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.
Highlights
Prions are infectious agents that have been affecting human and animal health for centuries
We have isolated compounds able to inhibit prion propagation in both yeast and mammalian systems [9,10,11,12], indicating that at least part of prionisation mechanisms are preserved from yeast to mammals. The use of such a screening process as a complement to animal-based models is highly fruitful and has been successfully used for other pathologies [14]. This screening procedure has allowed the identification of two active drugs, 6-aminophenanthridine (6AP) and Guanabenz (GA), that have proven to be valuable tools to identify a novel cellular mechanism potentially involved in the prion replication cycle, i.e. the protein folding activity of the ribosome (PFAR, [11,13,15,16])
We found that IQ and its chemical derivatives, acting as antiprions, were specific inhibitors of the protein folding activity of the ribosome, in addition to the already known Tolllike receptor 7 (TLR7) agonist activity of IQ
Summary
Prions are infectious agents that have been affecting human and animal health for centuries. Drugs that have a potent antiprion activity in both yeast- and ex vivo cell-based assays, and that display a limited or no toxicity ex vivo, have been tested in vivo in a mouse model for prion-based diseases These compounds have been used to characterize their cellular targets [11]. The use of such a screening process as a complement to animal-based models is highly fruitful and has been successfully used for other pathologies [14] This screening procedure has allowed the identification of two active drugs, 6-aminophenanthridine (6AP) and Guanabenz (GA), that have proven to be valuable tools to identify a novel cellular mechanism potentially involved in the prion replication cycle, i.e. the protein folding activity of the ribosome (PFAR, [11,13,15,16]). We found that IQ and its chemical derivatives, acting as antiprions, were specific inhibitors of the protein folding activity of the ribosome, in addition to the already known TLR7 agonist activity of IQ
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