Discovery and Preclinical Development of Novel Stress Granule-Inducing Antiviral Drugs

Antiviral drugs are an important component of global efforts to contain pandemic influenza outbreaks. Current front-line antiviral drugs block influenza virus replication by selectively inhibiting the function of a few essential viral proteins. A rapid replication cycle and high mutation rate has enabled the emergence of drug-resistant strains of influenza viruses, which have now become widespread. This necessitates the investigation of new drug targets. Recently, the search for effective new antiviral drugs has shifted focus from targeting viral proteins to targeting host cell processes that normally support viral infection. This approach has the potential to limit the emergence of drug resistant viruses. Our research has shown that there is a window of opportunity early in each infectious cycle when influenza viruses are sensitive to alterations in host cell protein synthesis capacity. With this knowledge we identified a drug candidate that can selectively disrupt influenza virus production without harming uninfected cells. This drug is currently in clinical use to treat cancer and inflammatory disorders. We are investigating its mechanism of action, and developing an infection model to test efficacy and characterize immune responses in animals. This drug can be delivered orally and there is a wealth of preexisting clinical safety and efficacy information available, which will accelerate our drug development plan. Meanwhile, we will continue our efforts to identify new drugs in this class, and conduct experiments to determine whether influenza viruses can evolve to resist these drugs.