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

  • Cell Chem Biol. 2016 Nov 17;23(11):1362-1371. doi: 10.1016/j.chembiol.2016.08.016.
Donna N Petersen  1 ,  Julie Hawkins  2 ,  Wanida Ruangsiriluk  2 ,  Kimberly A Stevens  2 ,  Bruce A Maguire  1 ,  Thomas N O'Connell  1 ,  Benjamin N Rocke  1 ,  Markus Boehm  3 ,  Roger B Ruggeri  1 ,  Tim Rolph  2 ,  David Hepworth  3 ,  Paula M Loria  4 ,  Philip A Carpino  5
Affiliations
  • 1. Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
  • 2. Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
  • 3. Medicine Design, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
  • 4. Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA. Electronic address: [email protected].
  • 5. Medicine Design, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 27746128 DOI: 10.1016/j.chembiol.2016.08.016
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.

Keywords
LDL; LDL receptor; PCSK9; R-IMPP; anti-secretagogue; high throughput screen (HTS); phenotypic screening; ribosome; secretion; translation.
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