Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor

Ziresovir (RO-0529, AK0529) is reported
here for the first time
as a promising respiratory syncytial virus (RSV) fusion (F) protein
inhibitor that currently is in phase 2 clinical trials. This article
describes the process of RO-0529 as a potent, selective, and orally
bioavailable RSV F protein inhibitor and highlights the in vitro and
in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529
demonstrates single-digit nM EC50 potency against laboratory
strains, as well as clinical isolates of RSV in cellular assays, and
more than one log viral load reduction in BALB/c mouse model of RSV
viral infection. RO-0529 was proven to be a specific RSV F protein
inhibitor by identification of drug resistant mutations of D486N,
D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced
cell–cell fusion in cellular assays.