A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation. Issue 11 (17th November 2016)

• Record Type: Journal Article
• Authors: Petersen, Donna N.; Hawkins, Julie; Ruangsiriluk, Wanida; Stevens, Kimberly A.; Maguire, Bruce A.; O'Connell, Thomas N.; Rocke, Benjamin N.; Boehm, Markus; Ruggeri, Roger B.; Rolph, Tim; Hepworth, David; Loria, Paula M.; Carpino, Philip A.
• Is Part Of: Cell chemical biology. Volume 23:Issue 11(2016)
• Page Start: 1362
• Page End: 1371
• Publication Date: 2016-11-17
• Subjects: PCSK9 -- R-IMPP -- translation -- ribosome -- phenotypic screening -- high throughput screen (HTS) -- secretion -- LDL -- LDL receptor -- anti-secretagogue; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.08.016
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Phenotypic screening yields a small-molecule anti-secretagogue of PCSK9 (R-IMPP) R-IMPP promotes uptake of LDL-C in hepatoma cells by increasing LDL-R levels PCSK9 translation is blocked by R-IMPP in a sequence-dependent manner Direct binding of R-IMPP to human 80S ribosomes is demonstrated Abstract : PCSK9 is a genetically validated target for the treatment of hypercholesterolemia. Petersen et al. describe the discovery of the first small-molecule anti-secretagogue of PCSK9 that acts by a novel mechanism involving inhibition of PCSK9 protein translation.