Description du projet
Des bactéries modifiées utilisées dans la découverte de médicaments
La fonction protéique s’appuie sur la conformation tridimensionnelle des protéines et nécessite un repliement correct de la chaîne polypeptidique. Le mauvais repliement des protéines provoque l’accumulation d’agrégats de protéines, qui entraînent une toxicité cellulaire et sont une caractéristique de certaines affections, comme les maladies d’Alzheimer et de Huntington. Le projet ProMiDis, financé par l’UE, développe une approche innovante pour la découverte de médicaments qui empêchent le mauvais repliement des protéines. Les chercheurs ont modifié des bactéries pour qu’elles produisent des molécules semblables à des médicaments et identifier celles qui sont capables d’inhiber le mauvais repliement et l’agrégation des protéines dans les cellules des mammifères. La plateforme de biotechnologie proposée devrait ouvrir la voie au développement de nouveaux traitements contre des maladies incurables.
Objectif
It is now widely recognized that a variety of major diseases, such as Alzheimer’s disease, Huntington’s disease, systemic amyloidosis, cystic fibrosis, type 2 diabetes etc., are characterized by a common molecular origin: the misfolding of specific proteins. These disorders have been termed protein misfolding diseases (PMDs) and the vast majority of them remain incurable. Here, I propose the development of a unified approach for the discovery of potential therapeutics against PMDs. I will generate engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the misfolding of PMD-associated proteins (MisPs). These compounds will be selected from libraries of drug-like molecules biosynthesized in engineered bacteria using a technology that allows the facile production of billions of different test molecules. These libraries will then be screened in the same bacterial cells that produce them and the rare molecules that rescue MisP misfolding effectively will be selected using an ultrahigh-throughput genetic screen. The effect of the selected compounds on MisP folding will then be evaluated by biochemical and biophysical methods, while their ability to inhibit MisP-induced pathogenicity will be tested in appropriate mammalian cell assays and in established animal models of the associated PMD. The molecules that rescue the misfolding of the target MisPs and antagonize their associated pathogenicity both in vitro and in vivo, will become drug candidates against the corresponding diseases. This procedure will be applied for different MisPs to identify potential therapeutics for four major PMDs: Huntington’s disease, cardiotoxic light chain amyloidosis, dialysis-related amyloidosis and retinitis pigmentosa. Successful realization of ProMiDis will provide invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
16672 Vari-Athens
Grèce