ABSTRACT
Using a yeast-based assay, a previously unsuspected antiprion activity was found for imiquimod (IQ), a potent Toll-like receptor 7 (TLR7) agonist already used for clinical applications. The antiprion activity of IQ was first detected against yeast prions [PSI (+) ] and [URE3], and then against mammalian prion both ex vivo in a cell-based assay and in vivo in a transgenic mouse model for prion diseases. In order to facilitate structure-activity relationship studies, we conducted a new synthetic pathway which provides a more efficient means of producing new IQ chemical derivatives, the activity of which was tested against both yeast and mammalian prions. The comparable antiprion activity of IQ and its chemical derivatives in the above life forms further emphasizes the conservation of prion controlling mechanisms throughout evolution. Interestingly, this study also demonstrated that the antiprion activity of IQ and IQ-derived compounds is independent from their ability to stimulate TLRs. Furthermore, we found that IQ and its active chemical derivatives inhibit the protein folding activity of the ribosome (PFAR) in vitro.
Subject(s)
Aminoquinolines/pharmacology , Glutathione Peroxidase/metabolism , Peptide Termination Factors/metabolism , Prion Diseases/drug therapy , Prions/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Aminoquinolines/chemical synthesis , Animals , Cell Line , Drug Evaluation, Preclinical , Guanosine/analogs & derivatives , Guanosine/pharmacology , Humans , Imidazoles/pharmacology , Imiquimod , Membrane Glycoproteins/agonists , Membrane Glycoproteins/metabolism , Mice , PrPSc Proteins/metabolism , Prion Diseases/metabolism , Protein Folding , Saccharomyces cerevisiae/drug effects , Structure-Activity Relationship , Toll-Like Receptor 7/agonists , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/agonists , Toll-Like Receptor 8/metabolismABSTRACT
Recently, we have developed a yeast-based (Saccharomyces cerevisiae) assay to isolate drugs active against mammalian prions. The initial assumption was that mechanisms controlling prion appearance and/or propagation could be conserved from yeast to human, as it is the case for most of the major cell biology regulatory mechanisms. Indeed, the vast majority of drugs we isolated as active against both [PSI(+)] and [URE3] budding yeast prions turned out to be also active against mammalian prion in three different mammalian cell-based assays. These results strongly argue in favor of common prion controlling mechanisms conserved in eukaryotes, thus validating our yeast-based assay and also the use of budding yeast to identify antiprion compounds and to study the prion world.