Strating, Jeroen R.P.M.van der Linden, LonnekeAlbulescu, LucianBigay, JoëlleArita, MinetaroDelang, LeenLeyssen, Pietervan der Schaar, Hilde M.Lanke, Kjerstin H.W.Thibaut, Hendrik JanUlferts, RachelDrin, GuillaumeSchlinck, NinaWubbolts, Richard W.Sever, NavdarHead, Sarah A.Liu, Jun O.Beachy, Philip A.De Matteis, Maria A.Shair, MatthewOlkkonen, Vesa M.Neyts, Johanvan Kuppeveld, Frank J.M.2016-03-012014Strating, J. R., L. van der Linden, L. Albulescu, J. Bigay, M. Arita, L. Delang, P. Leyssen, et al. 2014. “ITRACONAZOLE INHIBITS ENTEROVIRUS REPLICATION BY TARGETING THE OXYSTEROL-BINDING PROTEIN.” Cell reports 10 (4): 600-615. doi:10.1016/j.celrep.2014.12.054. http://dx.doi.org/10.1016/j.celrep.2014.12.054.2211-1247http://nrs.harvard.edu/urn-3:HUL.InstRepos:25658512SUMMARY Itraconazole (ITZ) is a well-known antifungal agent that also has anti-cancer activity. In this study, we identified 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 novel 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.en-USJournal Article2016-03-0110.1016/j.celrep.2014.12.054