title: The toll-like receptor agonist imiquimod is active against prions.
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.
authors: Laboratoire de Chimie Organique 2, INSERM U1022, Université Paris Descartes, Paris, France.
authors: Nassima
authors: N
authors: Oumata
authors: Phu Hai
authors: PH
authors: Nguyen
authors: Vincent
authors: V
authors: Beringue
authors: Flavie
authors: F
authors: Soubigou
authors: Yanhong
authors: Y
authors: Pang
authors: Nathalie
authors: N
authors: Desban
authors: Catherine
authors: C
authors: Massacrier
authors: Yannis
authors: Y
authors: Morel
authors: Carine
authors: C
authors: Paturel
authors: Marie-Astrid
authors: MA
authors: Contesse
authors: Serge
authors: S
authors: Bouaziz
authors: Suparna
authors: S
authors: Sanyal
authors: Hervé
authors: H
authors: Galons
authors: Marc
authors: M
authors: Blondel
authors: Cécile
authors: C
authors: Voisset
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077271:Imiquimod; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D051379:Mice; D010454:Peptide Termination Factors / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D007093:Imidazoles; D008562:Membrane Glycoproteins; D010454:Peptide Termination Factors; D018620:PrPSc Proteins; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C546771:gardiquimod; D006151:Guanosine; C068562:loxoribine; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae; D000077271:Imiquimod; C402365:resiquimod
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