Proteins typically undergo a proper folding via intracellular chaperone machinery. Folding confers to proteins the spatial characteristics that define their role in the cells, however the folding process might not always work properly. For intrinsic changes of protein characteristics (e.g. mutations and/or improper elongation, PTMs etc.) or for defective chaperone activity, proteins can assume a wrong conformation. In this case complex intracellular degradative systems are able to recognize the misfolded proteins and provide their degradation and clearance, through the ubiquitin-proteasome and autophagy systems.

Considering the complexity of the intracellular folding and degradation machinery, errors can occur on establishment of the tertiary proteins structure.
So, wrong conformations together with underperformed elimination of misfolded proteins can disrupt proteostasis. In this case proteins might accumulate and aggregate in cells thus becoming toxic.

Several diseases are caused by aggregated proteins, in particular neurodegenerative diseases such as Alzheimer’s (and other Tauopathies like FTD), Parkinson’s, Huntington’s, ALS, and many others, which still have a paucity of treatments.

Selvita scientists have been working for many years on the production of different aggregation-prone proteins and to develop assays for screening compounds that are able to bind to pre-aggregated proteins or disturb their aggregation kinetic. Typically, proteins are related to neurodegenerative diseases as Parkinson’s (e.g. alpha-synuclein), Alzheimer’s disease (e.g. beta-amyloid) and others.

The choice of the correct toxic aggregated protein is essential to have characteristics the closest possible to aggregated proteins present in an human neuronal environment. Binding screening studies allowed Selvita to develop the SAR of compounds able to bind specifically to these proteins (or peptides) and to be used, as example, as a warhead for PROTACs.

Here below some exemplificative results for the optimization of an assay for testing compounds designed as PROTACs warhead components (in presence also of a linker), able to bind to an aggregated CNS protein: