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Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues.
- Source :
- Journal of Enzyme Inhibition & Medicinal Chemistry; Dec2023, Vol. 38 Issue 1, p1-12, 12p
- Publication Year :
- 2023
-
Abstract
- Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP<superscript>Sc</superscript>) that forms insoluble amyloids to impair brain function. PrP<superscript>Sc</superscript> interacts with the non-pathogenic, cellular prion protein (PrP<superscript>C</superscript>) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP<superscript>Sc</superscript> but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC<subscript>50</subscript> = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC<subscript>50</subscript> = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrP<superscript>Sc</superscript> in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14756366
- Volume :
- 38
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Enzyme Inhibition & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 174161148
- Full Text :
- https://doi.org/10.1080/14756366.2023.2191164