THINC

"TARGETING HIV INTEGRATION CO-FACTORS, TARGETING CELLULAR PROTEINS DURING NUCLEAR IMPORT OR INTEGRATION OF HIV"

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 Obiettivo del progetto (Objective)

'Standard therapy of infection with the human immunodeficiency virus type 1 (HIV-1) is based on potent cocktails of drugs targeting viral proteins. This treatment is associated with severe side effects and is almost unaffordable for the patients living in sub-Saharan Africa. Incomplete suppression of HIV replication results in drug-resistance. Therefore, a continued research effort is required to develop more potent, cheaper and less toxic antivirals. The insight has grown that HIV requires cellular proteins to serve as co-factors for viral replication. Our over-all objective is to develop novel drugs by targeting co-factors required for HIV replication. The virus will find it difficult to develop antiviral resistance against drugs targeting interaction between invariable cellular proteins and conserved viral protein domains. We will focus on the cellular proteins that mediate HIV trafficking, nuclear import and integration, such as Lens Epithelium Derived Growth Factor (LEDGF/p75), a novel cofactor of HIV-1 integration. THINC is composed of 3 virologists, 2 medicinal chemists, 1 virologist from South Africa, 1 structural biologist, 1 pharmaceutical company. Our first objective is to identify and validate novel co-factors of HIV trafficking, nuclear import and integration as novel targets for anti-HIV therapy. The second objective is to develop new drugs against the validated cellular target LEDGF/p75. The third objective is to perform this work in the perspective of those who will benefit most: the HIV infected people all over the world. The initial steps of target validation and hit identification will mainly be taken by academic groups, while optimization and (pre)clinical development of drugs requires the participation of Tibotec, a European company devoted to the development of antiviral drugs. The project will also increase our generic understanding of protein-protein interactions (PPI).'

Introduzione (Teaser)

EU-funded scientists are developing drugs that prevent the HIV virus multiplying in the human cell to stop infection in its tracks.

Descrizione progetto (Article)

Anti-HIV drug cocktails have severe side-effects and are still very expensive in poor African countries where treatment is crucial. These anti-retrovirals target HIV's own proteins and, if HIV replication is not supressed completely, it becomes resistant to the drugs.

Once inside a human cell, HIV hijacks the cell's machinery to make copies of itself. The EU has invested in the THINC project, a collaboration that is developing drugs targeting the interaction between HIV and the cell's machinery, rather than HIV itself. THINC is composed of virologists (one from South Africa), medicinal chemists, a structural biologist and a pharmaceutical company.

The research team set out to find proteins, or cofactors, within the human cell used by HIV to get into the cell nucleus and integrate into the cell's DNA. They found two proteins that help HIV into the nucleus, PC2 (a codename) and Transportin-SR2, and these will be investigated as drug targets.

The team also developed LEDGINs, a first-in-class inhibitor against a protein called integrase-LEDGF/p75 that helps HIV integrate with human DNA. LEDGINs are active against a broad spectrum of HIV variants and have been licenced for further clinical development.

The researchers also found a correlation between the genetic variability of these cofactors and the susceptibility of African populations.

Another breakthrough was new technology to visualise how HIV integrates into the cell. Scientists can now watch HIV journey to the nucleus with the help of a green fluorescent tag.

The THINC project showed that combining academic drug discovery with public money can be very successful and could even result in financial return through out-licensing to European industry.

These potential findings of new HIV inhibitors are a huge step forward in the treatment of the disease, especially for poorer nations. In addition, many of the technologies developed during the research process could be extended to other fields like leukaemia and neurodegeneration.