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Prions are misfolded proteins (PrPSC) capable of inducing the same deformation to other identical proteins. These misfolded proteins are responsible of neurodegenerative diseases into animal and humans. Nowadays there are no actual cures to stop or prevent these diseases. The only intervention is via a preventive diagnostic screening. We have been focusing in screening compound collections for identifying small molecules capable of blocking the misfolded protein (PrPSC). As result, along the past years, we managed to find and assemble a set of compounds from different chemotypes that inhibits the prion activities on human infected cells and at the same time presenting a reasonable toxicity profile. In this study, we newly evaluated affinity for PrPSC using surface plasmon resonance (SPR) biosensor. The characteristics of each compound were classified using various parameters. In this preliminary work, we managed use this set as a training set for generating 2D substructures searches and identify additional chemical scaffolds, probe compound representatives from them and ultimately to identify two subset of prions inhibits from them, one that suppress the PrPSC and the PrPC levels simultaneously and the second subset that leaves unchanged the PrPC levels but reduces the PrPSC effect. These are novel compounds, having all the chemical characteristics for developing additional analogues for a judicial drug-design and further optimization works.