Strategic design and three-dimensional analysis of antiviral drug combinations

The development of new drugs effective against human viral diseases has proven to be both difficult and time-consuming. Indeed, there are but 10 drugs licensed for such applications in the United States today. An attractive solution to this problem may be to optimize the efficacy and selectivity of existing antiviral drugs by combining them with agents that strategically block carefully selected metabolic pathways. This approach was used in the rational design of a three-drug combination to increase the apparent potency of acyclovir against herpes simplex virus. Recent advances in analytical techniques have made the evaluation of this complex drug strategy both possible and practical. A modified version of a previously described analytical method was used to identify optimal drug concentrations and to quantitate statistically significant synergy. Concentrations of 0.25 microM 5-fluorodeoxyuridine, 3.6 microM 2-acetylpyridine thiosemicarbazone, and 0.3 microM acyclovir were determined to be optimal in terms of antiviral activity. The volume of synergy produced was nearly 2,000 microM3% at a 95% level of confidence (corresponding to a 186-fold decrease in the apparent 50% inhibitory concentration of acyclovir with the addition of 0.25 microM 5-fluorodeoxyuridine and 3.6 microM 2-acetylpyridine thiosemicarbazone). We anticipate that this strategic approach and the supporting three-dimensional analytical method will prove valuable in designing and understanding multidrug therapies.