title: Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307.
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.
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Lucian
authors.initials: L
authors.lastname: Albulescu
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, 660 Route des Lucioles, 06560 Valbonne, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Bigay
authors.affiliation: 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.
authors.forename: Bishyajit
authors.initials: B
authors.lastname: Biswas
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Marion
authors.initials: M
authors.lastname: Weber-Boyvat
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Dorobantu
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hilde M
authors.initials: HM
authors.lastname: van der Schaar
authors.affiliation: 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.
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Jung
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: 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.
authors.forename: Frank J M
authors.initials: FJM
authors.lastname: van Kuppeveld
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: J.Strating@uu.nl.
authors.forename: Jeroen R P M
authors.initials: JRPM
authors.lastname: Strating
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002783:Cholestenones / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004770:Enterovirus / Q000187:drug effects*; D016679:Genome, Viral / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects; D017955:Poliovirus / Q000187:drug effects; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012229:Rhinovirus / Q000187:drug effects; D012503:Saponins / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D000098825:Oxysterol Binding Proteins
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D002783:Cholestenones; D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D017964:Itraconazole; D017853:Phosphotransferases (Alcohol Group Acceptor); D011987:Receptors, Steroid; D012503:Saponins; D000098825:Oxysterol Binding Proteins; C000625580:TTP-8307; C106408:OSW 1; C581087:PI4KB protein, human
keywords: Antiviral; Enterovirus; OSBP; Replication; TTP-8307