[Systematic review of the therapeutics for prion diseases].
Prion diseases are fatal infectious neurodegenerative disorders; examples include the Creutzfeldt-Jakob disease affecting humans and bovine spongiform encephalopathy in cattle. The causative agents of these diseases--the prions--are thought to consist of the pathogenic isoform of the prion protein PrP(Sc), which is produced by the conformational conversion of the normal isoform PrP(c). Many lines of evidence indicate that the constitutive conversion of PrP(c) to PrP(Sc), resulting in a marked accumulation of PrP(Sc) in the brain, is a central event in the pathogenesis of prion diseases. A large number of compounds have been identified as anti-prion agents and capable of reducing the PrP(Sc) levels in infected cells. Some of these compounds have been found to be partially effective in infected animals, thus resulting in the prolongation of the incubation or survival times and a few of these compounds were or are under clinical trials. However, none of these compounds have proven to be therapeutically effective against this group of diseases. This is probably because (1) these compounds fail to cross the blood-brain barrier and (2) their effectiveness is reduced because they are administered only to patients with clinically advanced disease owing to a lack of diagnostic indicators for presymptomatic individuals. In this communication, we systematically list these anti-prion compounds and summarize their effectiveness and possible mechanisms of action.
Sakaguchi
Suehiro
S
Division of Molecular Neurobiology, The Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D020868:Gene Silencing; D006801:Humans; D010426:Pentosan Sulfuric Polyester / Q000627:therapeutic use; D000071228:Polyelectrolytes; D011108:Polymers / Q000627:therapeutic use; D018621:PrPC Proteins / Q000276:immunology; D018620:PrPSc Proteins / Q000378:metabolism / Q000472:pathogenicity*; D017096:Prion Diseases / Q000209:etiology* / Q000628:therapy*; D020033:Protein Isoforms; D011796:Quinacrine / Q000627:therapeutic use; D013045:Species Specificity
D000631:Aminopyridines; D000911:Antibodies, Monoclonal; D010426:Pentosan Sulfuric Polyester; D000071228:Polyelectrolytes; D011108:Polymers; D018621:PrPC Proteins; D018620:PrPSc Proteins; D020033:Protein Isoforms; D011796:Quinacrine; C034161:flupirtine