Abstract
Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, weidentify 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 600-615 |
| Number of pages | 16 |
| Journal | Cell Reports |
| Volume | 10 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 3 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. / Strating, Jeroen R P M; van der Linden, Lonneke; Albulescu, Lucian; Bigay, Joëlle; Arita, Minetaro; Delang, Leen; Leyssen, Pieter; van der Schaar, Hilde M.; Lanke, Kjerstin H W; Thibaut, Hendrik Jan; Ulferts, Rachel; Drin, Guillaume; Schlinck, Nina; Wubbolts, Richard W.; Sever, Navdar; Head, Sarah A.; Liu, Jun; Beachy, Philip A.; DeMatteis, Maria A.; Shair, Matthew D.; Olkkonen, Vesa M.; Neyts, Johan; van Kuppeveld, Frank J M.
In: Cell Reports, Vol. 10, No. 4, 03.02.2015, p. 600-615.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein
AU - Strating, Jeroen R P M
AU - van der Linden, Lonneke
AU - Albulescu, Lucian
AU - Bigay, Joëlle
AU - Arita, Minetaro
AU - Delang, Leen
AU - Leyssen, Pieter
AU - van der Schaar, Hilde M.
AU - Lanke, Kjerstin H W
AU - Thibaut, Hendrik Jan
AU - Ulferts, Rachel
AU - Drin, Guillaume
AU - Schlinck, Nina
AU - Wubbolts, Richard W.
AU - Sever, Navdar
AU - Head, Sarah A.
AU - Liu, Jun
AU - Beachy, Philip A.
AU - DeMatteis, Maria A.
AU - Shair, Matthew D.
AU - Olkkonen, Vesa M.
AU - Neyts, Johan
AU - van Kuppeveld, Frank J M
PY - 2015/2/3
Y1 - 2015/2/3
N2 - Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, weidentify 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.
AB - Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, weidentify 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.
UR - http://www.scopus.com/inward/record.url?scp=84922769738&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922769738&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.12.054
DO - 10.1016/j.celrep.2014.12.054
M3 - Article
C2 - 25640182
AN - SCOPUS:84922769738
VL - 10
SP - 600
EP - 615
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -