RT Journal Article
SR Electronic
T1 A compound that directly and selectively stalls PCSK9 translation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 083097
DO 10.1101/083097
A1 Nathanael G. Lintner
A1 Kim F. McClure
A1 Donna Petersen
A1 Allyn T. Londregan
A1 David W. Piotrowski
A1 Liuqing Wei
A1 Jun Xiao
A1 Michael Bolt
A1 Paula M. Loria
A1 Bruce Maguire
A1 Kieran F. Geoghegan
A1 Austin Huang
A1 Tim Rolph
A1 Spiros Liras
A1 Jennifer A. Doudna
A1 Robert G. Dullea
A1 Jamie H.D. Cate
YR 2016
UL http://biorxiv.org/content/early/2016/10/25/083097.abstract
AB Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome, which allows small molecules to specifically block translation of individual transcripts.One Sentence Summary A small-molecule PCSK9 inhibitor targets the human ribosome and selectively prevents PCSK9 synthesis.