Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein
Jeroen R.P.M. Strating, Lonneke van der Linden, Lucian Albulescu, Joelle Bigay,Minetaro Arita, Leen Delang, Pieter Leyssen, Hilde M. van der Schaar, Kjerstin H.W. Lanke,Hendrik Jan Thibaut, Rachel Ulferts1, , Guillaume Drin, Nina Schlinck, Richard W. Wubbolts, Navdar Sever, Sarah A. Head, Jun O. Liu, Philip A. Beachy, Maria A. De Matteis, Matthew D. Shair,Vesa M. Olkkonen, Johan Neyts, Frank J.M. van Kuppeveld
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.
