Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein

Jeroen R.P.M. Strating; Lonneke van der Linden; Lucian Albulescu; Joëlle Bigay; Minetaro Arita; Leen Delang; Pieter Leyssen; Hilde M. van der Schaar; Kjerstin H.W. Lanke; Hendrik Jan Thibaut; Rachel Ulferts; Guillaume Drin; Nina Schlinck; Richard W. Wubbolts; Navdar Sever; Sarah A. Head; Jun O. Liu; Philip A. Beachy; Maria A. DeMatteis; Matthew D. Shair; Vesa M. Olkkonen; Johan Neyts; Frank J.M. van Kuppeveld

doi:10.1016/j.celrep.2014.12.054

Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein

Jeroen R.P.M. Strating, Lonneke van der Linden, Lucian Albulescu, Joëlle Bigay, Minetaro Arita, Leen Delang, Pieter Leyssen, Hilde M. van der Schaar, Kjerstin H.W. Lanke, Hendrik Jan Thibaut, Rachel Ulferts, Guillaume Drin, Nina Schlinck, Richard W. Wubbolts, Navdar Sever, Sarah A. Head, Jun O. Liu, Philip A. Beachy, Maria A. DeMatteis, Matthew D. ShairVesa M. Olkkonen, Johan Neyts, Frank J.M. van Kuppeveld

School of Medicine

Research output: Contribution to journal › Article

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	https://doi.org/10.1016/j.celrep.2014.12.054
State	Published - Feb 3 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Strating, J. R. P. M., van der Linden, L., Albulescu, L., Bigay, J., Arita, M., Delang, L., Leyssen, P., van der Schaar, H. M., Lanke, K. H. W., Thibaut, H. J., Ulferts, R., Drin, G., Schlinck, N., Wubbolts, R. W., Sever, N., Head, S. A., Liu, J. O., Beachy, P. A., DeMatteis, M. A., ... van Kuppeveld, F. J. M. (2015). Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. Cell Reports, 10(4), 600-615. https://doi.org/10.1016/j.celrep.2014.12.054

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 O.; 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

Strating, JRPM, van der Linden, L, Albulescu, L, Bigay, J, Arita, M, Delang, L, Leyssen, P, van der Schaar, HM, Lanke, KHW, Thibaut, HJ, Ulferts, R, Drin, G, Schlinck, N, Wubbolts, RW, Sever, N, Head, SA, Liu, JO, Beachy, PA, DeMatteis, MA, Shair, MD, Olkkonen, VM, Neyts, J & van Kuppeveld, FJM 2015, 'Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein', Cell Reports, vol. 10, no. 4, pp. 600-615. https://doi.org/10.1016/j.celrep.2014.12.054

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 O. ; Beachy, Philip A. ; DeMatteis, Maria A. ; Shair, Matthew D. ; Olkkonen, Vesa M. ; Neyts, Johan ; van Kuppeveld, Frank J.M. / Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein. In: Cell Reports. 2015 ; Vol. 10, No. 4. pp. 600-615.

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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.",

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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 O.

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

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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.

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