Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.
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.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, United States of America.
Nathanael G
NG
Lintner
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
Kim F
KF
McClure
Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Donna
D
Petersen
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Allyn T
AT
Londregan
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
David W
DW
Piotrowski
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Liuqing
L
Wei
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Jun
J
Xiao
Drug Safety Research & Development, Pfizer Worldwide Research & Development, Andover, Massachusetts, United States of America.
Michael
M
Bolt
Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Paula M
PM
Loria
Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Bruce
B
Maguire
Pfizer Medicinal Chemistry, Structural Biology and Biophysics, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Kieran F
KF
Geoghegan
Pfizer Medicinal Chemistry, Computational Sciences, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
Austin
A
Huang
Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
Tim
T
Rolph
Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.|Pfizer Medicinal Chemistry, Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, United States of America.
Spiros
S
Liras
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, United States of America.|QB3 Institute, University of California, Berkeley, Berkeley, California, United States of America.|Department of Chemistry, University of California, Berkeley, Berkeley, California, United States of America.|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.|Howard Hughes Medical Institute (HHMI), University of California, Berkeley, Berkeley, California, United States of America.
Jennifer A
JA
Doudna
Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, United States of America.
Robert G
RG
Dullea
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, United States of America.|QB3 Institute, University of California, Berkeley, Berkeley, California, United States of America.|Department of Chemistry, University of California, Berkeley, Berkeley, California, United States of America.|Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
Jamie H D
0000-0001-5965-7902
JH
Cate
D000818:Animals; D002460:Cell Line; D002474:Cell-Free System; D002784:Cholesterol / Q000097:blood; D004926:Escherichia coli / Q000235:genetics; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D058990:Molecular Targeted Therapy; D000071449:Proprotein Convertase 9 / Q000097:blood / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D006576:Heterocyclic Compounds, 4 or More Rings; C000620903:PF-06446846; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9