title: RSV604, a novel inhibitor of respiratory syncytial virus replication.
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.
authors.affiliation: Arrow Therapeutics Ltd., Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom. jchapman@arrowt.co.uk
authors.forename: Joanna
authors.initials: J
authors.lastname: Chapman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Abbott
authors.forename: Dagmar G
authors.initials: DG
authors.lastname: Alber
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
authors.forename: Sian K
authors.initials: SK
authors.lastname: Bithell
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Henderson
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Carter
authors.forename: Phil
authors.initials: P
authors.lastname: Chambers
authors.forename: Ann
authors.initials: A
authors.lastname: Chubb
authors.forename: G Stuart
authors.initials: GS
authors.lastname: Cockerill
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Verity C L
authors.initials: VC
authors.lastname: Dowdell
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Keegan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kelsey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lockyer
authors.forename: Cindy
authors.initials: C
authors.lastname: Luongo
authors.forename: Pilar
authors.initials: P
authors.lastname: Najarro
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pickles
authors.forename: Mark
authors.initials: M
authors.lastname: Simmonds
authors.forename: Debbie
authors.initials: D
authors.lastname: Taylor
authors.forename: Stan
authors.initials: S
authors.lastname: Tyms
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Powell
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003588:Cytopathogenic Effect, Viral; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D019590:Nucleocapsid Proteins / Q000187:drug effects; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000235:genetics; D013778:Tetrazolium Salts; D014779:Virus Replication / Q000187:drug effects
chemical_list: C519521:1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)urea; D000998:Antiviral Agents; D001570:Benzodiazepinones; D019590:Nucleocapsid Proteins; D010671:Phenylurea Compounds; D013778:Tetrazolium Salts; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide