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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDL-R) levels, impacting LDL-cholesterol (LDL-C) clearance.
• Dysregulation of PCSK9 is linked to hypercholesterolemia and cardiovascular disease.
• Targeting PCSK9 offers a therapeutic strategy for managing cholesterol levels.

Purpose of the Study:

• To identify small-molecule inhibitors of PCSK9 secretion.
• To elucidate the mechanism of action of a novel PCSK9 inhibitor, R-IMPP.
• To explore novel therapeutic approaches for modulating protein activity via translation inhibition.

Main Methods:

• Phenotypic screening of a small-molecule compound library.
• Assessing the effect of R-IMPP on LDL-C uptake and LDL-R levels in hepatoma cells.
• Investigating PCSK9 transcription, degradation, and translation.
• Evaluating R-IMPP binding to human and bacterial ribosomes.

Main Results:

• Identified (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP) as a PCSK9 inhibitor.
• R-IMPP increased LDL-C uptake by upregulating LDL-R levels.
• R-IMPP selectively inhibited PCSK9 translation, not transcription or degradation.
• R-IMPP demonstrated selective binding to human ribosomes.

Conclusions:

• R-IMPP represents a novel class of PCSK9 inhibitors acting via translational control.
• This mechanism of inhibiting eukaryotic translation offers a new therapeutic avenue.
• Targeting protein translation provides a distinct strategy for drug development in cardiovascular disease.