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Antimicrobial Agents and Chemotherapy, December 2004, p. 4542-4549, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4542-4549.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Potent and Long-Acting Dimeric Inhibitors of Influenza Virus Neuraminidase Are Effective at a Once-Weekly Dosing Regimen

Simon J. F. Macdonald,1*,{dagger} Keith G. Watson,2,{dagger},{ddagger} Rachel Cameron,2 David K. Chalmers,2 Derek A. Demaine,1 Rob J. Fenton,1 David Gower,1 J. Nicole Hamblin,1 Stephanie Hamilton,2 Graham J. Hart,1 Graham G. A. Inglis,1 Betty Jin,2 Haydn T. Jones,1 Darryl B. McConnell,2,§ Andy M. Mason,1 Van Nguyen,2 Ian J. Owens,1 Nigel Parry,1 Phillip A. Reece,2 Stephen E. Shanahan,1 Donna Smith,1 Wen-Yang Wu,2 and Simon P. Tucker2

GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom,1 Biota Holdings, Melbourne, Victoria, Australia2

Received 1 March 2004/ Returned for modification 31 May 2004/ Accepted 29 August 2004

Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 Å, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.

* Corresponding author. Mailing address: Medicinal Chemistry 1, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. Fax: 44 0 1438 768302. E-mail: simon.jf.macdonald{at}gsk.com.

{dagger} S.J.F.M. and K.G.W. contributed equally to this work.

{ddagger} Present address: Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.

§ Present address: Boehringer-Ingelheim, A-1200 Vienna, Austria.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4542-4549, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4542-4549.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yamashita, M., Tomozawa, T., Kakuta, M., Tokumitsu, A., Nasu, H., Kubo, S. (2009). CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity. Antimicrob. Agents Chemother. 53: 186-192 [Abstract] [Full Text]  


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