RSV604, a novel inhibitor of respiratory syncytial virus replication

Antimicrob Agents Chemother. 2007 Sep;51(9):3346-53. doi: 10.1128/AAC.00211-07. Epub 2007 Jun 18.

Abstract

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / pharmacology*
  • Cell Line
  • Chemical Phenomena
  • Chemistry, Physical
  • Cytopathogenic Effect, Viral
  • Dose-Response Relationship, Drug
  • Drug Resistance, Viral / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / virology
  • Humans
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation
  • Nucleocapsid Proteins / drug effects
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / pharmacology*
  • Respiratory Syncytial Viruses / drug effects*
  • Respiratory Syncytial Viruses / genetics
  • Tetrazolium Salts
  • Virus Replication / drug effects

Substances

  • 1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)urea
  • Antiviral Agents
  • Benzodiazepinones
  • Nucleocapsid Proteins
  • Phenylurea Compounds
  • Tetrazolium Salts
  • 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide