Dengue virus is a major human pathogen that presents a daunting challenge to treatment design and implementation. No antivirals are currently available and, as for all positive-strand RNA viruses, it is anticipated that multi-drug therapy will be needed due to the high error rate ofthe viral polymerases which can lead to the rapid selection of drug-resistant viruses. However, we have developed a strategy to identify dominant drug targets' in RNA viruses and are testing this strategy with Dengue viruses. Specifically, when the target of a drug is an oligomeric protein or is involved in the generation of an oligomeric species, it is often true that drug-sensitive viruses are genetically dominant over the inevitable drug-resistant ones. Thus, the drug-resistant viruses are not selected from the cells in which they were generated. For Dengue virus, candidate proteins are the core protein C, the envelope protein E, the protease NS2/3, and certain inhibitors ofthe polymerase NSS. We have obtained inhibitors of E, NS2/3 and NS5 and selected and partially sequenced drug-resistant variants of each. For these and other inhibitors of Dengue virus, we will test in coinfections whether drug susceptibility or drug resistance is dominant. Then, we will test the frequency of the emergence of drug resistant viruses in murine infections. We anticipate that, for some drug targets and not others, drug resistance will be dramatically suppressed, paving the way for the use of fewer compounds to treat Dengue virus infection, and possibly even monotherapy. The development of logical strategies to counteract drug resistance is crucial to combatting many pathogens, with Dengue virus as a currently pressing example.
The emergence of drug-resistant variants is the single most formidable obstacle to the development of safe, effective antiviral compounds. This is especially the case for RNA viruses, many of which are Category A, B and C pathogens for which strong biodefense precautions should be in place. A successful strategy to combat drug resistance will greatly expedite the development of antivirals for many of these and other pathogens.
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