Efficacy of the nucleoside analog 4'-Fluorouridine against Nipah virus in the Syrian hamster model.

Abstract

Nipah virus (NiV) is a zoonotic paramyxovirus with pandemic potential, for which no licensed vaccines or therapeutics for human use are available. The nucleoside analog 4'-fluorouridine (4'-FlU, EIDD-2749) has broad activity against RNA viruses including in vitro activity against the Malaysia and Bangladesh clades of NiV (NiV-M and NiV-B, respectively). Here, we report the pharmacokinetic profile of orally administered 4'-FlU in Syrian Golden hamsters and its efficacy against NiV-B. 4'-FlU was orally bioavailable and provided sustained exposure of its bioactive anabolite 4'-FlU 5'-triphosphate (4'-FlU-TP) in the brain. A 7-day treatment course after NiV infection delayed time to death. Extending treatment to 21-28 days reduced viremia, incidence of lung disease, lung lesion severity, inflammation, and mortality. Lesions, viral antigen, or viral RNA could be detected in some survivors, suggesting persistent infections. Sequence analysis of NiV populations showed nonsynonymous single-nucleotide variants (SNVs) in some brain specimens from 4'-FlU-treated animals. Amino acid changes occurred in the nucleocapsid, the polymerase, or the phosphoprotein. It is currently unclear whether they reduce viral susceptibility to treatment or impact virulence but caused a slight increase in 4'-FlU potency compared to the genetic parent virus in vitro. However, none of these SNVs increased viral fitness in human brain astrocytes. This study established proof-of-concept for efficacious oral treatment of lethal NiV infection with a small-molecule nucleoside analog inhibitor in a relevant animal model.