Potent inhibition of scrapie prion replication in cultured cells by bis-acridines
AUTOR(ES)
May, Barnaby C. H.
FONTE
The National Academy of Sciences
RESUMO
Prion diseases are characterized by an accumulation of PrPSc, a misfolded isoform of the normal cellular prion protein, PrPC. We previously reported the bioactivity of acridine-based compounds against PrPSc replication in scrapie-infected neuroblastoma cells and now report the improved potency of bis-acridine compounds. Bis-acridines are characterized by a dimeric motif, comprising two acridine heterocycles tethered by a linker. A library of bis-(6-chloro-2-methoxy-acridin-9-yl) and bis-(7-chloro-2-methoxy-benzo[b][1,5]naphthyridin-10-yl) analogs was synthesized to explore the effect of structurally diverse linkers on PrPSc replication in scrapie-infected neuroblastoma cells. Structure–activity analysis revealed that linker length and structure are important determinants for inhibition of prion replication in cultured scrapied cells. Three bis-acridine analogs, (6-chloro-2-methoxy-acridin-9-yl)-(3-{4-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-piperazin-1-yl}-propyl)-amine, N,N′-bis-(6-chloro-2-methoxy-acridin-9-yl)-1,8-diamino-3,6-dioxaoctane, and (1-{[4-(6-chloro-2-methoxy-acridin-9-ylamino)-butyl]-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester, showed half-maximal inhibition of PrPSc formation at 40, 25, and 30 nM, respectively, and were not cytotoxic to uninfected neuroblastoma cells at concentrations of 500 nM. Our data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine, which is currently under clinical evaluation for the treatment of prion disease.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=152307Documentos Relacionados
- Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells.
- Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody
- Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells.
- Two mutant prion proteins expressed in cultured cells acquire biochemical properties reminiscent of the scrapie isoform.
- PrP Polymorphisms Tightly Control Sheep Prion Replication in Cultured Cells