Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein

被引：205

作者：

Strating, Jeroen R. P. M. ^{[1
,2
]}

van der Linden, Lonneke ^{[2
,3
]}

Albulescu, Lucian ^{[1
,2
]}

Bigay, Joelle ^{[4
,5
]}

Arita, Minetaro ^{[6
]}

Delang, Leen ^{[3
]}

Leyssen, Pieter ^{[3
]}

van der Schaar, Hilde M. ^{[1
,2
]}

Lanke, Kjerstin H. W. ^{[2
]}

Thibaut, Hendrik Jan ^{[1
]}

Ulferts, Rachel ^{[1
,2
]}

Drin, Guillaume ^{[4
,5
]}

Schlinck, Nina ^{[7
]}

Wubbolts, Richard W. ^{[8
]}

Sever, Navdar ^{[9
]}

Head, Sarah A. ^{[10
]}

Liu, Jun O. ^{[10
]}

Beachy, Philip A. ^{[9
]}

De Matteis, Maria A. ^{[11
]}

Shair, Matthew D. ^{[12
]}

Olkkonen, Vesa M. ^{[13
]}

Neyts, Johan ^{[3
]}

van Kuppeveld, Frank J. M. ^{[1
,2
]}

机构：

[1] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Div Virol, NL-3584 CL Utrecht, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 GA Nijmegen, Netherlands

[3] Univ Louvain, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium

[4] Univ Nice Sophia Antipolis, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France

[5] CNRS, UMR 7275, F-06560 Valbonne, France

[6] Natl Inst Infect Dis, Dept Virol 2, Tokyo 2080011, Japan

[7] NanoTemper Technol GmbH, D-81369 Munich, Germany

[8] Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, NL-3584 CM Utrecht, Netherlands

[9] Stanford Univ, Sch Med, Howard Hughes Med Inst, Inst Stem Cell Biol & Regenerat Med,Dept Biochem, Stanford, CA 94305 USA

[10] Johns Hopkins Sch Med, Dept Pharmacol, Baltimore, MD 21205 USA

[11] Telethon Inst Genet & Med, I-80131 Naples, Italy

[12] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[13] Minerva Fdn, Inst Med Res, Helsinki 00290, Finland

来源：

CELL REPORTS | 2015年 / 10卷 / 04期

关键词：

PHASE-II TRIAL; ENDOPLASMIC-RETICULUM; CHOLESTEROL; ANTIFUNGAL; CANCER; TRAFFICKING; ACTIVATION; DOMAIN;

D O I：

10.1016/j.celrep.2014.12.054

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication, whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e., shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs.

引用

页码：600 / 615

页数：16

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