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Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain

Journal Article · · PLoS Biology (Online)
 [1];  [2];  [3];  [4];  [5];  [5];  [5];  [6];  [3];  [3];  [7];  [8];  [9];  [10];  [11];  [9];  [12]
  1. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; DOE/OSTI
  2. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit
  3. Pfizer Worldwide Research and Development, Groton, CT (United States). Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism
  4. Pfizer Worldwide Research and Development, Groton, CT (United States). Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit
  5. Pfizer Worldwide Research and Development, Groton, CT (United States). Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit
  6. Pfizer Worldwide Research & Development, Andover, MA (United States). Drug Safety Research & Development
  7. Pfizer Worldwide Research and Development, Groton, CT (United States). Pfizer Medicinal Chemistry, Structural Biology and Biophysics
  8. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Pfizer Medicinal Chemistry, Computational Sciences
  9. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Cardiovascular, Metabolic and Endocrine Disease Research Unit
  10. Pfizer Worldwide Research and Development, Cambridge, MA (United States). Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit; Pfizer Worldwide Research and Development, Groton, CT (United States). Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit,
  11. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). QB3 Inst.; Univ. of California, Berkeley, CA (United States). Dept. of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division; Univ. of California, Berkeley, CA (United States). Howard Hughes Medical inst. (HHMI)
  12. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). QB3 Inst.; Univ. of California, Berkeley, CA (United States). Dept. of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
+ Show Author Affiliations
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 inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627175
Journal Information:
PLoS Biology (Online), Journal Name: PLoS Biology (Online) Journal Issue: 3 Vol. 15; ISSN 1545-7885
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (20)

Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects journal March 2020
The exon–intron gene structure upstream of the initiation codon predicts translation efficiency journal April 2018
Hallmarks of ribosomopathies journal July 2019
Cellular response to small molecules that selectively stall protein synthesis by the ribosome posted_content November 2018
Correction: Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain journal April 2018
Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries journal January 2019
The Expanding Riboverse journal October 2019
Synthesis of Moracin C and Its Derivatives with a 2-arylbenzofuran Motif and Evaluation of Their PCSK9 Inhibitory Effects in HepG2 Cells journal March 2021
TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response journal June 2018
Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis journal November 2017
Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis journal November 2017
Lipid Management in Chronic Kidney Disease: Systematic Review of PCSK9 Targeting journal January 2018
Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists journal August 2017
Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule journal June 2019
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