The rapid evolution of drug-resistant viruses is the single greatest reason that there are so few effective compounds available to treat RNA viral infections. Several approaches to circumvent the high frequencies of drug resistance have been pursued. Targeting host factors is an excellent strategy represented by several proposals in the present consortium. Multi-drug therapy is being used successfully to treat HIV infections, but obviously requires the existence of multiple drugs. We are developing a new paradigm, to develop inhibitors of 'dominant drug targets': those viral products that, when drug-bound, dominantly interfere with the growth of drug-resistant products within the same cell. The premise here is that drug-resistant viruses will always be made, but that it is possible to blunt the selection pressure on them by targeting oligomeric proteins that will be chimeric mixtures of drug-resistant and drug-susceptible subunits. To this end, we have identified five potential dominant drug targets on which to focus structure-based modeling. These highly oligomeric targets are the core protein structures of HCV and Dengue viruses, the icosahedrally symmetric Dengue virus envelope and the capsid structures of hepatitis A and enterovirus 71. For each modeling project, a unique approache will be the use of a heavily curated data base of known or approved drugs, termed WONTKILL (World of Non-Toxic Khemicals, ILIegal and Legal). This database has recently been mined to identify a repurposed compound currently in clinical trials for Trypanosma cruzi infections. Innovative mining techniques developed in the Pande laboratory include molecular similarity and rapid cheminformatics approaches. Selected potential compounds will be evaluated for efficacy in inhibiting viral growth and, just as importantly, the frequency of emergence of drug resistance in tissue culture and mouse models. Successful completion of these experiments will yield novel or, even better, repurposed compounds that both inhibit the target RNA viruses and display lowered risk of being rendered useless by the emergence of drug resistance.