The objective of the NewHiv Targets project was to design novel screening assays allowing the identification of novel classes of HIV inhibitors.
Despite the success of highly active antiretrovirals to control 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 spread of drug-resistant HIV variants.
The project partners aimed to identify lead compounds that could impact HIV through new mechanisms. Academic experts in virology and cellular biology joined forces with antiviral-research specialists and pharmacologists to perform anti-HIV high-throughput screening (HTS) assays. The partners defined one unexploited viral target, for which there are no available inhibitors: the critical step of viral release from the cell. This novel target was chosen because important recent discoveries have shed new light into the molecular mechanisms of virus budding, thereby rendering this critical step in the HIV lifecycle a feasible target for drug development.
The NewHiv Targets partners designed one cell-based assay that did not require the use of infectious virus, allowing for the screening of chemicals libraries. As proof of concept, they screened 2 000 compounds, and were able to identify one interesting hit. In secondary analysis with infectious HIV, this compound displayed very little antiviral activity.
The next aim was to extend the screening to a higher number of compounds (2 libraries of 20 000 and 4 000 compounds. The partners sought to further document the activity of the first hit. More fundamentally, they are studying the mechanisms of HIV-1 assembly and transfer through cell-to-cell contact.
Identification of novel antiviral treatment.