A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation
| Autor: | Wanida Ruangsiriluk, Kimberly A. Stevens, Markus Boehm, Benjamin N. Rocke, Paula M. Loria, Julie Jia Li Hawkins, Thomas N. O'Connell, Tim Rolph, Roger B. Ruggeri, Philip A. Carpino, David Hepworth, Bruce A. Maguire, Donna N. Petersen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Biology Biochemistry Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Cell Line Tumor Drug Discovery medicine Humans Secretion Molecular Biology Pharmacology PCSK9 Inhibitors Isoquinolines Proprotein convertase 030104 developmental biology Mechanism of action Protein Biosynthesis 030220 oncology & carcinogenesis LDL receptor Molecular Medicine Kexin lipids (amino acids peptides and proteins) Secretagogue Proprotein Convertase 9 medicine.symptom Eukaryotic Ribosome Ribosomes |
| Zdroj: | Cell Chemical Biology. 23:1362-1371 |
| ISSN: | 2451-9456 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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