Abstract
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.
MeSH terms
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Administration, Oral
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Animals
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Antiviral Agents / administration & dosage
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Antiviral Agents / chemical synthesis
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / therapeutic use*
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Benzazepines / administration & dosage
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Benzazepines / chemical synthesis
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Benzazepines / pharmacokinetics
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Benzazepines / therapeutic use*
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Dogs
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Drug Discovery
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Female
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Haplorhini
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Male
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Mice, Inbred BALB C
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Molecular Docking Simulation
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Molecular Structure
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Quinazolines / administration & dosage
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Quinazolines / cerebrospinal fluid
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Quinazolines / chemical synthesis
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Quinazolines / pharmacokinetics
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Quinazolines / therapeutic use*
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Rats, Wistar
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Respiratory Syncytial Virus Infections / drug therapy*
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Respiratory Syncytial Virus, Human / chemistry
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Respiratory Syncytial Virus, Human / drug effects*
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Structure-Activity Relationship
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Sulfones
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Thiazepines / administration & dosage
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Thiazepines / cerebrospinal fluid
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Thiazepines / pharmacokinetics
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Thiazepines / therapeutic use*
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Viral Fusion Proteins / antagonists & inhibitors*
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Viral Fusion Proteins / chemistry
Substances
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Antiviral Agents
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Benzazepines
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F protein, human respiratory syncytial virus
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Quinazolines
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Sulfones
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Thiazepines
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Viral Fusion Proteins
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ziresovir