Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein

作者：Strating Jeroen R P M; van der Linden Lonneke; Albulescu Lucian; Bigay Joelle; 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; De Matteis Maria A; Shair Matthew D; Olkkonen Vesa M; Neyts Johan; van Kuppeveld Frank J M^*

来源：Cell Reports, 2015, 10(4): 600-615.

DOI：10.1016/j.celrep.2014.12.054

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.

• 出版日期2015-2-3
• 单位河北医科大学