A new level of anti-influenza drugs

The 2009 pandemic and recent outbreaks of highly pathogenic avian influenza strains have highlighted the need for effective antiviral drugs. A broad choice of drugs is necessary for treatment before a new vaccine becomes available to counter the problem of viral resistance.

Health

Currently, vaccines and antiviral drugs target three influenza envelope proteins: haemagglutinin, neuraminidase and the M2 ion channel protein. New classes of antivirals are needed to interfere with other essential viral processes such as the replication machinery (polymerase). The EU-funded FLU-PHARM (New drugs targeting influenza virus polymerase) consortium developed new molecules to target this complex so essential to the influenza virus. The influenza RNA-dependent RNA polymerase is a heterotrimeric enzyme composed of PA, PB1 and PB2 subunits, and is responsible for the replication of the viral RNA that is then incorporated into new infectious viruses. Moreover, polymerase produces the virus's messenger RNA to produce viral proteins. FLU-PHARM has improved fundamental understanding of the underlying mechanisms of polymerase function, and used this knowledge to advance antiviral drug design. Researchers determined the structure down to the atomic level of the helical portion of the viral ribonucleoprotein particles (RNPs) coated with nucleoproteins and bound to polymerase. This will shed light on viral gene expression and multiplication in infected cells. Other scientific highlights were the crystal structures of influenza A polymerase bound to the promoter and influenza A and B's polymerase both in complex with the viral promoter. A concerted medicinal chemistry programme synthesised and tested 2 500 candidate molecules for their ability to inhibit the polymerase's endonuclease activity. Several candidate molecules were tested for their efficacy against influenza infection in mice. Out of these, four significantly improved the animals' survival, thus providing proof of concept. The partners also created a protocol for analysing drug-resistance development against candidate drugs. As a result of the success of the drug screening, the FLU-PHARM drug development programme was taken over by one of the world’s largest biotech companies. The consortium presented results and progress of the project in 29 publications. Dissemination has not been aimed exclusively at the pharma/medical sectors. Out of 55 dissemination activities, 15 were aimed at the civil society, including secondary schools. Fundamental studies focusing on the function of the polymerase and its interactions with host cells will potentially provide improved cellular assays for polymerase inhibitors.