Final Report Summary - FLUINHIBIT (Small molecule inhibitors of the trimeric influenza virus polymerase complex)
The objective of FLUINHIBIT has been to identify new drug candidates with broad-spectrum activity against human, avian and swine influenza viruses. These small molecule inhibitors of viral replication employ a novel mechanism of action, which is expected to be less prone to resistance development than the currently available drugs.
Due to its ability to rapidly mutate its genome, influenza A virus is capable of causing recurring worldwide pandemics as well as seasonal epidemics. Over the past century, mankind has relied mainly on vaccination in the fight against viral pathogens. As a consequence, very few antiviral drugs are available to date. Of the two classes of drugs specific for influenza, the oldest and most affordable face several problems, such as development of resistance, safety in pregnant women, reduced dose in elderly patients and the need of close clinical monitoring in certain patient groups. The second and newer class, the neuraminidase (NA) inhibitors, have a better safety profile but their price and limited supply are major constraints for worldwide use. In addition, the rapid development of resistance to NA inhibitors has been reported.
Nonetheless, antiviral drugs have important roles to play at the start and in the course of a pandemic. In the absence of vaccines during the first wave of infections, antivirals will be the only medical intervention for providing both protection against disease and therapeutic benefit in diseased persons. Thus, the development of novel, more effective therapeutic approaches to inhibit the replication of the influenza virus is of utmost importance and urgency.
FLUINHIBIT aims at the identification of small molecule inhibitors of the interaction between the influenza virus polymerase subunits PA and PB1 as novel antiviral drug candidates. Due to the high level of conservation of this interaction among different virus strains, inhibitors are expected to bear a lower risk of resistance development. This will be a significant advantage with a rapidly mutating virus. The viral trimeric polymerase complex is an attractive and novel target for inhibition of viral replication. Starting from an inhibitory peptide, a high-throughput assay has been developed in order to screen large chemical libraries. The resulting hits have been profiled in cell-based assays and lead candidates with submicromolar activity against human and avian influenza strains (incl. highly pathogenic Tamiflu®-resistant H5N1, 1918 H1N1 and 2009 pandemic H1N1) have been developed. These lead candidates are currently being optimised and will be processed into preclinical development in the near future.
Due to its ability to rapidly mutate its genome, influenza A virus is capable of causing recurring worldwide pandemics as well as seasonal epidemics. Over the past century, mankind has relied mainly on vaccination in the fight against viral pathogens. As a consequence, very few antiviral drugs are available to date. Of the two classes of drugs specific for influenza, the oldest and most affordable face several problems, such as development of resistance, safety in pregnant women, reduced dose in elderly patients and the need of close clinical monitoring in certain patient groups. The second and newer class, the neuraminidase (NA) inhibitors, have a better safety profile but their price and limited supply are major constraints for worldwide use. In addition, the rapid development of resistance to NA inhibitors has been reported.
Nonetheless, antiviral drugs have important roles to play at the start and in the course of a pandemic. In the absence of vaccines during the first wave of infections, antivirals will be the only medical intervention for providing both protection against disease and therapeutic benefit in diseased persons. Thus, the development of novel, more effective therapeutic approaches to inhibit the replication of the influenza virus is of utmost importance and urgency.
FLUINHIBIT aims at the identification of small molecule inhibitors of the interaction between the influenza virus polymerase subunits PA and PB1 as novel antiviral drug candidates. Due to the high level of conservation of this interaction among different virus strains, inhibitors are expected to bear a lower risk of resistance development. This will be a significant advantage with a rapidly mutating virus. The viral trimeric polymerase complex is an attractive and novel target for inhibition of viral replication. Starting from an inhibitory peptide, a high-throughput assay has been developed in order to screen large chemical libraries. The resulting hits have been profiled in cell-based assays and lead candidates with submicromolar activity against human and avian influenza strains (incl. highly pathogenic Tamiflu®-resistant H5N1, 1918 H1N1 and 2009 pandemic H1N1) have been developed. These lead candidates are currently being optimised and will be processed into preclinical development in the near future.
