Keywords: HIV, Nef, small molecule inhibitor
Efficacy of anti-retroviral therapy (ARV) in HIV-infected people is limited by the appearance of drug resistance. Non-enzyme drug targets need to be probed as alternative viral inhibition. The HIV Nef protein, shown to be an important determinant for in vivo pathogenicity, is being studied in this project as such a potential drug target for HIV host interactions.
Although HIV-1 Nef was originally named 'negative factor', it has been shown to be critical for efficient persistence 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 ARV 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 the consortium have already identified small molecule inhibitors targeting Nef function. The first project aim is to validate the molecular events elicited by these molecules in both virus-free as well as in HIV infection in vitro assays. In a complementary 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, nuclear factor of activated T-cells (NFAT) activation and the Nef SH3-binding domain, that are likely to contribute to the importance of Nef in HIV-1 pathogenicity.
In addition, functional screenings to discover druggable 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.
|Official Address||Other Information|
|1||Frank Kirchhoff||University of Ulm
|2||Kalle Saksela||Haartman Institute
|3||Olivier Schwartz||Institut Pasteur
|4||Koen Van Aken||Ecosynth
|5||Paul Jolicoeur||Clinical Research Institute of Montreal