FLUCURE

Development of novel antiviral drugs against Influenza

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 Obiettivo del progetto (Objective)

'Influenza viruses cause a highly contagious respiratory disease in both humans and animals. Typically, influenza spreads worldwide in seasonal epidemics resulting in an estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths annually. In addition to these seasonal epidemics there have been several pandemics since the early 1900’s, where highly virulent strains emerged, the most devastating being the ‘Spanish Flu’ of 1918, which caused 20-40 million deaths globally. Vaccination is currently the primary means of controlling the spread of influenza virus infections but due to the virus’s notorious ability to mutate, new vaccines must be developed each year. There are a few antiviral drugs that are currently on the market; however, their therapeutic potential is restricted through rapid appearance of drug-resistant viruses during treatment. Thus, the need for novel effective drugs against influenza is evident. The FLUCURE project aims at developing innovative, first-in-class therapeutics against influenza by targeting the viral ribonucleoprotein complex, which is replication core of the virion and a major contributor to viral virulence. The high level of conservation combined with slow mutation rates of the ribonucleoprotein complex should result in therapeutics with broad viral strain specificity associated with a reduced risk for developing resistance. FLUCURE builds further on two successful EU-FP7 drug discovery projects, FLUINHIBIT and FluDrugStrategy, both targeting specific but different protein-protein interactions of the viral ribonucleoprotein complex with small molecule inhibitors. A consortium of 10 partners with the required complementary skills will progress the lead candidates from these two projects synergistically through lead optimization and preclinical development phases, with the final objective to deliver one or more drug candidates suitable for entering clinical development within 4 years.'

Introduzione (Teaser)

An effective drug against influenza (i.e. one not rendered ineffective by virus mutation) will provide a long-term solution to the treatment of the infection. An EU-funded initiative is hoping to complement existing therapeutic options by providing a regimen that could potentially target many viral strains.

Descrizione progetto (Article)

Influenza virus infections occur in seasonal epidemics, resulting in millions of cases of severe illness and hundreds of thousands estimated annual deaths. In addition to these seasonal epidemics, highly virulent strains emerged during several pandemics, such as the Spanish Flu of 1918.

Vaccination is currently the primary means of controlling the spread of influenza virus infections, but due to the virus' notorious ability to mutate, new vaccines must be developed each year. The key objective of the EU-funded ?Development of novel antiviral drugs against influenza? (Flucure) project is to develop innovative therapeutics against influenza by targeting the viral ribonucleoprotein (RNP) complex, a major contributor to viral virulence.

The high level of conservation of the RNP complex, combined with slow mutation rates, should result in therapeutics with broad viral strain specificity associated with a reduced risk for developing resistance. Through iterative cycles of hypothesis-driven molecular design, organic synthesis, and pharmacological evaluation of structural analogues of lead molecules, scientists have come up with various lead candidates.

The consortium is employing three-dimensional pharmacophore models to define the structural requirements of the ligands to bind the targeted sites of action. Using this approach, over 500 novel molecules have been designed and the most promising candidates will be synthesised.

Much effort is also being devoted to establishing biophysical assays that would help reveal how these compounds interfere with the RNP complex. Co-crystallisation experiments will determine their exact site and mode of binding.

So far, the work of the Flucure project has yielded a new compound targeting the influenza nucleoprotein with high antiviral activity, resulting in a patent application.

Given the magnitude of the influenza health problem globally, the Flucure deliverables potentially will have important consequences for protecting the health of European citizens. The broad applicability of the Flucure treatment approach means that in the event of a serious pandemic involving a highly pathogenic virus such as H5N1, affected individuals could be treated even before the exact nature of the viral strain will have been determined.