Projektbeschreibung
Künstlich hergestellte Bakterien für den Einsatz in der Wirkstoffforschung
Die Funktion von Proteinen beruht auf ihrer dreidimensionalen Konformation und setzt voraus, dass die Polypeptidkette richtig gefaltet ist. Durch die Fehlfaltung von Proteinen kommt es zur Anhäufung von Proteinaggregaten, die wiederum zu Zelltoxiziät führt und Erkrankungen wie Alzheimer und Huntington charakterisiert. Das EU-finanzierte Projekt ProMiDis arbeitet an einem innovativen Ansatz für die Erforschung an Wirkstoffen, die eine Proteinfehlfaltung verhindern können. Die Forschenden haben Bakterien künstlich hergestellt, um wirkstoffähnliche Moleküle zu erzeugen und davon diejenigen zu identifizieren, die in der Lage sind, die Fehlfaltung und Anhäufung von Proteinen in Säugetierzellen zu verhindern. Die vorgestellte Biotechnologie-Plattform wird voraussichtlich den Weg zur Entwicklung neuer Therapien für unheilbare Krankheiten ebnen.
Ziel
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.
Wissenschaftliches Gebiet
- 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
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
16672 Vari-Athens
Griechenland