PT - JOURNAL ARTICLE AU - Nathanael G. Lintner AU - Kim F. McClure AU - Donna Petersen AU - Allyn T. Londregan AU - David W. Piotrowski AU - Liuqing Wei AU - Jun Xiao AU - Michael Bolt AU - Paula M. Loria AU - Bruce Maguire AU - Kieran F. Geoghegan AU - Austin Huang AU - Tim Rolph AU - Spiros Liras AU - Jennifer A. Doudna AU - Robert G. Dullea AU - Jamie H.D. Cate TI - A compound that directly and selectively stalls PCSK9 translation AID - 10.1101/083097 DP - 2016 Jan 01 TA - bioRxiv PG - 083097 4099 - http://biorxiv.org/content/early/2016/10/25/083097.short 4100 - http://biorxiv.org/content/early/2016/10/25/083097.full 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.