Keywords: AIDS/HIV, capsid assembly, Env incorporation, antiretrovirals, screening, HIV budding, medicinal chemistry, virology, cell biology, drug discovery, drug development
Background
AIDS is one of the major life threatening infectious diseases in the world today. A constant supply of novel antiretrovirals (ARVs) is needed to respond to the limitations of current drugs. The currently available therapeutic arsenal against HIV comprises ARVs which block all major steps of HIV replication, except for particle assembly and budding.
Combinations of the currently available anti-viral drugs within highly active anti-retroviral therapy (HAART) have transformed the course of HIV infection into a chronic disease, but even so, HAART faces three major limitations: viral resistance, viral persistence, and drug toxicity. There is a consensus that a constant supply of new antiretroviral molecules based on novel mechanisms of action is needed to respond to the major limitations of drugs currently available.
HIV-ACE is composed of 8 teams from 5 European countries including a Biopharma small to medium-sized enterprise (SME), CellVir. These laboratories are led by prominent world-class scientists in virology, cell biology, immunology, organic and medicinal chemistry, working in highly regarded research organisations. To efficiently achieve the ambitious goals of HIV-ACE, strong management is led by a very experienced organisation, INSERM Transfert.
Aims and expected results
On the basis of novel and fully validated targets, the objectives of HIV-ACE are to achieve the following:
- assay development, drug screening and pre-clinical development of small molecule inhibitors of capsid assembly and Env incorporation, up to the stage of early drug candidates with acceptable toxicity profile determined by ADME/Tox studies, activity against multi-drug-resistant viral strains and primary non-B isolates, antiviral activity in primary T cells and macrophages (Work Package 1 or WP1);
- elucidation of 3D structures of these validated targets and rational drug design guided by molecular modelling and docking of inhibitors (WP2);
- validation and exploitation of the HIV-susceptible transgenic rat model to allow preclinical in vivo evaluation of novel drug candidates from HIV-ACE and to provide the European pharmaceutical industry with an efficient in vivo platform for predictive testing of any kind of anti-HIV drug (WP3);
- elucidation of the mechanisms responsible for activity of the validated inhibitors, and discovery/validation of novel targets in the budding pathway of HIV-1 (WP4).
By the end of 2007, the therapeutic arsenal against HIV is expected to comprise antiviral molecules acting at almost every major step of the viral replication cycle, except for the crucial step of assembly and budding of viral particles. The goal of the consortium is to translate progress in understanding of the mechanisms involved in HIV-1 capsid assembly, budding and Env incorporation into innovative ARVs.
If successful, the consortium will demonstrate that it is possible to discover new early drug candidates with acceptable toxicity based on completely different mechanisms of action to currently available drugs. Importantly HIV-ACE will pave the way for the application of a new paradigm in drug discovery of ARVs, i.e. inhibition of protein-protein interactions instead of the more classical approach of inhibition of the catalytic activity of viral enzymes.
Potential applications:
Discovery of new early drug candidates targeting late-stage steps of the viral replication cycle will enable us to propose new chemically optimised hits and leads to the pharmaceutical industry for the development of new drugs complementary to existing treatments. These new reagents should make novel combinatory approaches less likely to induce resistance.
Coordinator:
Clarisse BERLIOZ-TORRENT
Institut National de la Santé et de la Recherche médicale
101 rue de Tolbiac,
Paris 75654,
France
berlioz@cochin.inserm.fr
