Live Variola Virus Considerations for Continuing Research (2009) / Chapter Skim
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6 Development of Therapeutics
6 Development of Therapeutics
Pages 67-86
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From page 67... ...
The 1999 IOM report identified the development of antiviral agents as the most significant reason to retain stocks of live variola virus, primarily because of the lack of availability of an effective therapeutic agent (either currently or historically) that could serve as a standard for purposes of comparison: 67
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From page 68... ...
potential therapeutics for smallpox Potential therapeutics for smallpox include two drugs approved by the FDA for other purposes, newly developed drugs, agents to block newly identified poxvirus targets, and drugs that enhance or modulate the host's immune response. Use of Drugs Approved by the FDA for Other Purposes Because de novo drug development is an expensive and time-consuming process (costing in excess of $500 million and requiring approximately 8–10 years of continuous effort)
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From page 69... ...
However, the protective benefit of Gleevec was evident only at lower virus titers and only when the drug was given less than 48 hours after exposure. Studies of Gleevec in rabbits infected with rabbitpox and in mice infected with ectromelia showed much lower antiviral activity than in other animal models (personal communication, Dr.
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From page 70... ...
TABLE 6-1 Development of Therapeutics for Smallpox 70 Drug Chemical Structure Mode of Action Reference Cidofovira ATP analog that inhibits Baker et al., 2003; Magee et al., (CDV) NH2 DNA polymerase.
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From page 71... ...
vector, editable HPMP-5-azaCb NH2 N N O N O O P O OR STI-571 Blocks the Abl-family McFadden, 2005; Reeves et al., 2005 (Gleevec or N tyrosine kinases needed for imatinib the actin motility of mesylate) HN N N intracellular viral particles Table 6-1, HPMP-5-azaC (IMV)
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From page 72... ...
TABLE 6-1 Continued 72 Drug Chemical Structure Mode of Action Reference ST-246d H Inhibits virus release by Yang et al., 2005; Quenelle et al., targeting a pox protein (p37 2007a,b H H or 60L for cowpox or F13L H for vaccinia) that is essential O for envelopment of IMV.
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From page 73... ...
used at 20 µg/ml in cell cultures re duces EMV by 6 logs and reduces IMV by 2 logs. Table 6-1, 4'-thioIDU e1-(2′-deoxy-4′-thio-β-D-ribofuranosyl)
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From page 74... ...
This antiviral drug targets the vaccinia virus protein F13, which is essential for envelopment and egress of the intracellular mature virions (MV) and subsequent viral spread (Yang et al., 2005)
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From page 75... ...
VECTOR reports having conducted screening of more than 5,000 chemical compounds for their antiviral activity, and about 80 compounds active against surrogate orthopoxviruses (vaccinia virus, cowpox virus, and ectromelia virus) are said to have been identified.
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From page 76... ...
Agents That Enhance or Modulate the Host Immune Response Enhancing or modulating the host immune response is an alternative or adjunctive therapeutic approach to controlling smallpox through antiviral drugs that disrupt the replication cycle. Providing passive immunity through the transfer of protective antibodies from an immune to a susceptible individual can lend temporary, but potentially life-saving, protection.
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From page 77... ...
. More recently, humanized chimpanzee monoclonal antibodies specific for the B5 and A33 envelope glycoproteins of vaccinia virus and the variola virus homologs have been reported to inhibit the spread of vaccinia and variola viruses in vitro and have conferred protection in a mouse model of poxvirus infection (Chen and Ron, 2006; Chen et al., 2007)
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From page 78... ...
Cidofovir can be used on an investigational basis for treating severe orthopoxvirus infections, including smallpox. FDA-approved preparations of VIG are also available.
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From page 79... ...
or any other currently available regulatory pathway to achieve licensure is essentially precluded by the exceptionally narrow host range of variola virus; the lack of any previously recognized effective drug for use in head-to-head comparison with any new compound; and known and possible differences between variola and other orthopoxviruses in disease characteristics, drug susceptibility, and host range (Jordan and Hruby, 2006; Bolken and Hruby, 2008)
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From page 80... ...
Although preliminary testing of antivirals can use related orthopox viruses, live variola virus should be used in cell culture as the ultimate test. Host cell responses that define the course of variola infection in cell culture or in vivo, such as changes in gene expression or changes in signaling pathways, miRNA, or secreted cytokines, should be investigated to identify networks of responses that could serve as biomarkers of inhibition of virus infection by a candidate drug.
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From page 81... ...
If such biological parameters can be validated, it may eventually be possible to use these measures in developing an alternative to testing with live variola virus. For example, a VIG formulation containing monoclonal antibodies to variola B6 could be tested in mice infected with a vaccinia virus expressing the orthologous vaccinia B5.
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From page 82... ...
2007. Characterization of chimpanzee/human monoclonal antibodies to vaccinia virus A33 glycoprotein and its variola virus homolog in vitro and in a vaccinia virus mouse protec tion model.
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From page 83... ...
2009. Activities of certain 5′-substituted 4′-thiopyrimidine nucleosides against orthopoxvirus infections.
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From page 84... ...
2007. Selective phosphorylation of antiviral drugs by vaccinia virus thymidine kinase.
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From page 85... ...
2006. Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection.
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From page 86... ...
Synthesis and antiviral activity against orthopox viruses. Bioorganic & Medicinal Chemistry Letters 15 (1)
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