The toll-like receptor agonist imiquimod is active against prions

• Published in: PloS one 2013-08, Vol.8 (8), p.e72112-e72112
• Main Authors: Oumata, Nassima, Nguyen, Phu Hai, Beringue, Vincent, Soubigou, Flavie, Pang, Yanhong, Desban, Nathalie, Massacrier, Catherine, Morel, Yannis, Paturel, Carine, Contesse, Marie-Astrid, Bouaziz, Serge, Sanyal, Suparna, Galons, Hervé, Blondel, Marc, Voisset, Cécile
• Format: Article
• Language: English
• Subjects: Aminoquinolines; Aminoquinolines - chemical synthesis; Aminoquinolines - pharmacology; Analysis; Animals; Biochemistry, Molecular Biology; Cell Line; Conservation; Derivatives; Disease; Drug Evaluation, Preclinical; E coli; Escherichia coli; Genetic engineering; Glutathione Peroxidase; Glutathione Peroxidase - metabolism; Guanosine; Guanosine - analogs & derivatives; Guanosine - pharmacology; Humans; Imidazoles; Imidazoles - pharmacology; Imiquimod; Immune system; Intelligence; Life Sciences; Mammals; Medical research; Membrane Glycoproteins; Membrane Glycoproteins - agonists; Membrane Glycoproteins - metabolism; Mice; Molecular biology; Peptide Termination Factors; Peptide Termination Factors - metabolism; Prion Diseases; Prion Diseases - drug therapy; Prion Diseases - metabolism; Prion protein; Prions; Prions - metabolism; Propagation; Protein Folding; Proteins; PrPSc Proteins; PrPSc Proteins - metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins; Saccharomyces cerevisiae Proteins - metabolism; Structural Biology; Structure-Activity Relationship; Therapeutic applications; TLR7 protein; Toll-Like Receptor 7; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 7 - metabolism; Toll-Like Receptor 8; Toll-Like Receptor 8 - agonists; Toll-Like Receptor 8 - metabolism; Toll-like receptors; Transgenic mice; Yeast
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072112

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.