title: Mechanistic insights into the cure of prion disease by novel antiprion compounds.
abstract: Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. We have prepared two Congo red derivatives, designed without these liabilities, with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of Congo red derivatives, including compounds that are ineffective and are effective at the cure of prion disease, for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Congo red derivatives that are effective at the cure of prion disease increased the degradation of abnormal PrP by the proteasome. Therefore, the principal mechanism of action of the Congo red analogues was to prevent inhibition of proteasomal activity by PrPSc.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Webb
authors.forename: Tamuna
authors.initials: T
authors.lastname: Lekishvili
authors.forename: Corinna
authors.initials: C
authors.lastname: Loeschner
authors.forename: Shane
authors.initials: S
authors.lastname: Sellarajah
authors.forename: Frances
authors.initials: F
authors.lastname: Prelli
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: David R
authors.initials: DR
authors.lastname: Brown
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D003224:Congo Red / Q000031:analogs & derivatives; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D018620:PrPSc Proteins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy*; D012608:Scrapie / Q000188:drug therapy*
chemical_list: D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D018620:PrPSc Proteins; C524010:WSP677; C524011:WSP740; D003224:Congo Red