The objective of ExCellENT-HIT is the exploitation of the cellular pathways responsible for the nuclear export of unprocessed HIV-1 transcripts, as a novel anti-HIV therapeutic strategy. Our approach is innovative, the objectives are very clear and focused, and achievable within two years. Combination therapies with drugs targeting viral proteins are the current standard of care for HIV-1 infections. However, drug resistant strains emerge, resulting in therapeutic failure. Consequently, new anti-HIV drugs are needed, which should represent novel chemical entities targeting new steps of the HIV replication cycle. Viruses need the host cellular metabolism in order to generate a progeny. By targeting cellular co-factors essential for HIV replication and whose inhibition is not harming the uninfected cells, drug resistance is less likely to occur.
Nuclear export of unspliced viral RNAs is an essential step of the HIV life cycle, regulated by the viral protein Rev. Compelling experimental evidence recently identified the cellular DEAD-box RNA helicase DDX3 as an essential cofactor for viral mRNA export. Therefore, we seek to inhibit the nuclear export of unspliced viral RNAs activity by a 'two hit strategy' targeting the cellular enzyme DDX3 and the viral protein Rev, thereby minimizing the appearance of drug resistance HIV mutants. Basic science, biotechnology and provocative chemistry, will integrate with the ultimate goal of targeting the Rev/DDX3 axis by the identification of molecular decoys that inhibit DDX3 helicase activity, Rev/DDX3 nuclear export and protein-protein interaction required for Rev/DDX3 function. The knowledge and technology generated in this project on therapeutic targeting of nuclear export, protein-protein interaction and helicase activity is likely to cumulate in hit discovery and will have a wide applicability in the pharmaceutical industry.'
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