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.

Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule

“…PF846 blocks production of proprotein convertase subtilisin/kexin type 9 (PCSK9)-an important target for regulating plasma low-density lipoprotein cholesterol levels-by interfering with the elongation phase of translation 10,11 . PF846 selectively stalls the ribosome on very few translated protein nascent chains, generally early in their formation and with no clear sequence pattern 10 .…”

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

“…Kidney biopsy showed multifocal tubular necrosis and signs of oligonucleotide accumulation, all changes being reversible upon termination of SPC5001 administration [198, 199]. Recently, a small molecule compound (R-IMPP) was identified which inhibit translocation of PCSK9 at the level of the 80S ribosome; however, data on the efficiency of such approach for LDL-C management are lacking [143]. …”

Liver‐Targeted Small‐Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis

“…[2] Thes urface contacts between PCSK9 and the LDLR are distributed and pH-sensitive,m aking smallmolecule intervention extremely challenging. [5] From this screen, PF-00932 239 (1)was identified as ahit ( Figure 1). [4] Previously, we described the identification of as mall molecule inhibitor of PCSK9 synthesis by ac ell-based high-throughput screen (HTS) designed to find molecules that decrease PCSK9 secretion to the cell media.…”

“…[4] Previously, we described the identification of as mall molecule inhibitor of PCSK9 synthesis by ac ell-based high-throughput screen (HTS) designed to find molecules that decrease PCSK9 secretion to the cell media. [5] From this screen, PF-00932 239 (1)was identified as ahit ( Figure 1). Cells treated with 1 show decreased PCSK9 secretion, increased cell surface LDLR, and increased LDLC uptake consistent with am echanism involving inhibition of PCSK9 synthesis.S eparately,w e described am ore optimized compound, PF-06446846 [6] (2), that shows specific binding to 80S ribosomes and inhibits the translation of fewer than 30 transcripts including PCSK9.…”