Project: Development of novel clinical drug candidates for the treatment of pandemic and seasonal influenza
Influenza is a highly contagious acute viral infection, which causes annual epidemics as well as recurring devastating pandemics. _x000D_Due to its ability to rapidly mutate its genome, influenza virus is capable of causing worldwide pandemics. Over the past century, mankind has relied COly 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 drugs face several problems, e.g. 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 world wide use. In addition, the increasing development of resistance to NA inhibitors has been reported. Nonetheless, antiviral drugs have important roles to play at the start and during 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._x000D_The fluctuations in the influenza antivirals market due to the varying severity of the annual flu season hamper the precise forecasting of future sales of a novel drug in this therapeutic area. Future annual sales are estimated to peak anywhere between 1000-2500 million USD._x000D_The viral trimeric polymerase complex is an attractive and novel target for inhibition of viral replication. Due to the high degree of conservation among different virus strains, subunit interaction inhibitors will bear a lower risk of resistance development. This may be a big advantage with a rapidly mutating virus._x000D_In the context of a project funded by the EU Seventh Framework Programme for Research and Technological Development (FP7), coordinated by PiKe Pharma, FLUINHIBIT, inhibitors of the protein-protein interaction between two subunits of the polymerase complex, PB1 and PA, have been discovered. Since the PA-interaction doCO of PB1 is highly conserved, molecules able to block the interaction can be expected to inhibit most, if not all, influenza A and B strains. The most promising initial hits have been selected through subsequent cell-based and antiviral assays. AntiFlu will employ medicinal chemistry supported by computational approaches in order to develop drug leads with suitable pharmacokinetic, physicochemical and toxicologic properties for subsequent preclinical development. This will include in vivo testing in different animal models and toxicology assessments in vitro and in vivo. The resulting candidates are expected to enter clinical phase I approximately 18 months after completion of AntiFlu. Despite their close connection, AntiFlu and FLUINHIBIT are discrete projects and will not generate conflicts of interest due to overlapping research activities. Further information on this issue can be found in the work package section._x000D_The interdisciplinary consortium consisting of 2 SME Ps, PiKe Pharma and Inteligand, who have actively participated in the discovery of the original small molecule hits, and 2 new Ps, Prestwick Chemical and ETH Zürich (subcontractor), refelects the entry into a new drug development stage in the course of the transition from FLUINHIBIT to AntiFlu. PiKe Pharma with its core expertise in early-stage antiviral drug discovery will perform the in vitro and in vivo tests that are necessary to evaluate the efficacy of novel compounds synthesized by Prestwick Chemical, a well established center of competence for medicinal chemistry with an impressive track record in lead optimization in various therapeutic areas. Constant improvement of SAR models as the basis for iterative optimization cycles will be ensured by Inteligand. The company is very familiar with the structural features of the target and will complement “wet” chemistry and testing with virtual screening of targeted libraries, molecular modelling and continuously updated pharmacophore models. The Institute of Pharmaceutical Sciences at ETH Zürich will assist PiKe Pharma with pharmacokinetic and metabolic studies and support the formulation of the drug candidates for animal experiments. This includes the use of cell-based and in vivo models as well as synthesis of radiolabeled analogs. As a whole, the consortium will resemble a very effective and flexible “virtual drug discovery unit” with joint resources of three SMEs and one academic institution._x000D_The results of the project, drug leads enterring phase 0 will be either commercialized in a Pship with a large pharmaceutical company or further developed by PiKe Pharma and out-licensed at a later stage._x000D__x000D_
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Acronym
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AntiFlu
(Reference Number: 4792)
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Duration
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01/04/2009 - 30/09/2010
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Project Topic
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Starting from recently discovered small molecule inhibitors of the influenza virus polymerase, AntiFlu will deliver a new class of antiviral drug candidates. The novel mechanism of action will ensure broad-spectrum efficacy against both human and avian influenza and minimize resistance development.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 2
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Project partner
