A new form of antiviral combination therapy predicted to prevent resistance from arising, and a model system to test it

Combination therapy in the treatment of viral infections in which, for exam ple, three different drugs against three different targets on three indepen dent proteins are administered, has been highly successful clinically. Howe ver, it is only a matter of time before a virus will arise resistant to all three drugs, because the mutations leading to drug resistance are independ ent of each other. But, what if the mutations leading to drug resistance ar e not independent of each other, but confer some cost to the virus? If the cost is too great, than resistance may not arise. To impose such a cost in the clinical treatment of viral infections, we propose a new form of combin ation therapy. Here, three different drugs against three different targets on the same virus-coded protein are administered. If the physiological func tions of the three different target sites are not independent of each other , then, a mutation at one site may alter the physiological functions at the other sites. We present a model system in which to test the efficacy of th is new form of triple combination therapy. Human adenovirus has a virus-cod ed proteinase that is essential for the synthesis of infectious virus. It c ontains an active site and two cofactor binding sites; the functions of the active site are dependent upon the cofactors interacting with their bindin g sites. We describe how to obtain drugs against the three different sites.