Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

Background6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.
Methodology/Principal FindingsHere we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.
Conclusion/Significance6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

背景：研究人员通过基于酵母的检测体系，筛选得到抗朊病毒药物6-氨基菲啶（6-Aminophenanthridine，简称6AP）与胍那苄（Guanabenz，简称GA，一种当前用于临床治疗高血压的药物）。这两种结构迥异的分子，在多项细胞水平检测实验以及朊病毒疾病小鼠模型的体内研究中，同样展现出抗哺乳动物朊病毒的活性。
方法与主要发现：本研究报道了这两种药物的细胞靶点鉴定工作。我们利用针对两种药物制备的亲和层析基质，证实了6AP与GA可与核糖体发生RNA依赖的相互作用。这类特异性相互作用既不会影响核糖体的肽基转移酶活性，也不会干扰整体翻译过程。与之相反，6AP与GA能够特异性抑制核糖体中由核糖体RNA介导的蛋白质折叠活性。
结论与意义：因此，6AP与GA是首批能够选择性抑制核糖体蛋白质折叠活性的化合物。它们由此成为研究该蛋白质折叠活性尚未被充分探索的生物学功能的宝贵工具。