Protein Misfolding Diseases
Protein misfolding diseases (PMDs) are a large group of >50 human disorders caused by the misfolding of specific proteins. They include serious conditions with high socio-economic impact, such as Alzheimer’s disease, systemic amyloidosis, amyotrophic lateral sclerosis, cystic fibrosis, retinitis pigmentosa and type 2 diabetes. The vast majority of PMDs remain incurable and, thus, effective therapeutics against these conditions are in enormous demand. Different PMDs are associated with different proteins (soluble or membrane-bound, globular or intrinsically disordered etc.), they affect different organs (brain, lungs, heart, eyes etc.) and they present very distinct pathologies (neurodegeneration, heart failure, blindness, carcinogenesis etc.). Yet, quite remarkably, protein misfolding has been recognized as a common molecular feature underlying all of them. This mechanistic unification constitutes a tremendous opportunity for drug discovery.
ResQ Biotech is exploiting the common molecular origin of PMDs, i.e., the tendency of certain pathogenic proteins to misfold and form harmful aggregates, so as to develop a common framework for the efficient discovery of anti-PMD therapeutics.
We have generated engineered microbial cells that function as a stand-alone, living discovery platform for putative drugs against PMDs. These modified microbes have been programmed to biosynthesize combinatorial libraries of short, drug-like cyclic peptides & simultaneously screen them to identify chemical rescuers of disease-associated protein misfolding and aggregation. This biotechnology approach offers a number of important advantages:
It allows the investigation of an extremely large number of test molecules (up to tens of billions), thus, increasing the chances of discovering molecules with the desired properties
Cyclic peptides are an emerging class of therapeutic molecules that can combine the high specificity and low toxicity of antibodies with the beneficial pharmacokinetics of small molecules
Our cyclic peptides libraries comprise previously untested molecules, thus yielding new bioactive molecular entities
Our approach can be generally applied for the discovery of therapeutic leads for potentially every protein misfolding disease
ResQ Biotech applies this innovative approach for hit identification and lead optimization and then performs preclinical development on the most promising compounds.
ResQ Biotech has several ongoing research programs focused on diseases caused by the misfolding of both soluble and integral membrane proteins.
ResQ Biotech has developed the specialized Escherichia coli strains SuptoxD and SuptoxR for high-level production of difficult-to-express integral membrane proteins.
When used as expression hosts, these strains exert a dual positive effect on recombinant membrane protein production compared to wild-type bacteria:
(1) they suppress the toxicity that frequently accompanies the membrane protein overexpression process, thus enabling enhanced levels of final bacterial biomass, and
(2) they markedly increase the cellular accumulation of membrane-incorporated and properly folded protein.
Combined, these two positive effects result in dramatically enhanced volumetric yields for various recombinant membrane proteins of both prokaryotic and eukaryotic origin.