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Inhibiting Nef: a novel drug target for HIV-host interactions

Objective

Although HIV-1 Nef was originally named "negative factor," it has been shown to be critical for efficient persistance of HIV-1 infected humans thus playing a major role in the progression to AIDS. Remarkably; until now Nef has not been evaluated as an antiretroviral drug target. It is well established that Nef promotes HIV-1 replication and facilitates viral immune evasion by interacting with various host factors. Disrupting these essential interactions may delay or even prevent disease progression. Partners in this consortium have already identified small molecule inhibitors targeting Nef function. The first objective of this project is therefore to validate the molecular events elicited by these molecules in both virus-free as well as in HIV infection in vitro assays. In a complementing approach, small compound libraries already available to the consortium will be used and adapted to screen for inhibitors of Nef induced modulation of cellular receptors, NFAT activation and the Nef SH3 binding domain, that likely contribute to the importance of Nef in HIV-1 pathogenicity. In addition, functional screenings to discover drugable cellular Nef partners using RNA interference libraries will be performed. After validation of their importance in relation to the established host proteins co-interacting in the Nef cellular pathways, a selection will be additionally targeted by the developed small molecule inhibitors. Our ultimate goal is to deliver a complementary portfolio of candidate drugs that target the most important parameters in the Nef-host interaction pathway. Critical cellular interaction partners are much more conserved than viral enzymes that are usually targeted in highly-active-antiretroviral therapy (HAART). Therefore, it is believed by the partners that the novel approach presented in this project proposal will yield compounds less likely to be subject to the occurrence of drug resistance

Field of science

  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

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

UNIVERSITEIT GENT
Address
Sint Pietersnieuwstraat 25
9000 Gent
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 605 520
Administrative Contact
Bruno Verhasselt (Prof.)

Participants (8)

UNIVERSITAET ULM
Germany
EU contribution
€ 471 600
Address
Helmholtzstrasse 16
89081 Ulm
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Frank Gleixner (Mr.)
HELSINGIN YLIOPISTO
Finland
EU contribution
€ 449 920,01
Address
Yliopistonkatu 3
00014 Helsingin Yliopisto
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Kalle Saksela (Prof.)
INSTITUT PASTEUR
France
EU contribution
€ 448 920
Address
Rue Du Docteur Roux 25-28
75724 Paris Cedex 15
Activity type
Research Organisations
Administrative Contact
Nadia Khelef (Dr.)
ECOSYNTH
Belgium
EU contribution
€ 248 039,99
Address
Industrielaan 12
9800 Deinze
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Koen Van Aken (Dr.)
INSTITUTES DE RECHERCHES CLINIQUES DE MONTREAL
Canada
Address
110, Avenue Des Pins Ouest
H2W 1R7 Montreal
Activity type
Research Organisations
Administrative Contact
Louis-Gilles Durand (Dr.)
MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany
EU contribution
€ 164 360
Address
Hofgartenstrasse 8
80539 Munich
Activity type
Other
Administrative Contact
Barbara Dobruchowski
UNIVERSITE DE STRASBOURG
France
EU contribution
€ 82 180
Address
Rue Blaise Pascal 4
67081 Strasbourg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Laurence Petin-Monteil
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
Address
Rue De Tolbiac 101
75654 Paris
Activity type
Research Organisations
Administrative Contact
Mihaja Auguste