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Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein

Jeroen R P M Strating1, Lonneke van der Linden2, Lucian Albulescu1

  • 1Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584CL Utrecht, the Netherlands; Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 6525GA Nijmegen, the Netherlands.

Cell Reports
|February 3, 2015
PubMed

Insights

Itraconazole inhibits enteroviruses by targeting oxysterol-binding protein (OSBP) and related proteins. This discovery reveals a new antiviral strategy by disrupting lipid transport essential for viral replication.

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • Itraconazole (ITZ) is known for antifungal and anticancer properties.
  • Enteroviruses cause significant human diseases, necessitating new antiviral therapies.

Purpose of the Study:

  • To identify novel antiviral activities of Itraconazole (ITZ).
  • To elucidate the molecular targets and mechanisms of ITZ's antiviral action against enteroviruses.
  • To explore the role of oxysterol-binding protein (OSBP) and related proteins in viral replication.

Main Methods:

  • In vitro assays to assess ITZ's effect on enterovirus replication.
  • Identification of ITZ molecular targets using biochemical and genetic approaches.
  • Analysis of OSBP and ORP4 function in viral replication and membrane dynamics.

Main Results:

  • Itraconazole (ITZ) demonstrates broad-spectrum inhibition of enteroviruses, including poliovirus, coxsackievirus, and rhinovirus.
  • ITZ targets oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4), inhibiting viral RNA replication.
  • OSBP/ORP4 antagonism and knockdown inhibit viral replication, while overexpression counteracts ITZ's effects.
  • ITZ disrupts OSBP-mediated lipid transport, perturbing virus-induced membrane alterations crucial for replication.
  • ITZ also inhibits hepatitis C virus replication, indicating a broader role for OSBP in viral processes.

Conclusions:

  • OSBP and ORP4 are key molecular targets of Itraconazole (ITZ) for antiviral activity.
  • OSBP/ORP4-mediated lipid exchange is essential for the replication of various viruses.
  • Targeting OSBP/ORP4 offers a promising strategy for developing novel antiviral drugs.

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