Epiphany Biosciences, Inc., San Francisco, CA 94111, United States. Electronic address: firstname.lastname@example.org.
Ribavirin is an important broad-spectrum antiviral drug. However, its utilization can be limited by its potential to cause hemolytic anemia as well as its variability in dosing levels and efficacy outcomes. To overcome these issues, we report on a new alkoxyalkylphosphodiester prodrug of ribavirin (2) that is designed to release the active ribavirin-monophosphate species selectively in nucleated cells while limiting its exposure in anucleated red blood cells (RBCs). Prodrug 2 displays improved in vitro antiviral activity against the hepatitis C virus replicon and influenza virus. Unlike ribavirin, prodrug 2 does not significantly decrease ATP levels in RBCs. Prodrug 2 demonstrates decreased uptake in RBCs but increased uptake in HepG2 hepatocytes when compared to ribavirin. In vivo, prodrug 2 is orally bioavailable and well-tolerated in rats in which it is processed to ribavirin and accumulates in the liver. These results indicate that prodrug 2 has the potential for safer, lower, less frequent, and less variable administration than ribavirin.