title: Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates.
abstract: Luminescent conjugated polymers (LCPs) interact with ordered protein aggregates and sensitively detect amyloids of many different proteins, suggesting that they may possess antiprion properties. Here, we show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prion-containing brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrP(C) (PrP(Sc)) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrP(Sc) to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on cerebellar organotypic cultured slices and in vitro conversion assays with mouse PrP(23-231) indicated that poly(thiophene-3-acetic acid) may additionally interfere with the generation of PrP(Sc) by stabilizing the conformation of PrP(C) or of a transition intermediate. Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrP(Sc) deposits.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, CH-8091 Zurich, Switzerland.
authors.forename: Ilan
authors.initials: I
authors.lastname: Margalith
authors.forename: Carlo
authors.initials: C
authors.lastname: Suter
authors.forename: Boris
authors.initials: B
authors.lastname: Ballmer
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tiberi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sonati
authors.forename: Jeppe
authors.initials: J
authors.lastname: Falsig
authors.forename: Sofie
authors.initials: S
authors.lastname: Nyström
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.forename: Andreas
authors.initials: A
authors.lastname: Aslund
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.forename: Alice
authors.initials: A
authors.lastname: Yam
authors.forename: Eric
authors.initials: E
authors.lastname: Whitters
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011108:Polymers / Q000494:pharmacology*; D018620:PrPSc Proteins / Q000378:metabolism* / Q000472:pathogenicity; D011328:Prions / Q000378:metabolism* / Q000472:pathogenicity; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D011108:Polymers; D018620:PrPSc Proteins; D011328:Prions; D013876:Thiophenes; C428437:prion protein (23-231); C066730:polythiophene