Oral lipid prodrug V2043 (1- <i>O</i> -octadecyl-2- <i>O</i> -benzyl- <i>sn</i> -glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection

ABSTRACT Dengue virus and related flaviviruses are significant threats to global health, with no approved antiviral treatments available. Remdesivir triphosphate (RVn-TP) is a nucleotide analog that inhibits RNA-dependent RNA polymerases from many clinically important RNA viruses, including dengue virus. An orally bioavailable prodrug that efficiently delivers RVn-TP could facilitate early treatment for non-hospitalized dengue patients. To that end, we developed 1- O -octadecyl-2- O -benzyl- sn -glyceryl-P-remdesivir nucleoside (V2043, ODBG-P-RVn), a phospholipid prodrug that achieves RVn-TP delivery through improved oral bioavailability, potency, and pharmacokinetics. Here, we show that when compared to the parent compound remdesivir nucleoside (RVn), V2043 is a more potent in vitro inhibitor of multiple flaviviruses, including dengue, Zika, West Nile, and Japanese encephalitis viruses. In lethal prophylactic and therapeutic mouse models that recapitulate key aspects of severe dengue in humans, once-daily oral V2043 significantly decreased dengue serum viremia, clinical severity, weight loss, and mortality. Additionally, oral V2043 was well tolerated when administered daily for 14 days. These results demonstrate the potential therapeutic efficacy of V2043 to treat several clinically relevant flaviviruses, including dengue virus, the most prevalent and widespread arbovirus infection in the world.