Combined small molecule and loss-of-function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets.
Antiviral Agents
/ pharmacology
Aspartate Carbamoyltransferase
/ antagonists & inhibitors
Aspartic Acid
/ analogs & derivatives
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
/ antagonists & inhibitors
Cell Line
Dihydroorotase
/ antagonists & inhibitors
Estrogen Receptor Antagonists
/ pharmacology
Estrogen Receptor alpha
/ antagonists & inhibitors
Fulvestrant
/ pharmacology
Gene Silencing
Hepatitis D, Chronic
/ drug therapy
Hepatitis Delta Virus
/ physiology
Hepatocytes
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Insulin Resistance
Life Cycle Stages
Loss of Function Mutation
Phosphonoacetic Acid
/ analogs & derivatives
Pyrimidines
/ biosynthesis
RNA Interference
RNA, Small Interfering
/ genetics
RNA, Viral
/ metabolism
Signal Transduction
Virus Replication
antiviral therapy
hepatitis D
liver
screening
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
26
06
2018
revised:
24
01
2019
accepted:
10
02
2019
pubmed:
6
3
2019
medline:
24
12
2019
entrez:
6
3
2019
Statut:
ppublish
Résumé
Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent. Here, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection. Functional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by The discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.
Identifiants
pubmed: 30833451
pii: gutjnl-2018-317065
doi: 10.1136/gutjnl-2018-317065
pmc: PMC6943243
doi:
Substances chimiques
Antiviral Agents
0
CAD trifunctional enzyme
0
ESR1 protein, human
0
Estrogen Receptor Antagonists
0
Estrogen Receptor alpha
0
HIF1A protein, human
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Pyrimidines
0
RNA, Small Interfering
0
RNA, Viral
0
Fulvestrant
22X328QOC4
Aspartic Acid
30KYC7MIAI
sparfosic acid
78QVZ7RG8L
Aspartate Carbamoyltransferase
EC 2.1.3.2
Dihydroorotase
EC 3.5.2.3
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
EC 6.3.5.5
pyrimidine
K8CXK5Q32L
Phosphonoacetic Acid
N919E46723
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
158-167Subventions
Organisme : European Research Council
ID : 671231
Pays : International
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
Biochem Biophys Res Commun. 2018 Feb 5;496(2):726-730
pubmed: 29357281
Nat Commun. 2017 Sep 11;8(1):517
pubmed: 28894087
Nat Rev Gastroenterol Hepatol. 2011 Apr;8(4):212-23
pubmed: 21386812
RNA. 2018 Sep;24(9):1229-1240
pubmed: 29954950
Drugs. 2005;65(15):2209-44
pubmed: 16225378
ACS Infect Dis. 2015 Sep 11;1(9):420-7
pubmed: 27617925
Lancet. 2017 Feb 18;389(10070):674-675
pubmed: 28087068
PLoS Pathog. 2013;9(10):e1003678
pubmed: 24098125
Nat Med. 2011 May;17(5):589-95
pubmed: 21516087
Biomed Res Int. 2014;2014:409272
pubmed: 25101278
Proc Natl Acad Sci U S A. 1985 Oct;82(20):6802-6
pubmed: 2995985
Hepatology. 2018 Nov;68(5):1695-1709
pubmed: 29679386
Nat Rev Clin Oncol. 2015 Oct;12(10):573-83
pubmed: 26122181
J Biol Chem. 1974 Nov 10;249(21):6945-50
pubmed: 4371054
Semin Liver Dis. 2012 Aug;32(3):195-200
pubmed: 22932967
World J Hepatol. 2016 Jan 18;8(2):123-30
pubmed: 26807208
Dev Biol. 2006 Aug 15;296(2):409-20
pubmed: 16828468
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16410-5
pubmed: 19717417
Crit Rev Microbiol. 2013 Nov;39(4):362-72
pubmed: 22917057
Antimicrob Agents Chemother. 2014;58(1):267-73
pubmed: 24145541
Genes Dev. 1995 Feb 15;9(4):481-90
pubmed: 7883169
Curr Opin Drug Discov Devel. 2001 Sep;4(5):651-6
pubmed: 12825459
J Hepatol. 2016 Apr;64(1 Suppl):S102-S116
pubmed: 27084031
Lancet. 2011 Jul 2;378(9785):73-85
pubmed: 21511329
Curr Opin Virol. 2016 Jun;18:135-43
pubmed: 27447092
World J Gastroenterol. 2015 Nov 14;21(42):12171-8
pubmed: 26576101
Curr Opin Virol. 2015 Oct;14:41-6
pubmed: 26262886
Drugs. 2014 Apr;74(6):659-74
pubmed: 24740824
Curr Res Transl Med. 2017 Jan - Mar;65(1):7-9
pubmed: 28340697
Science. 2008 Feb 15;319(5865):921-6
pubmed: 18187620
Lancet Infect Dis. 2015 Oct;15(10):1167-1174
pubmed: 26189433
Nat Chem Biol. 2016 May;12(5):361-6
pubmed: 27018887
J Hepatol. 2016 Sep;65(3):490-8
pubmed: 27132170
Mol Endocrinol. 2016 Oct;30(10):1046-1058
pubmed: 27489947
Trends Mol Med. 2005 Sep;11(9):430-7
pubmed: 16098809
J Biol Chem. 2004 Aug 6;279(32):33035-8
pubmed: 15096496
Nat Biotechnol. 2015 May;33(5):549-554
pubmed: 25798937
Lancet. 2017 Feb 18;389(10070):709-717
pubmed: 28087069
Mol Cancer Ther. 2009 Feb;8(2):366-75
pubmed: 19174558
Cell Rep. 2016 Oct 25;17(5):1357-1368
pubmed: 27783949
Expert Opin Investig Drugs. 2017 Sep;26(9):999-1005
pubmed: 28730878
Matrix Biol. 2014 Apr;35:25-33
pubmed: 24128412
Gut. 2000 Mar;46(3):420-6
pubmed: 10673308
Biochemistry. 2018 Mar 6;57(9):1440-1450
pubmed: 29388767
PLoS Pathog. 2017 Jun 15;13(6):e1006404
pubmed: 28617871
Breast Cancer Res Treat. 2003 Nov;82(2):103-11
pubmed: 14692654
Trends Pharmacol Sci. 1999 May;20(5):218-25
pubmed: 10354618
Hepatology. 2016 Jan;63(1):35-48
pubmed: 26224662
Hepatol Int. 2016 Jul;10(4):567-73
pubmed: 26979861
Nat Microbiol. 2016 Dec 19;2:16247
pubmed: 27991882