Key result
6-Aminophenanthridine and Guanabenz selectively inhibit the protein folding activity of the ribosome by interacting with domain V of the large ribosomal RNA, without affecting protein synthesis.
6AP and Guanabenz are the first compounds identified to selectively inhibit the protein folding activity of the ribosome, providing a novel mechanism for their antiprion effects.
May support antiprion drug development via ribosomal targeting; hypothesis-generating and not ready for clinical translation.
BACKGROUND: 6-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 FINDINGS: Here 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/SIGNIFICANCE: 6AP 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.
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Tribouillard‐Tanvier et al. (2008) studied Prion diseases. 6-Aminophenanthridine (6AP) and Guanabenz (GA) vs. Inactive derivatives (6APi, GAi) or vehicle (DMSO) was evaluated on Inhibition of ribosomal RNA-mediated protein folding activity. 6-Aminophenanthridine and Guanabenz selectively inhibit the protein folding activity of the ribosome by interacting with domain V of the large ribosomal RNA, without affecting protein synthesis.
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