title: Anti-prion drug mPPIg5 inhibits PrP(C) conversion to PrP(Sc).
abstract: Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrP(Sc), an abnormal isoform of the cellular protein PrP(C), is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrP(Sc) in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrP(C) to PrP(Sc) conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future.
authors: School of Biology and Environmental Science, University College Dublin, Belfield, Dublin, Ireland. jim.mccarthy@ucd.ie
authors: James M
authors: JM
authors: McCarthy
authors: Markus
authors: M
authors: Franke
authors: Ulrike K
authors: UK
authors: Resenberger
authors: Sibeal
authors: S
authors: Waldron
authors: Jeremy C
authors: JC
authors: Simpson
authors: Jörg
authors: J
authors: Tatzelt
authors: Dietmar
authors: D
authors: Appelhans
authors: Mark S
authors: MS
authors: Rogers
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D050091:Dendrimers / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D051379:Mice; D018613:Microscopy, Confocal; D010879:Piperazines / Q000494:pharmacology; D011126:Polypropylenes / Q000494:pharmacology*; D018622:PrP 27-30 Protein / Q000302:isolation & purification; D018621:PrPC Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013498:Suramin / Q000494:pharmacology
chemical_list: D001549:Benzamides; D050091:Dendrimers; D010879:Piperazines; D011126:Polypropylenes; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011743:Pyrimidines; C443641:poly(propyleneimine); D018622:PrP 27-30 Protein; D013498:Suramin; D000068877:Imatinib Mesylate
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