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A unified drug discovery platform for protein misfolding diseases

Project description

Engineered bacteria in drug discovery efforts

Protein function relies on the proteins’ three-dimensional conformation and requires correct folding of the polypeptide chain. Protein misfolding leads to the accumulation of protein aggregates, which cause cellular toxicity and are a hallmark of diseases such as Alzheimer’s and Huntington’s. The EU-funded ProMiDis project is working on an innovative approach for the discovery of drugs that prevent protein misfolding. Researchers have engineered bacteria to produce drug-like molecules and identify those with an ability to inhibit protein misfolding and aggregation in mammalian cells. The proposed biotechnology platform is expected to pave the way towards the development of novel therapies against incurable diseases.

Objective

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.

Host institution

EREVNITIKO KENTRO VIOIATRIKON EPISTIMON ALEXANDROS FLEMINGK
Net EU contribution
€ 877 327,86
Address
FLEMING STREET 34
16672 Vari-Athens
Greece

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Region
Αττική Aττική Ανατολική Αττική
Activity type
Research Organisations
Links
Total cost
€ 877 327,86

Beneficiaries (2)