Treatment of Vaccinia and Cowpox Virus Infections in Mice with CMX001 and ST-246

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.

Keywords: antiviral; cowpox virus; murine model; orthopoxvirus; vaccinia virus.

Figure 1

Synergistic interactions of CMX001 and ST-246 against vaccinia and cowpox virus in vitro. Effect of combinations of CMX001 and ST-246 against vaccinia virus and cowpox virus. Inhibition of vaccinia virus replication was evaluated in a CellTiter-Glo® assay with a matrix of drug concentrations and an isobologram depicts EC₅₀ values at each drug combination (A). A synergy plot is also shown that represents greater than expected inhibition with increasing synergistic intensity represented by maroon, yellow and green regions, respectively (B). This analysis determined that combinations of ST-246 and CMX001 were strongly synergistic with volumes of 326 μM²% at the 95% confidence level. Efficacy of this drug combination was also determined against cowpox virus in a neutral red assay and the EC₅₀ isobologram is shown (C). A synergy plot also identified several combinations of concentrations where synergistic interactions occurred and are shown at the 65% confidence level (D). This analysis calculated the volume of synergy at 106 μM²% at the 95% confidence level. Excerpted from [24].