FLUINHIBIT

Small Molecule Inhibitors of the Trimeric Influenza Virus Polymerase Complex

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 Obiettivo del progetto (Objective)

'The clock is counting down to the next influenza pandemic. Since 1997, the avian influenza virus strain H5N1 has infected over 250 people worldwide with a fatality rate of ~60%, although so far without sustained human-to-human transmission. In view of the very few efficacious drugs against influenza virus infections and the time it takes to develop a matching vaccine, there is an unmet worldwide need for new anti-influenza drugs. The viral trimeric RNA polymerase complex, consisting of the subunits PA, PB1 and PB2, is an attractive target for inhibition of viral replication. However, due to the absence of detailed structural information and clear understanding of the subunit functions so far, inhibitors of the RNA polymerase developed as drug candidates are extremely scarce. Based on the recent finding that a short peptide corresponding to the PA-binding domain of the PB1 subunit blocks both polymerase activity and viral spread, FLUINHIBIT aims at discovering small molecule inhibitors of this subunit interaction crucial for viral replication. Starting from the peptide, and supported by characterization of the PB1-binding domain of PA, molecular modeling will be employed to rationally design and synthesize peptidomimetics via traditional medicinal chemistry and a novel fragment based library synthesis approach. In parallel, a fluorescence polarization high-throughput assay will be developed to screen large compound collections and unique in-house small molecule libraries. The resulting hits will be profiled in cell-based assays and lead candidates with antiviral activity will be identified for preclinical development.'

Introduzione (Teaser)

Since first breaking out, the avian influenza virus strain has hit some 250 people worldwide and racked up a fatality rate of around 60%. Considering time doesn't favour development of a suitable vaccine, there is an urgent need for anti-influenza drugs.

Descrizione progetto (Article)

Absence of vaccines and the fact that antiviral drugs can play an important role at the beginning and during the course of a pandemic, mean that antivirals have the potential to provide protection against disease as well as therapeutic benefit to those already afflicted.

There are two classes of drugs specific to targeting influenza. The first is the most affordable, but is prone to development of resistance; it raises safety concerns for pregnant women, requires smaller doses in the elderly and must be clinically monitored in certain patient groups. The second and newer class of neuraminidase inhibitors has a better safety profile. However, cost and limited supply represent major obstacles to worldwide use, and there have been reports of rapid resistance development.

The 'Small molecule inhibitors of the trimeric influenza virus polymerase complex' (Fluinhibit) project aimed to identify new drug candidates with wide-ranging activity against avian (H5N1), human and swine influenza viruses. First, there was a need to determine which small molecules could inhibit interaction between the influenza virus polymerase subunits PA and PB1. The viral trimeric ribonucleic acid (RNA) polymerase complex is an attractive target for inhibition of viral replication and is expected to grant a lower risk of resistance development.

Starting from an inhibitory peptide, large chemical libraries were screened, and resulting hits were profiled in cell-based assays. Lead candidates with submicromolar activity against avian and human influenza strains have been developed and are currently being optimised for future processing into preclinical development.

Avoiding the next possible flu pandemic is a major concern. Developing anti-influenza drugs as opposed to relying on vaccination programmes that become redundant through viral evolution seems to be the most promising path forward.