg/ml xylazine at a ratio of 0.1 ml to 10 g body weight. Intranasal infections with 5 l/nare of MPXV-ZAI-79 were used to seed the upper respiratory tract as described previously (39).…”

Section: Methodsmentioning

confidence: 99%

“…Previously it has been shown that mice can be protected from lethal orthopoxvirus disease by the administration of antivirals, such as CMX001 and ST-246 (3,39,41,62). To test whether C57BL/6 stat1 Ϫ/Ϫ mice could be used to evaluate the efficacy of antivirals following MPXV challenges, we infected and treated C57BL/6 stat1 Ϫ/Ϫ mice with CMX001, which is a DNA polymerase inhibitor, or with ST-246, which prevents viral release from infected cells (35,62).…”

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confidence: 99%

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A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

Stabenow¹,

Buller²,

Schriewer³

et al. 2010

J Virol

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Monkeypox virus (MPXV) is an orthopoxvirus closely related to variola, the etiological agent of smallpox. In humans, MPXV causes a disease similar to smallpox and is considered to be an emerging infectious disease. Moreover, the use of MPXV for bioterroristic/biowarfare activities is of significant concern. Available small animal models of human monkeypox have been restricted to mammals with poorly defined biologies that also have limited reagent availability. We have established a murine MPXV model utilizing the STAT1-deficient C57BL/6 mouse. Here we report that a relatively low-dose intranasal (IN) infection induces 100% mortality in the stat1 ؊/؊ model by day 10 postinfection with high infectious titers in the livers, spleens, and lungs of moribund animals. Vaccination with modified vaccinia virus Ankara (MVA) followed by a booster vaccination is sufficient to protect against an intranasal MPXV challenge and induces an immune response more robust than that of a single vaccination. Furthermore, antiviral treatment with CMX001 (HDP-cidofovir) and ST-246 protects when administered as a regimen initiated on the day of infection. Thus, the stat1 ؊/؊ model provides a lethal murine platform for evaluating therapeutics and for investigating the immunological and pathological responses to MPXV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

Stabenow¹,

Buller²,

Schriewer³

et al. 2010

J Virol

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“…97,102 Although it is not a natural mode of transmission, aerosolization of the virus has been used to mimic a poxvirus bioterrorism event. 96 With aerosol infection, the virus is taken up by alveolar macrophages and/or epithelium of the upper and lower respiratory tract and transported by macrophages to the regional lymph nodes and spleen. 33,101 Virus is also present in the olfactory epithelium and extends through the cribriform plate to the olfactory bulb.…”

Section: Ectromelia Virusmentioning

confidence: 99%

“…101 IN infection of ECTV has been used as a route to more closely imitate the natural route of infection for smallpox. 33,96 The progression of ECTV-induced disease in mice can be measured by percentage body weight change and viral titers in the liver, spleen, and other tissues. 59 Body weight change is a simple variable to measure and is advantageous for evaluating antiviral drug efficacy.…”

Section: Ectromelia Virusmentioning

confidence: 99%

Animal Models of Orthopoxvirus Infection

et al. 2010

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Smallpox was one of the most devastating diseases known to humanity. Although smallpox was eradicated through a historically successful vaccination campaign, there is concern in the global community that either Variola virus (VARV), the causative agent of smallpox, or another species of Orthopoxvirus could be used as agents of bioterrorism. Therefore, development of countermeasures to Orthopoxvirus infection is a crucial focus in biodefense research, and these efforts rely on the use of various animal models. Smallpox typically presented as a generalized pustular rash with 30 to 40% mortality, and although smallpox-like syndromes can be induced in cynomolgus macaques with VARV, research with this virus is highly restricted; therefore, animal models with other orthopoxviruses have been investigated. Monkeypox virus causes a generalized vesiculopustular rash in rhesus and cynomolgus macaques and induces fatal systemic disease in several rodent species. Ectromelia virus has been extensively studied in mice as a model of orthopoxviral infection in its natural host. Intranasal inoculation of mice with some strains of vaccinia virus produces fatal bronchopneumonia, as does aerosol or intranasal inoculation of mice with cowpox virus. Rabbitpox virus causes pneumonia and fatal systemic infections in rabbits and can be naturally transmitted between rabbits by an aerosol route similar to that of VARV in humans. No single animal model recapitulates all known aspects of human Orthopoxvirus infections, and each model has its advantages and disadvantages. This article provides a brief review of the Orthopoxvirus diseases of humans and the key pathologic features of animal models of Orthopoxvirus infections.

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Highlights in Antiviral Drug Research: Antivirals at the Horizon

Clercq

2012

Medicinal Research Reviews

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This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses.

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Efficacy of Therapeutic Intervention with an Oral Ether Lipid Analogue of Cidofovir (CMX001) in a Lethal Mousepox Model

Cited by 9 publications

References 0 publications

A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

Animal Models of Orthopoxvirus Infection

Highlights in Antiviral Drug Research: Antivirals at the Horizon

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