29023 Therapeutics for prion diseases
A research group at the University of Sheffield have discovered a novel class of compounds in cellular assays for anti-prion activity. The best known property of cellular prion protein (PrPC) is its unique ability to undergo conformational change into a pathogenic conformer, PrPSc, that accumulates in the brain as insoluble aggregates. This process leads to neuronal dysfunction and progressive neurodegeneration, a distinctive feature shared by all transmissible spongiform encephalopathies (TSE), a family of lethal neurodenenerative diseases including scrapie in sheep, “mad cow disease” (BSE) in cattle, Kuru and Creutzfeldt-Jakob disease in humans. There is currently no effective treatment.
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Prion diseases, or transmissible spongiform encephalopathies (TSEs), are invariably fatal neurodegenerative disorders affecting humans and animals. As yet, no effective curative or prophylactic therapy exists.
Cellular prion protein, PrPC, is a membrane-anchored, neuronal glycoprotein. Its primary sequence consists of a linear peptide chain of approximately 210 amino acids encoded by the human PRNP gene, located on chromosome 20. The protein is synthesised in the endoplasmic reticulum, transits the Golgi, then is delivered to the outer membrane as a peripheral membrane protein covalently attached to lipid rafts (via GPI anchor) where it participates in its normal function(s). PrPC is expressed in many cell types, especially neuronal cells, and its architecture is well reserved across vertebrates, although a clearly defined role in evolution and normal physiological function remain elusive. In the past two decades, an impressive number of studies have investigated nearly every aspect of prion function.
The best known property of PrPC is its unique ability to undergo conformational change into a pathogenic conformer, PrPSc, that accumulates in the brain as insoluble aggregates. This process leads to neuronal dysfunction and progressive neurodegeneration, a distinctive feature shared by all transmissible spongiform encephalopathies (TSE), a family of lethal neurodenenerative diseases including scrapie in sheep, “mad cow disease” (BSE) in cattle, Kuru and Creutzfeldt-Jakob disease in humans. There is currently no effective treatment.
A research group at the University of Sheffield has been engaged in discovering lead compounds against prion proteins. We have now filed a patent application on a novel class of indole-3-glyoxylamide compounds with potent antiprion activities in cellular assay. This class of compounds have good preliminary in vitro DMPK profiles in general. For summary information please download the summary document below:
290231pagesummary.pdf