2. Academic Validation
  3. Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307

Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307

  • Antiviral Res. 2017 Apr;140:37-44. doi: 10.1016/j.antiviral.2017.01.008.
Lucian Albulescu 1,  Joëlle Bigay 2,  Bishyajit Biswas 3,  Marion Weber-Boyvat 4,  Cristina M Dorobantu 1,  Leen Delang 5,  Hilde M van der Schaar 1,  Young-Sik Jung 3,  Johan Neyts 5,  Vesa M Olkkonen 4,  Frank J M van Kuppeveld 6,  Jeroen R P M Strating 7
Affiliations

Affiliations

  • 1 Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • 2 Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 660 Route des Lucioles, 06560 Valbonne, France.
  • 3 Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 305-340, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon 305-355, Republic of Korea.
  • 4 Minerva Foundation Institute for Medical Research, Helsinki, Finland.
  • 5 KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
  • 6 Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: F.J.M.vanKuppeveld@uu.nl.
  • 7 Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: J.Strating@uu.nl.
PMID: 28088354 DOI: 10.1016/j.antiviral.2017.01.008
Abstract

The genus Enterovirus (e.g. poliovirus, coxsackievirus, rhinovirus) of the Picornaviridae family of positive-strand RNA viruses includes many important pathogens linked to a range of acute and chronic diseases for which no approved Antiviral therapy is available. Targeting a step in the life cycle that is highly conserved provides an attractive strategy for developing broad-range inhibitors of Enterovirus infection. A step that is currently explored as a target for the development of antivirals is the formation of replication organelles, which support replication of the viral genome. To build replication organelles, enteroviruses rewire cellular machinery and hijack lipid homeostasis pathways. For example, enteroviruses exploit the PI4KIIIβ-PI4P-OSBP pathway to direct Cholesterol to replication organelles. Here, we uncover that TTP-8307, a known Enterovirus replication inhibitor, acts through the PI4KIIIβ-PI4P-OSBP pathway by directly inhibiting OSBP activity. However, despite a shared mechanism of TTP-8307 with established OSBP inhibitors (itraconazole and OSW-1), we identify a number of notable differences between these compounds. The Antiviral activity of TTP-8307 extends to other viruses that require OSBP, namely the picornavirus encephalomyocarditis virus and the Flavivirus hepatitis C virus.

Keywords

Antiviral; Enterovirus; OSBP; Replication; TTP-8307.

Figures
Products