跳转至内容
Merck
  • A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.

A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.

Cell chemical biology (2016-10-18)
Donna N Petersen, Julie Hawkins, Wanida Ruangsiriluk, Kimberly A Stevens, Bruce A Maguire, Thomas N O'Connell, Benjamin N Rocke, Markus Boehm, Roger B Ruggeri, Tim Rolph, David Hepworth, Paula M Loria, Philip A Carpino
摘要

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but not E. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.

材料
货号
品牌
产品描述

Sigma-Aldrich
单克隆抗 β-肌动蛋白抗体 小鼠抗, clone AC-15, ascites fluid
Sigma-Aldrich
R-IMPP hydrochloride, ≥98% (HPLC)