1. A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.
- Author
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Petersen DN, Hawkins J, Ruangsiriluk W, Stevens KA, Maguire BA, O'Connell TN, Rocke BN, Boehm M, Ruggeri RB, Rolph T, Hepworth D, Loria PM, and Carpino PA
- Subjects
- Cell Line, Tumor, Humans, Isoquinolines chemistry, Ribosomes metabolism, Small Molecule Libraries chemistry, Isoquinolines pharmacology, PCSK9 Inhibitors, Proprotein Convertase 9 metabolism, Protein Biosynthesis drug effects, Ribosomes drug effects, Small Molecule Libraries pharmacology
- Abstract
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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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