Post doctoral research associate positions in biomolecular engineering funded by the ERC

Project summary:

Α 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 and the vast majority of them remain incurable. The goal of the ProMiDis project is to develop an efficient technology for early drug discovery against these conditions, which will be generally applicable to various protein misfolding diseases. This includes diseases caused by the misfolding of both soluble and integral membrane proteins.

In the framework of the ProMiDis project, we will generate engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the problematic folding of misfolding-prone and disease-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 in detail by biochemical and biophysical methods of protein analysis, 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 in the nematode C. elegans. 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: (i) Huntington’s disease; (ii) cardiotoxic light chain amyloidosis; (iii) dialysis-related amyloidosis; and (iv) retinitis pigmentosa. ProMiDis will deliver invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.

R

Relevant literature:

1. Matis, I., Delivoria, D.C., Mavroidi, B., Papaevgeniou, N., Panoutsou, S., Bellou, S., Papavasileiou, K.D., Linardaki, Z., Stavropoulou, A.V., Vekrellis, K., Boukos, N., Kolisis, F.N., Gonos, E.S., Margarity, M., Papadopoulos, M.G., Efthimiopoulos, S., Pelecanou, M., Chondrogianni, N., Skretas, G. 2017. An integrated and generalizable bacterial discovery platform for chemical rescuers of disease-associated protein misfolding. Nature Biomedical Engineering. 1, 838–852.
2. Delivoria, D. C., Chia S., Habchi, J., Perni, M., Matis, I., Papaevgeniou, N., Chondrogianni, N., Dobson, C. M., Vendruscolo, M., Skretas, G.* 2019. Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation. Science Advances. 5 : eaax5108.
3. Kostelidou, K., Matis, M., and Skretas, G. 2018. Microbial genetic screens and selections for monitoring protein misfolding: tools for the identification of disease-relevant genes and the discovery of potential therapeutic compounds against neurodegenerative diseases. Current Pharmaceutical Design. 24(19):2055-2075.
4. Gialama, D., Kostelidou, K., Michou, M., Delivoria, D.C., Kolisis, F.N., Skretas, G*. 2017. Development of Escherichia coli strains that withstand membrane protein-induced toxicity and achieve high-level recombinant membrane protein production. ACS Synthetic Biology. 6(2): 284-300.
5. Vasilopoulou, Ε., Giannakopoulou, A., Kapsalis, H., Michou, M., Michoglou-Sergiou, A., Kolisis, F.N., Skretas, G.* 2022. Second-generation Escherichia coli SuptoxR strains for further enhanced production of recombinant membrane proteins in bacteria. ACS Synthetic Biology. 11, 8, 2599–2609.