RSV604, a novel inhibitor of respiratory syncytial virus replication.
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.
Chapman
Joanna
J
Arrow Therapeutics Ltd., Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom. jchapman@arrowt.co.uk
Abbott
Elizabeth
E
Alber
Dagmar G
DG
Baxter
Robert C
RC
Bithell
Sian K
SK
Henderson
Elisa A
EA
Carter
Malcolm C
MC
Chambers
Phil
P
Chubb
Ann
A
Cockerill
G Stuart
GS
Collins
Peter L
PL
Dowdell
Verity C L
VC
Keegan
Sally J
SJ
Kelsey
Richard D
RD
Lockyer
Michael J
MJ
Luongo
Cindy
C
Najarro
Pilar
P
Pickles
Raymond J
RJ
Simmonds
Mark
M
Taylor
Debbie
D
Tyms
Stan
S
Wilson
Lara J
LJ
Powell
Kenneth L
KL
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
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