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Abstract
Although a large number of compounds have been identified with antiviral activity against orthopoxviruses in tissue culture systems, it is highly preferred that these compounds have activity in vivo before they can be seriously considered for further development. One of the most commonly used animal models for the confirmation of this activity has been the use of mice infected with either vaccinia or cowpox viruses. These model systems have the advantage that they are relatively inexpensive, readily available and do not require any special containment facilities; therefore, relatively large numbers of compounds can be evaluated in vivo for their activity. The two antiviral agents that have progressed from preclinical studies to human safety trials for the treatment of orthopoxvirus infections are the cidofovir analog, CMX001, and an inhibitor of extracellular virus formation, ST-246. These compounds are the ones most likely to be used in the event of a bioterror attack. The purpose of this communication is to review the advantages and disadvantages of using mice infected with vaccinia and cowpox virus as surrogate models for human orthopoxvirus infections and to summarize the activity of CMX001 and ST-246 in these model infections.
Highlights
Background and IntroductionFollowing the tragic events of September 11th and the anthrax mailings in 2001 in the U.S, several laboratories strengthened their ongoing efforts in the discipline of biodefense
Funding from government agencies as well as some biotechnology companies was increased and allocated into research and development programs targeted towards the discovery of novel or improved compounds that may be valuable as therapies against orthopoxvirus infections
CMX001 and ST-246 are being considered for inclusion
Summary
Following the tragic events of September 11th and the anthrax mailings in 2001 in the U.S, several laboratories strengthened their ongoing efforts in the discipline of biodefense. Immunodeficient mice provide models for humans that are immunosuppressed, including post-operative solid organ transplant recipients, leukemia or AIDS patients. To simulate these conditions, severe combined immunodeficient (SCID), athymic, and knock-out mice have been infected with orthopoxviruses and used for antiviral evaluations [2,3,4]. The disadvantages of rodent models infected with vaccinia or cowpox viruses include the fact that initiation of infection requires a substantial viral inoculum to obtain a lethal infection This necessity is dissimilar to a smallpox bioterror event where inhalation or contact with only a few airborne infectious viruses to humans could begin a pandemic event [5]. A disadvantage of this model is the requirement for more stringent containment procedures which may preclude its use for large scale in vivo screening studies
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