To discover, as the result of a large-scale collaborative effort, new antiviral compounds as potent and selective inhibitors of HIV (Human Immunodeficiency Virus), to identify the molecular targets of the virus replicative cycle with which they interact, and to develop drug treatment regimens that would completely suppress or even "knock out" the virus.
This Centralised Facility/Concerted Action should be viewed as the continuation of the BIOMED l Centralised Facility/Concerted Action on the Design, Synthesis, Evaluation and Development of New Antiviral Compounds Against AIDS. This Centralised Facility is essentially aimed at the discovery of new antiviral agents as potent and selective inhibitors of HIV (Human Immunodeficiency Virus) that should be effective in the treatment of AIDS and may ultimately lead to a full recovery from the disease. To accomplish this task, we can count on the collaborative help of about 130 collaborative centers world-wide (about 70 belonging to the European Union), which will provide through chemical synthesis, or, where applicable, through extraction and purification from natural products, the candidate anti-HIV agents for a thorough evaluation of their antiviral properties, particularly their potency and selectivity against HIV. The anti-HIV activity will be determined in a variety of assay systems with different cell types (including peripheral Iymphocytes and macrophages) and different virus strains (including mutant strains resistant to the established anti-HIV drugs). In designing potential anti-HIV drug candidates, all major steps of the HIV replicative cycle will be envisaged as targets: virus adsorption, virus-cell fusion, viral uncoating, reverse transcription (viral RNA o proviral DNA), proviral DNA integration, transcription, translation, posttranslational modification (myristoylation, proteolysis and glycosylation) and budding (release/maturation). The structure-activity relationship derived from the antiviral evaluation of the different classes of compounds, together with the elucidation of the molecular coordinates of their viral target site, should enable us to design, through molecular modelling, and develop, through chemical synthesis, specific HIV inhibitors with increased potency and/or selectivity. At the molecular level, the viral target sites will be identified through amino acid sequence analysis of mutant viral proteins and site-directed mutagenesis. Viral target proteins will be directly examined for their interaction with, and affinity for the inhibitors, and, where appropriate, the inhibitors should be chemically modified so as to interact with the mutant viral proteins as well. To maximise the chances for a complete suppression of virus replication, compounds interacting with different viral target sites should be combined with one another, and if administered from the start at sufficiently high concentrations, they may completely "knock out" the virus and thus "sterilise" or "cure" the cells from the virus. Our principal objective would thus be the development of the optimal drugs and treatment regimens for the chemotherapy of AIDS, that when applied in the patient, should have the highest likelihood of completely suppressing virus replication, preventing the breakthrough of virus (whether drug-resistant or not) and, if at all possible, achieving a complete "cure" of the disease.