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Small Molecule PCSK9 Inhibitors: Hit to lead optimization

ABSTRACT: Ribosome profiling is used to demonstrate improved selectivity of compounds that promote PCSK9 translational stalling

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE110426 | GEO | 2018/06/20

REPOSITORIES: GEO

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Small Molecule PCSK9 Inhibitors: Hit to lead optimization

Project description:Small Molecule PCSK9 Inhibitors: Hit to lead optimization

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SECRETOME DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”

Project description:Human genetics as well as pharmacological intervention reveal that Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.

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CELL LYSATE DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”

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Project description:Cardiovascular diseases (CVD) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, sPCSK9 correlated positively with increasing age and the development of cardiovascular dysfunction. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats suggesting that PCSK9 plays an important role in cardiovascular aging.

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