Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication

被引：162

作者：

Borawski, Jason ^{[1
]}

Troke, Philip ^{[1
]}

Puyang, Xiaoling ^{[1
]}

Gibaja, Veronica ^{[1
]}

Zhao, ShanChaun ^{[1
]}

Mickanin, Craig ^{[1
]}

Leighton-Davies, Juliet ^{[1
]}

Wilson, Christopher J. ^{[1
]}

Myer, Vic ^{[1
]}

CornellaTaracido, Ivan ^{[1
]}

Baryza, Jeremy ^{[1
]}

Tallarico, John ^{[1
]}

Joberty, Gerard ^{[2
]}

Bantscheff, Marcus ^{[2
]}

Schirle, Markus ^{[1
]}

Bouwmeester, Tewis ^{[2
]}

Mathy, Joanna E. ^{[1
]}

Lin, Kai ^{[1
]}

Compton, Teresa ^{[1
]}

Labow, Mark ^{[1
]}

Wiedmann, Brigitte ^{[1
]}

Gaither, L. Alex ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Cellzome AG, D-69117 Heidelberg, Germany

来源：

JOURNAL OF VIROLOGY | 2009年 / 83卷 / 19期

关键词：

NEURONAL CALCIUM SENSOR-1; RNA REPLICATION; CYCLOPHILIN INHIBITOR; EFFICIENT REPLICATION; ENDOPLASMIC-RETICULUM; CELLULAR COFACTORS; ANTIVIRAL ACTIVITY; IRON HOMEOSTASIS; TISSUE-CULTURE; IDENTIFICATION;

D O I：

10.1128/JVI.02418-08

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.

引用

页码：10058 / 10074

页数：17

共 72 条

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