title: A Small-Molecule Anti-secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation.
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.
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Donna N
authors.initials: DN
authors.lastname: Petersen
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Wanida
authors.initials: W
authors.lastname: Ruangsiriluk
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Stevens
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Maguire
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: O'Connell
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Rocke
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Ruggeri
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Rolph
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA. Electronic address: paula.m.loria@pfizer.com.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Medicine Design, Worldwide Research & Development, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA. Electronic address: philip.a.carpino@pfizer.com.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D000091362:PCSK9 Inhibitors; D054852:Small Molecule Libraries; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: LDL; LDL receptor; PCSK9; R-IMPP; anti-secretagogue; high throughput screen (HTS); phenotypic screening; ribosome; secretion; translation