CORDIS - EU research results

Exploiting cellular export of nuclear transcripts as HIV innovative therapy

Final Report Summary - EXCELLENT-HIT (Exploiting Cellular Export of Nuclear Tanscripts as HIV Innovative Therapy)

Before embarking on establishing protein-protein interactions the EXCELLENT-HIT project had to validate DDX3 as a genuine anti-HIV target. In November 2008, they had clear evidence that DDX3 indeed plays an important role in HIV replication. DDX3 thus is a novel anti-HIV target and drug discovery targeting DDX3 is thus reasonable.

The project has evidence that DDX3 affects HIV replication through the Rev-RRE pathway, but the effect on viral replication was to be investigated in more detail. In addition, in the course of this project several research papers regarding the cellular function of DDX3 were published. The possible involvement of DDX3 in other pathways has been suggested. Therefore, the project aims to further investigate the mechanism of DDX3 in the cell and as a viral cofactor.

More generic nuclear export assays have already been successfully designed and evaluated by the consortium. The biochemistry of DDX3 was unravelled to a great extent. In the meantime, the project started with the drug discovery subproject. They were able to identify hits that showed activity in in vitro helicase assays and one compound with anti- HIV activity was also identified. In a nuclear export assay, inhibitors were identified and one showed specific activity when added four hours after infection. The phage display project has been initiated as well.

In summary, the EXCELLENT-HIT consortium has reached the majority of its goals, namely:
- establishing the basic scientific and technological platforms for functional studies;
- obtaining the essential tools (recombinant proteins, vectors, constructs) for progressing;
- providing proof-of-principle for the validity of the drug targeting approach through the identification of the first hit compounds targeting DDX3 enzymatic activity and inhibiting the replication of HIV in cells.

Another major achievement was the coordination of the activities of the different partners into a coherent and cooperative workflow. Finally, the EXCELLENT-HIT partners decided to continue their collaboration in the future.