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Identifying novel classes of anti-HIV inhibitors

Final Report Summary - NEWHIVTARGETS (Identifying novel classes of anti-HIV inhibitors)

Despite the success of highly active antiretrovirals to control human immunodeficiency virus (HIV) replication in infected patients, at least in countries that can afford these treatments, new drugs are still needed. Widely used drugs mainly target two viral enzymes, reverse transcriptase and protease. However, about 20 % of patients cannot tolerate antiviral cocktails in the short term, and long-term treatments are often associated with severe side effects. There is also increasing concern about the spreading of drug-resistant HIV variants.

The project partners aim was to identify lead compounds that could impact HIV through new mechanisms. Academia experts in virology and cellular biology have joined forces with antiviral-research specialists and pharmacologists, in order to perform anti-HIV high-throughput screening (HTS) assays. We have defined one unexploited viral target, for which there are no available inhibitors: the critical step of viral release from the cell. This novel target has been chosen because important recent discoveries have shed new light into the molecular mechanisms of virus budding, thereby rendering this critical step in HIV life cycle a feasible target for drug development.

They have designed one cell-based assay, which does not require the use of infectious virus, allowing the screening of libraries of chemicals. As a proof of concept they have 2,000 compounds and were able to identify one interesting hit. In secondary analysis with infectious HIV, this compound display very little antiviral activity. On a more fundamental point of view, they studied the mechanisms of HIV-1 assembly and transfer through cell to cell contacts. They hope that the screening will allow the identification of hits or lead compounds, which could in a further step be improved by using classical drug design approach.

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