Description du projet
Ciblage allostérique des protéines: une nouvelle classe de médicaments
Les protéines constituent des cibles clés pour la conception et la modulation de médicaments, ou de petites molécules qui se lient au site actif primaire sont responsables de l’inhibition de la fonction. Cependant, la fonction de différentes macromolécules biologiques peut être régulée sur d’autres sites distants, appelés «sites allostériques». Le projet ALLODD, financé par l’UE, entend aplanir les difficultés existantes liées à la conception de modulateurs allostériques. En ayant recours à des technologies de pointe, les chercheurs visent à identifier et à caractériser des ligands capables de se lier aux sites allostériques de protéines pertinentes sur le plan thérapeutique. Des efforts considérables seront également déployés pour produire des anticorps allostériques, ce qui ouvrira de nouvelles possibilités dans le domaine de la découverte de médicaments.
Objectif
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).
Champ scientifique
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Régime de financement
MSCA-ITN - Marie Skłodowska-Curie Innovative Training Networks (ITN)Coordinateur
115 27 Athina
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