A review of compounds exhibiting anti-orthopoxvirus activity in animal models

Smee, Donald F.; Sidwell, Robert W.

doi:10.1016/s0166-3542(02)00199-7

Cited by 107 publications

(76 citation statements)

References 90 publications

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“…infection of mice with cowpox (Brighton strain) virus has been used as a small animal model to study treatments with antiviral agents [1,2]. Mice develop severe pneumonitis by this route of infection [3], and the virus disseminates to many organs and tissues [4].…”

Section: Introductionmentioning

confidence: 99%

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Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

Smee

Gowen

Wandersee

et al. 2008

International Journal of Antimicrobial Agents

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The causes of death from intranasal cowpox virus infections in mice remain unclear. Hypotheses include severe pneumonitis, hepatitis, and/or hyperproduction of cytokines and chemokines. This work explores these hypotheses by studying the influence of low and high volume virus inoculums on viral pathogenesis. BALB/c mice were infected intranasally with a syncytium-forming variant of cowpox virus in 5-μl or 50-μl volumes containing the same infectious virus challenge dose. The 50-μl infection produced a more rapidly lethal disease associated with severe pneumonitis, high lung and nasal virus titers, and increases in cytokine and chemokine levels in lungs and nasal tissue, while liver infection was minimal. The 5-μl inoculum infection was also lethal, but the infection was primarily confined to the upper respiratory tract, and included elevated nasal cytokine and chemokine levels. The pro-inflammatory cytokine, interleukin-6, was particularly high in both infections. Treatment of the infections with cidofovir (100 mg/kg/day for 2 days starting 24 h after virus exposure) led to survival and suppression of tissue virus titers. Treatment reduced pneumonitis in the 50-μl infection, and lessened cytokine hyperproduction in both infections. We conclude that 5-μl volume inoculum of cowpox virus causes a lethal upper respiratory tract infection, while the 50-μl inoculum targets both upper and lower respiratory tracts, with excessive release of systemic proinflammatory factors occurring. Cidofovir effectively treated both infections and slowed viral replication sufficiently to subdue the exaggerated release of pro-inflammatory mediators.

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Section: Introductionmentioning

confidence: 99%

“…The first hypothesis is that death results from severe pneumonitis. Results from the mouse model appear to support this hypothesis [1][2][3]. However, other investigators believe hepatitis is the cause of death.…”

Section: Introductionmentioning

confidence: 99%

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

Smee

Gowen

Wandersee

et al. 2008

International Journal of Antimicrobial Agents

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“…Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5,10,12); however, these compounds are inactive when given orally.…”

mentioning

confidence: 99%

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

Keith

Wan

Ciesla

et al. 2004

Antimicrob Agents Chemother

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A new series of ether lipid esters of cidofovir (CDV) were evaluated against vaccinia and cowpox viruses. Activity was dependent on number of atoms in the alkyl or alkoxyalkyl chain, the linker moiety, and the presence of a double bond in the alkoxyalkyl chains linked to the phosphonate moiety of CDV.The threat of an intentional or unintentional spread of poxvirus infections to a vulnerable population has led to increased efforts to find safe, rapidly deployable treatments against such infections. Although vaccination is now being offered to some healthcare workers and other "first responders," there are valid concerns about potential vaccine risks (3, 9). Vaccination is not recommended for those with eczema and other exfoliative skin disorders or those with immunodeficiencies or for pregnant women. Therefore, the use of antiviral therapy in the event of a poxvirus outbreak or in the treatment of vaccination complications against smallpox virus (4) points to the continued need to examine available antiviral therapies as well as to develop new and more efficient treatment.Cidofovir (CDV) and cyclic CDV (cCDV) have been shown to be potent inhibitors of poxvirus replication in vitro (1,7,8,13) and in animal model studies (5, 10, 12); however, these compounds are inactive when given orally.Previous in vitro studies have shown that multiple-log increases in antiviral activity against orthopoxvirus replication (8), as well as enhanced inhibition of cytomegalovirus and herpesvirus replication by these esters (2), were observed with hexadecyloxypropyl (HDP) and octadecyloxyethyl (ODE) derivatives of CDV and cCDV (HDP-CDV, HDP-cCDV, ODE-CDV, and ODE-cCDV) compared to the results seen with the parent compounds. HDP-CDV, ODE-CDV, and oleyloxypropyl-CDV (OLP-CDV) have oral bioavailabilities of 88 to 93% in mice (6) and have oral activity against vaccinia virus (VV) and cowpox virus (CV) infections in mice (11).In this study, the unmodified acyclic nucleoside phosphonates CDV and cCDV (along with a new series of analogs synthesized by esterification of these compounds with an alkyl chain with or without the propoxy-or ethoxy-linker moieties) were evaluated (using methodologies described previously) (7) for activity (plaque reduction assay) against VV and CV and for cytotoxicity (neutral red uptake assay) in human foreskin fibroblast (HFF) cells. To determine efficacy, briefly, HFF cells seeded in 6-well plates 2 days prior to use were infected with either VV or CV by the addition of 20 to 30 PFU per well. After a 1-h incubation period, various concentrations of drug were added to triplicate wells and plates were incubated at 37°C for 3 days. Toxicity was evaluated using HFF cells seeded in 96-well plates incubated with various concentrations of drug for 7 days at 37°C. After incubation, cell monolayers were stained with a 0.01% solution of neutral red. The compounds were synthesized as reported previously (8).As presented in Table 1, the most active ether lipid esters of CDV were OLE-CDV, ODBG-CDV, TDP-CDV, OLP-CDV, and ODP-...

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“…Active and potent compounds against variola virus were identified by cell culture screening [5], and new animal models were developed using cowpox and monkeypox viruses in mice and monkeys, respectively [6][7][8]. An extensive review of the research performed on anti-orthopoxviruses found to be active in animal models from 1950 to 2002 was published in 2003 [9]. …”

mentioning

confidence: 99%

“…Aerosol infection of monkeys with monkeypox virus has served as a surrogate model for studying the antiviral treatment of variola (smallpox) virus infection. Prior to 2003 the search was on to identify a potential model for variola virus in monkeys, work that reached fruition after that time.Other types of orthopoxvirus infections are known to occur in their natural host, such as those caused by buffalopox, camelpox, raccoonpox, taterapox, volepox and African horsepox virus [9]. There have been no reported small animal models for these infections.…”

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confidence: 99%

Progress in the Discovery of Compounds Inhibiting Orthopoxviruses in Animal Models

Smee

2008

Antivir Chem Chemother

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Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Although variola virus, the etiological agent in smallpox infection, was declared eradicated from the earth in 1980, the reality of using variola virus and the related monkeypox virus as bioweapons is apparent [1][2][3][4]. Hence, in the 1990s the US government began pursuing the goal of identifying at least two orthopoxvirus inhibitors, ideally with different modes of antiviral action, that could be stockpiled and used as approved drugs for treatment of infections causes by these or other orthopoxviruses. A vigorous research effort in the USA and abroad commenced, and involved pioneering work at the US Army Medical Research Institute of Infectious Diseases (USAM-RIID) at Fort Detrick, Maryland. Active and potent compounds against variola virus were identified by cell culture screening [5], and new animal models were developed using cowpox and monkeypox viruses in mice and monkeys, respectively [6][7][8]. An extensive review of the research performed on anti-orthopoxviruses found to be active in animal models from 1950 to 2002 was published in 2003 [9]. Rabbitpox and vaccinia (WR strain)Since 2002, considerable progress has been made in anti-orthopoxvirus research. Many new animal models have been developed, genetically modified orthopoxviruses applicable to the work have been prepared, and important new compounds have been synthesized and found active in animal models. Because of these developments, it was deemed appropriate to write an update in the form of this review, covering the period from 2003 to the present time. An attempt was made to include all published sources of compounds that have shown efficacy in animal models of orthopoxvirus infection. Pertinent published abstracts were also included, when a full research paper had not yet been published. A brief summary of the previous work [9] has also been given to bring the reader to the point where this review begins. (Table 1). Mice infected intracerebrally with rabbitpox, vaccinia and variola viruses developed encephalitis. However, these models have not been used since 1979 for antiviral studies [9]. More popular models in mice used during the time period were intranasal or aerosol challenges with cowpox and vaccinia viruses causing pneumonitis, scarific...

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A review of compounds exhibiting anti-orthopoxvirus activity in animal models

Cited by 107 publications

References 90 publications

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro

Progress in the Discovery of Compounds Inhibiting Orthopoxviruses in Animal Models

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