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The Development of Mechanism-Based Inhibitors of Influenza Neuraminidase to target Drug Induced Resestance

Objective

The recent emergence of the highly pathogenic H5N1 strain of avian influenza now circulating in Asia, EU and Africa has increased concerns that a new, and devastating, influenza pandemic may be imminent. Antiviral drugs represent the first line of defence for pandemic outbreaks, and governments are currently stockpiling the influenza neuraminidase inhibitors Relenza® (Zanamivir) and Tamiflu® (Oseltamivir) in preparedness. These neuraminidase inhibitors are highly potent and specific inhibitors against all known influenza A and B strains, including the avian H5N1 virus. There are, however, several problems associated with Relenza and Tamiflu. Unfortunately, as Relenza is only delivered to the respiratory tract, its usefulness is limited if the pandemic influenza strain spreads to other organs, and, more alarmingly, drug-induced resistance to Tamiflu has already been observed in clinical isolates from H5N1 infected patients. As such, there is an urgent need to develop new and improved classes of anti-virals for the treatment of influenza. Dr Watts has recently filed a provisional patent application for the use of fluorinated sialic acid analogues as ‘mechanism-based’ neuraminidase inhibitors for the treatment of influenza. These novel compounds are known to covalently inhibit influenza neuraminidases by specifically targeting amino acid residues essential for catalytic activity and, as such, drug-induced resistance is less likely to evolve in response to these compounds. We propose to synthesise a series of modified fluoro-sialic acids as ‘mechanism-based’ inhibitors of influenza neuraminidases, incorporating structural features designed to improve the pharmacokinetic properties and inhibitory activities of the original inhibitors. We will then perform detailed kinetic analyses of their inhibitory activity against purified influenza neuraminidases, and potent inhibitors will then be tested for efficacy towards a panel of wild-type and drug-resistant influenza viruses.

Field of science

  • /medical and health sciences/health sciences/epidemiology/pandemics
  • /medical and health sciences/health sciences/infectious disease/RNA virus/influenza
  • /natural sciences/biological sciences/microbiology/virology
  • /natural sciences/chemical sciences/organic chemistry/amines

Call for proposal

FP7-PEOPLE-IEF-2008
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

UNIVERSITY OF BATH
Address
Claverton Down
BA2 7AY Bath
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 171 867,63
Administrative Contact
Hazel Wallis (Ms.)