Laboratoire de Chimie Organique 2, INSERM U1022, Université Paris Descartes, Paris, France.
PLoS One. 2013 Aug 16;8(8):e72112. doi: 10.1371/journal.pone.0072112. eCollection 2013.
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.
利用酵母检测方法，发现咪喹莫特（IQ）具有以前未被怀疑的抗朊病毒活性，这种物质是一种已被用于临床应用的有效 Toll 样受体 7（TLR7）激动剂。IQ 的抗朊病毒活性首先在酵母朊病毒[PSI（+）]和[URE3]中被检测到，然后在细胞检测中在体外和在转染了朊病毒疾病的转基因小鼠模型中在体内被检测到。为了便于进行结构-活性关系研究，我们进行了新的合成途径，为生产新的 IQ 化学衍生物提供了更有效的方法，对这些衍生物的活性在酵母和哺乳动物朊病毒中进行了检测。在上述生命形式中，IQ 及其化学衍生物的可比抗朊病毒活性进一步强调了朊病毒控制机制在整个进化过程中的保守性。有趣的是，这项研究还表明，IQ 和其衍生化合物的抗朊病毒活性与其刺激 TLR 的能力无关。此外，我们发现 IQ 和其活性化学衍生物在体外抑制核糖体的蛋白折叠活性（PFAR）。
