Descrizione del progetto
Batteri ingegnerizzati negli sforzi per la scoperta di farmaci
La funzione delle proteine si basa sulla loro conformazione tridimensionale e richiede un corretto ripiegamento della catena polipeptidica. L’errato ripiegamento proteico comporta un accumulo di aggregati proteici, che a sua volta provoca la tossicità cellulare e costituisce un tratto distintivo di malattie quali il morbo di Alzheimer e quello di Huntington. Il progetto ProMiDis, finanziato dall’UE, sta lavorando a un approccio innovativo per la scoperta di farmaci che impediscano il ripiegamento errato delle proteine. I ricercatori hanno ingegnerizzato alcuni batteri per produrre molecole simili a farmaci e individuare quelle dotate della capacità di inibire l’errato ripiegamento proteico, nonché l’aggregazione di proteine, nelle cellule di mammifero. La piattaforma di biotecnologia proposta dovrebbe spianare la strada verso lo sviluppo di nuove terapie volte a contrastare patologie incurabili.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
16672 Vari-Athens
Grecia