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PLoS Biol. 2017 Mar 21;15(3):e2001882. doi: 10.1371/journal.pbio.2001882. eCollection 2017 Mar.

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

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, United States of America.
2
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
3
Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
4
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
5
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Andover, Massachusetts, United States of America.
6
Pfizer Medicinal Chemistry, Structural Biology and Biophysics, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
7
Pfizer Medicinal Chemistry, Computational Sciences, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
8
Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
9
QB3 Institute, University of California, Berkeley, Berkeley, California, United States of America.
10
Department of Chemistry, University of California, Berkeley, Berkeley, California, United States of America.
11
Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
12
Howard Hughes Medical Institute (HHMI), University of California, Berkeley, Berkeley, California, United States of America.

Abstract

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 PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.

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PMID:
28323820
PMCID:
PMC5360235
DOI:
10.1371/journal.pbio.2001882
[Indexed for MEDLINE]
Free PMC Article

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