NAINH

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

Coordinatore	UNIVERSITY OF BATH    more  Organization address address: CLAVERTON DOWN city: BATH postcode: BA2 7AY contact info Titolo: Ms. Nome: Hazel Cognome: Wallis Email: send email Telefono: +44(0)1225 386822 Fax: +44(0)1225 383276
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	0 €
EC contributo	171˙867 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-IEF-2008
Funding Scheme	MC-IEF
Anno di inizio	2009
Periodo (anno-mese-giorno)	2009-06-01   -   2011-05-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITY OF BATH  Organization address address: CLAVERTON DOWN city: BATH postcode: BA2 7AY contact info Titolo: Ms. Nome: Hazel Cognome: Wallis Email: send email Telefono: +44(0)1225 386822 Fax: +44(0)1225 383276	UK (BATH)	coordinator	171˙867.62

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 Obiettivo del progetto (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.'