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Antimicrobial Agents and Chemotherapy, September 2007, p. 3346-3353, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00211-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication{triangledown}

Joanna Chapman,1* Elizabeth Abbott,1 Dagmar G. Alber,1,{ddagger} Robert C. Baxter,1 Sian K. Bithell,1 Elisa A. Henderson,1 Malcolm C. Carter,1 Phil Chambers,2 Ann Chubb,1 G. Stuart Cockerill,1 Peter L. Collins,3 Verity C. L. Dowdell,1 Sally J. Keegan,1 Richard D. Kelsey,1 Michael J. Lockyer,1 Cindy Luongo,3 Pilar Najarro,1 Raymond J. Pickles,4 Mark Simmonds,2 Debbie Taylor,2 Stan Tyms,2 Lara J. Wilson,1 and Kenneth L. Powell1

Arrow Therapeutics Ltd., Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom,1 Virogen Ltd., MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, United Kingdom,2 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, 7 Center Drive, MSC 0720, Bethesda, Maryland,3 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina4

Received 13 February 2007/ Returned for modification 30 March 2007/ Accepted 12 June 2007

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.

* Corresponding author. Mailing address: Arrow Therapeutics Ltd., Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom. Phone: 44 (0)20 70151000. Fax: 44 (0)20 70151020. E-mail: jchapman{at}arrowt.co.uk

{triangledown} Published ahead of print on 18 June 2007.

{ddagger} Present address: BHF Laboratories, The Rayne Institute, University College London, London, United Kingdom.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3346-3353, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00211-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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