Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues.

Autor: Kim DH; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Kim J; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Lee H; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Lee D; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Im SM; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Kim YE; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Yoo M; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Cheon YP; Division of Developmental Biology and Physiology, Department of Biotechnology, Sungshin University, Seoul, Korea., Bartz JC; Department of Medical Microbiology and Immunology, School of Medicine, Creighton University, Omaha, NE, USA., Son YJ; Department of Pharmacy, Sunchon National University, Suncheon, Republic of Korea., Choi EK; Ilsong Institute of Life Science, Hallym University, Seoul, Republic of Korea.; Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Korea., Kim YS; Ilsong Institute of Life Science, Hallym University, Seoul, Republic of Korea., Jeon JH; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Kim HS; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Lee S; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Ryou C; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea., Nam TG; Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Republic of Korea.
Jazyk: angličtina
Zdroj: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2023 Dec; Vol. 38 (1), pp. 2191164.
DOI: 10.1080/14756366.2023.2191164
Abstrakt: Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrP Sc ) that forms insoluble amyloids to impair brain function. PrP Sc interacts with the non-pathogenic, cellular prion protein (PrP C ) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrP Sc 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 50 = 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 50 = 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 Sc 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.
Databáze: MEDLINE
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