title: Prion inhibition with multivalent PrPSc binding compounds.
abstract: Quinacrine and related heterocyclic compounds have antiprion activity. Since the infectious pathogen of prion diseases is composed of multimeric PrP(Sc) assemblies, we hypothesized that this antiprion property could be enhanced by attaching multiple quinacrine-derived chloroquinoline or acridine moieties to a scaffold. In addition to exploring Congo red dye and tetraphenylporphyrin tetracarboxylic acid scaffolds, which already possess intrinsic prion-binding ability; trimesic acid was used in this role. In practice, Congo red itself could not be modified with chloroquinoline or acridine units, and a modified dicarboxyl analog was also unreactive. The latter also lacked antiprion activity in infected cultured cells. While addition of chloroquinoline to a tetraphenylporphyrin tetracarboxylic acid scaffold resulted in some reduction of PrP(Sc), moieties attached to a trimesic acid scaffold exhibited sub-micromolar IC(50)'s as well as a toxicity profile superior to quinacrine. Antiprion activity of these molecules was influenced by the length, polarity, and rigidity associated with the variable linear or cyclic polyamine tethers, and in some instances was modulated by host-cell and/or strain type. Unexpectedly, several compounds in our series increased PrP(Sc) levels. Overall, inhibitory and enhancing properties of these multivalent compounds offer new avenues for structure-based investigation of prion biology.
authors: Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors: Charles E
authors: CE
authors: Mays
authors: Shaon
authors: S
authors: Joy
authors: Lei
authors: L
authors: Li
authors: Linghui
authors: L
authors: Yu
authors: Sacha
authors: S
authors: Genovesi
authors: Frederick G
authors: FG
authors: West
authors: David
authors: D
authors: Westaway
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D002739:Chloroquinolinols / Q000737:chemistry / Q000494:pharmacology; D003224:Congo Red / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000037:antagonists & inhibitors*; D011796:Quinacrine / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002739:Chloroquinolinols; D011166:Porphyrins; D018620:PrPSc Proteins; D011328:Prions; D014233:Tricarboxylic Acids; C409084:tetraphenylporphyrin; D003224:Congo Red; D011796:Quinacrine; C069849:trimesic acid