Keywords: Screening assays; HTS; HIV; antiviral drugs; viral release
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 spreading of drug-resistant HIV variants.
The aim is 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 the HIV life cycle a feasible target for drug development.
Two assays are currently being designed to allow the screening of libraries of chemicals. One is a cell-based assay and the other is a cell-free, protein/protein interaction assay. These assays do not require the use of an infectious virus. Two libraries of 20 000 and 4 000 compounds respectively will be screened.
It is hoped that these two complementary assays will allow the identification of hits or lead compounds, which could be improved by using a classical drug design approach.
About twenty anti-HIV drugs are currently available, which mainly target two viral enzymes, the reverse transcriptase and the protease. Because current treatments do not eradicate HIV from infected patients, there is the urgent need to identify new classes of antivirals suitable for long-term use, and can supplement existing drugs. Several steps of the virus cycle are currently being evaluated as potential targets. Inhibitors of viral entry and fusion, of the viral integrase, are available in clinical trials or are already on the market. However, no compounds are yet available which could interfere with other critical steps of viral cycle.
The aim of this project is to identify novel compounds interfering with unexploited viral targets such as viral budding for which there are no available inhibitors. The budding of enveloped viruses from the host cell is an active process, mediated by virus-encoded proteins. Some members of the consortium have been involved in the recently discovered mechanism used by the host cells machinery and responsible for HIV budding. Interfering with this machinery using small molecules would therefore interfere with th particle release and hence viral propagation. Therefore the specific objective are: 1) the design of two standardised screening assays, usable in 96 well plate format, targeting the viral release step of HIV replication; 2) the screening of two libraries of non-peptidic compounds in these two assays.
Two new screening assays are expected to be designed, in order to identify potential compounds inhibiting HIV replication through novel mechanisms of action.
In the long term, potential hit compounds could be improved and constitute novel families of antiviral drugs.
Virus & Immunity Group, CNRS URA 1930, Institut Pasteur
25 rue du Dr Roux
75724 Paris Cedex 15
Tel: +33 1 45 68 83 53
Fax: +33 1 45 68 89 40
|Official Address||Other Information|
|2||Kalle Saksela||University of Tampere |
Institute of Medical Technology
|Tel: +358 3 215 7029 |
Fax: +358 3 215 8597
|3||Barbara Mueller||University of Heidelberg, Hygiene-Institut / Abt. Virologie |
Im Neuenheimer Feld 324
|Tel: +49 6221 56 1325 |
Fax: +49 6221 56 5003
|4||Maurizio Federico||Department of Infectious, Parasitic and Immune-mediated Diseases |
Istituto Superiore di Sanita
Viale Regina Elena, 299
|Tel: +39 06 4990 3248 |
Fax: +39 06 4990 3002
|5||Marcel HIBERT||Laboratoire de Pharmacochimie de la Communication Cellulaire |
UMR CNRS/ULP 7081
Faculté de Pharmacie de Strasbourg
74 route du Rhin, BP 24
FR-67401 Illkirch Cedex
|Tel: +33 3 90 24 42 32 |
Fax: +33 3 90 24 43 10