Descripción del proyecto
Bacterias genomanipuladas en trabajos de descubrimiento de fármacos
La función proteica se basa en la conformación tridimensional de las proteínas y requiere un plegamiento correcto de la cadena polipeptídica. El mal plegamiento de las proteínas conduce a la acumulación de agregados proteicos, que causan toxicidad celular y son un rasgo característico de enfermedades como la enfermedad de Huntington y la enfermedad de Alzheimer. El proyecto ProMiDis, financiado con fondos europeos, trabaja en un método innovador para el descubrimiento de fármacos que eviten el mal plegamiento de las proteínas. Los investigadores han diseñado bacterias para producir moléculas de tipo fármaco e identificar aquellas capaces de inhibir el mal plegamiento y la agregación de proteínas en las células de los mamíferos. Se espera que la plataforma de biotecnología propuesta allane el camino hacia el desarrollo de tratamientos novedosos contra enfermedades incurables.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
16672 Vari-Athens
Grecia