Protein folding activity of ribosomal RNA is a selective target of two unrelated antiprion drugs.
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.


RESULTS
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.


CONCLUSIONS
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.
Tribouillard-Tanvier
Déborah
D
INSERM U613, Brest, France.
Dos Reis
Suzana
S
Gug
Fabienne
F
Voisset
Cécile
C
Béringue
Vincent
V
Sabate
Raimon
R
Kikovska
Ema
E
Talarek
Nicolas
N
Bach
Stéphane
S
Huang
Chenhui
C
Desban
Nathalie
N
Saupe
Sven J
SJ
Supattapone
Surachai
S
Thuret
Jean-Yves
JY
Chédin
Stéphane
S
Vilette
Didier
D
Galons
Hervé
H
Sanyal
Suparna
S
Blondel
Marc
M
D015153:Blotting, Western; D002460:Cell Line; D002846:Chromatography, Affinity; D004591:Electrophoresis, Polyacrylamide Gel; D006143:Guanabenz / Q000494:pharmacology*; D011328:Prions / Q000187:drug effects*; D017510:Protein Folding; D012335:RNA, Ribosomal / Q000187:drug effects / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D011328:Prions; D012335:RNA, Ribosomal; D006143:Guanabenz