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      • Record: found
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      ITRACONAZOLE INHIBITS ENTEROVIRUS REPLICATION BY TARGETING THE OXYSTEROL-BINDING PROTEIN

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          SUMMARY

          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.

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          A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP.

          Bruno Mesmin, Joëlle Bigay, Joachim Moser von Filseck … (2013)
          Several proteins at endoplasmic reticulum (ER)-Golgi membrane contact sites contain a PH domain that interacts with the Golgi phosphoinositide PI(4)P, a FFAT motif that interacts with the ER protein VAP-A, and a lipid transfer domain. This architecture suggests the ability to both tether organelles and transport lipids between them. We show that in oxysterol binding protein (OSBP) these two activities are coupled by a four-step cycle. Membrane tethering by the PH domain and the FFAT motif enables sterol transfer by the lipid transfer domain (ORD), followed by back transfer of PI(4)P by the ORD. Finally, PI(4)P is hydrolyzed in cis by the ER protein Sac1. The energy provided by PI(4)P hydrolysis drives sterol transfer and allows negative feedback when PI(4)P becomes limiting. Other lipid transfer proteins are tethered by the same mechanism. Thus, OSBP-mediated back transfer of PI(4)P might coordinate the transfer of other lipid species at the ER-Golgi interface. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.

            J. Taipale, J. Chen, M Cooper … (2000)
            Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response, is a potential 'mechanism-based' therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.
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              Small molecule modulation of Smoothened activity.

              James K. Chen, Jussi Taipale, Keith E. Young … (2002)
              Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101573691
                Journal ID (pubmed-jr-id): 39703
                Journal ID (nlm-ta): Cell Rep
                Journal ID (iso-abbrev): Cell Rep
                Title: Cell reports
                ISSN (Electronic): 2211-1247
                Publication date Nihms-submitted: 8 February 2015
                Publication date (Electronic): 29 January 2015
                Publication date (Print): 3 February 2015
                Publication date PMC-release: 03 February 2016
                Volume: 10
                Issue: 4
                Pages: 600-615
                Affiliations
                [1 ]Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, NL-3584CL Utrecht, The Netherlands
                [2 ]Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, NL-6525GA Nijmegen, The Netherlands
                [3 ]Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven, BE-3000 Leuven, Belgium
                [4 ]Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, UMR 7275, Valbonne, France
                [5 ]Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
                [6 ]NanoTemper Technologies GmbH, D-81369 München, Germany
                [7 ]Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, NL-3584CM Utrecht, The Netherlands
                [8 ]Department of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
                [9 ]Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
                [10 ]Telethon Institute of Genetics and Medicine, Naples 80131, Italy
                [11 ]Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
                [12 ]Minerva Foundation Institute for Medical Research, FI-00290 Helsinki, Finland
                Author notes
                [* ]Corresponding author. Phone: +31-30-2534173. F.J.M.vanKuppeveld@ 123456uu.nl
                [☯]

                These authors contributed equally

                [¶]

                Present address: Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands

                Article
                Manuscript ID: NIHMS661351
                DOI: 10.1016/j.celrep.2014.12.054
                PMC ID: 4383725
                PubMed ID: 25640182
                SO-VID: 42101743-c42f-438b-b514-239fea5f2e36
                Copyright © © 2014 Published by Elsevier Inc.
                License:

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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                ScienceOpen disciplines: Cell biology

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