Projet ALLODD (Horizon 2020, appel à projets 2020)
Action : Doctoral Networks
Panel : Chemistry
Statut du projet : SIGNED

Most current drugs are designed to bind directly to the primary active sites (also known as orthosteric sites) of their biological targets. Allosteric modulators offer a powerful yet underexploited therapeutic approach. They can elicit a richer variety of biological responses and, since they target less conserved binding sites, higher selectivity and less adverse effects may be obtained (Changeux, Drug Disc Today 2013). This proposal aims to train a new generation of scientists in exploiting the concept of allostery in drug design, putting together a whole array of technologies to identify and characterize allosteric modulators of protein function that will be applied to therapeutically relevant systems. Our approach is based on a combination of experimental and simulation techniques, including fragment Screening with structural characterization (X-ray, NMR, H/D exchange), proteomics (MS/MS), ITC, DNA encoding libraries, Virtual Screening, Molecular Dynamics simulations-based methods, Synthetic Chemistry, and in vitro and cellular assays for the verification of results. It should also be noted that allosteric targeting need not be achieved solely through the design of synthetic small molecules but also can also be reached via conformationally specific allosteric antibodies, which represents an important field of future research. There are already clear examples of monoclonal antibodies that allosterically target ion channels (Lee et al., 2014b), GPCRs (Mukund et al., 2013), and RTKs (De Smet et al., 2014), as well as cytokine and integrin receptors (Rizk et al., 2015; Schwarz et al., 2006).

Mots clés : allostery, allosteric inhibitors, structure based drug design

Participants :
- University of Urbino (Italie) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 261499.68 €
- Karolinska Institutet (Suède) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 281982.96 €
- Université de Strasbourg (France) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 274802.04 €
- Merck (Germany) (Allemagne) — Partner, beneficiary, Organismes privés (hors enseignement), subvention : 252788.4 €
- Forschungsverbund Berlin (Allemagne) — Partner, beneficiary, Recherche, subvention : 252788.4 €
- Hungarian Research Network (Hongrie) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 229715.28 €
- Janssen (Belgium) (Belgique) — Partner, beneficiary, Organismes privés (hors enseignement), subvention : 256320.0 €
- University of Barcelona (Espagne) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 501809.76 €
- Forschungszentrum Jülich (Allemagne) — Partner, beneficiary, Recherche, subvention : 252788.4 €
- Heptares Therapeutics (United Kingdom) (Royaume-Uni) — Partner, beneficiary, Organismes privés (hors enseignement), subvention : 303172.56 €
- University of Vienna (Autriche) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 264207.24 €
- Charité - Universitätsmedizin Berlin (Allemagne) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 252788.4 €
- Biomedical Research Foundation of the Academy of Athens (Grèce) — Coordinator, beneficiary, Recherche, subvention : 243017.64 €
- University of Birmingham (Royaume-Uni) — Partner, beneficiary, Enseignement supérieur ou secondaire, subvention : 0.0 €