Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain

• DOI: 10.1371/journal.pbio.2001882
• Publication Date: 2017-03-21T14:03:21Z
• Authors: Nathanael G. Lintner; Kim F. McClure; Donna Petersen; Allyn T. Londregan; David W. Piotrowski; Liuqing Wei; Jun Xiao; Michael Bolt; Paula M. Loria; Bruce Maguire; Kieran F. Geoghegan; Austin Huang; Tim Rolph; Spiros Liras; Jennifer A. Doudna; Robert G. Dullea; Jamie H. D. Cate
• Keywords: Proprotein Convertases; Kexin; Ribosome profiling; PCSK9; Subtilisin

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 compound PF-06446846 inhibits translation PCSK9 by inducing ribosome to stall around codon 34, mediated sequence nascent chain within exit tunnel. We further show reduces and total rats following oral dosing. Using profiling, is highly selective for inhibition translation. The mechanism action employed reveals previously unexpected tunability human allows small molecules specifically block individual transcripts.