Antiviral targeting to suppress drug resistance

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The last decades have emphasized the pandemic potential of the flaviviruses, picornaviruses and coronaviruses. Traditional drug discovery approaches for antiviral agents have generally focused on direct-acting inhibitors of viral targets, usually enzymes, that disrupt function and thus inhibit viral growth. However, the effectiveness of loss-of-function antivirals can be rapidly overcome by the outgrowth of drug-resistant variants. Multi-drug therapy is an effective solution to this problem that has been employed for HIV and hepatitis C viruses. Unfortunately, multi-drug therapy remains an expensive, long-term approach ill-suited to rapid response to new pandemic viruses and use in impoverished settings. To address this challenge in antiviral drug development, Project 1 will use a combination of genetic strategies and deep mutational analysis to identify specific viral proteins and small molecule targeting strategies with the aim of suppressing the selection of drug-resistant viral variants. We will focus on identifying proteins that have the potential, when bound to inhibitors, to be 'dominant disruptors' of viral RNA replication or virion function by producing or acting as 'molecular poisons' towards all developing viruses inside an infected cell. In this scenario, the drug-susceptible parent viruses can act as dominant killers of drugresistant variants, thus blocking the propagation of resistance. Our data have identified both viral proteases and capsid protein targets as having potential to induce dominant-disruptor phenotypes upon binding smallmolecules drugs. In addition, deep mutational scanning and biochemical methods will enable us to identify specific small-molecule binding sites on diverse viral targets that further avoid resistance by targeting locations at which mutations are not tolerated due to fitness cost. The combination of these approaches will yield both genetically validated viral targets, and particular regions of viral targets, that can suppress the formation of drug resistance as well as approaches for small-molecule targeting that are unlikely to allow the selection for resistance through classical mutational variation. These targets can then enter the consortium pipeline for rapid progression to screening, hit-to-lead development and validation in animal models of infection.