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Small Molecule Inhibitors of the Trimeric Influenza Virus Polymerase Complex

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.

Field of science

  • /medical and health sciences/basic medicine/medicinal chemistry
  • /medical and health sciences/health sciences/infectious disease/RNA virus/influenza

Call for proposal

FP7-HEALTH-2007-A
See other projects for this call

Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

PIKE PHARMA GMBH
Address
Technoparkstrasse 1
CH-8005 Zuerich
Switzerland
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 378 750
Administrative Contact
Ulrich Kessler (Dr.)

Participants (5)

UNIVERSITAETSKLINIKUM FREIBURG
Germany
EU contribution
€ 286 500
Address
Hugstetter Strasse 49
79106 Freiburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Jürgen Dreyer (Mr.)
BIOTECHNOLOGIJOS INSTITUTAS
Lithuania
EU contribution
€ 185 250
Address
Graiciuno 8
2028 Vilnius
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Leonas Pasakarnis (Mr.)
INTE:LIGAND SOFTWARE-ENTWICKLUNGS-UND CONSULTING GMBH
Austria
EU contribution
€ 233 250
Address
Clemens Maria Hofbauer Gasse 6
2344 Maria Enzersdorf
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Thierry Langer (Prof.)
HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Germany
EU contribution
€ 194 250
Address
Inhoffenstrasse 7
38124 Braunschweig
Activity type
Research Organisations
Administrative Contact
Michael Strätz (Dr.)
UNIVERSITA DEGLI STUDI DI SIENA
Italy
EU contribution
€ 206 250
Address
Via Banchi Di Sotto 55
53100 Siena
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Silvano Focardi (Prof.)