Protein aggregation inhibitors as disease-modifying drugs for neurodegenerative diseases
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and prion diseases share molecular mechanisms including protein aggregation and deposition. Small molecules that can prevent or even reverse protein aggregation therefore have the potential to directly interfere with the disease process. This could provide a disease-modifying therapy for neurodegenerative diseases, most of which are currently treated at the symptomatic level only.
A high-throughput screening was used to identify protein aggregation inhibitors in vitro and in cell culture. Compounds
selected in the primary screens were validated in dilution
series in order to identify compounds active at very low concentrations. Clustering of the compound hits subsequently revealed a consensus structure common to active protein aggregation inhibitors. This lead structure was further modified to optimize its medicinal-chemical properties. The
resulting candidates strongly reduced scrapie prion proteins in cell culture at nanomolar concentrations. They also revealed high therapeutic potential in mice infected with scrapie prions. The same compounds also inhibit formation
of toxic alpha-synuclein aggregates in model systems.
Further reading: Bertsch U, Winklhofer KF, Hirschberger T, Bieschke J, Weber P, Hartl FU, Tavan P, Tatzelt J, Kretzschmar HA, Giese A (2005) Systematic identification of antiprion drugs by high-throughput screening based on scanning for intensely fluorescent targets. J Virol 79, 7785-7791.
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