title: Influence of surface groups on poly(propylene imine) dendrimers antiprion activity.
abstract: Prion diseases are characterized by the accumulation of PrP(Sc), an aberrantly folded isoform of the host protein PrP(C). Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP(Sc) in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP(Sc) in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP(Sc) by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups.
authors.affiliation: School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland. jim.mccarthy@ucd.ie
authors.forename: James M
authors.initials: JM
authors.lastname: McCarthy
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rasines Moreno
authors.forename: Damien
authors.initials: D
authors.lastname: Filippini
authors.forename: Hartmut
authors.initials: H
authors.lastname: Komber
authors.forename: Marek
authors.initials: M
authors.lastname: Maly
authors.forename: Michaela
authors.initials: M
authors.lastname: Cernescu
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brutschy
authors.forename: Dietmar
authors.initials: D
authors.lastname: Appelhans
authors.forename: Mark S
authors.initials: MS
authors.lastname: Rogers
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D011126:Polypropylenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D013499:Surface Properties
chemical_list: D050091:Dendrimers; D011126:Polypropylenes; D018620:PrPSc Proteins; C443641:poly(propyleneimine)