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Interaction of the Indole Class of Vacuolar H+-ATPase Inhibitors with Lipid Bilayers
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    Interaction of the Indole Class of Vacuolar H+-ATPase Inhibitors with Lipid Bilayers
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    Centro de Química-Física Molecular, Instituto Superior Técnico, Lisbon, Portugal, Departamento de Química, Universidade de Évora, Évora, Portugal, Laboratory of Biophysics, Wageningen University, Wageningen, The Netherlands, and Department of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom
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    Biochemistry

    Cite this: Biochemistry 2006, 45, 16, 5271–5279
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    https://doi.org/10.1021/bi0522753
    Published April 5, 2006
    Copyright © 2006 American Chemical Society

    Abstract

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    The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.

    Copyright © 2006 American Chemical Society

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     This work was supported by Contract QLG-CT-2000-01801 of the European Commission (MIVase Consortium) and by FCT (Portugal) under the Program POCTI. M.A.H. and M.P. are members of the COST D22 Action of the European Union. F.F. acknowledges Grant SFRH/BD/14282/2003 from FCT (Portugal).

     Instituto Superior Técnico.

    §

     Universidade de Évora.

     Wageningen University.

     University of Leeds.

    *

     Corresponding author. E-mail:  [email protected]. Telephone:  (+351) 218413248. Fax:  (+351) 218464455.

    Cited By

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    This article is cited by 5 publications.

    1. Renukadevi Patil, Arpita Kulshrestha, Anjali Tikoo, Sara Fleetwood, Gajendra Katara, Bala Kolli, William Seibel, Alice Gilman-Sachs, Shivaputra Patil, Kenneth Beaman. Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H+)-ATPase Inhibitors. Molecules 2017, 22 (9) , 1559. https://doi.org/10.3390/molecules22091559
    2. Yibo Nie, Zhuan Duan, Mingwu Ding. Efficient Regioselective Synthesis of 3‐Iodoindole N ‐Carboximidamides and N ‐Carboximidoates by a Sequential Aza‐Wittig/Iodine Induced Cyclization. Chinese Journal of Chemistry 2012, 30 (8) , 1807-1812. https://doi.org/10.1002/cjoc.201200281
    3. Markus Huss, Helmut Wieczorek. Inhibitors of V-ATPases: old and new players. Journal of Experimental Biology 2009, 212 (3) , 341-346. https://doi.org/10.1242/jeb.024067
    4. Renske W. Hesselink, Alexander Fedorov, Marcus A. Hemminga, Manuel Prieto. Membrane‐bound peptides from V‐ATPase subunit a do not interact with an indole‐type inhibitor. Journal of Peptide Science 2008, 14 (4) , 383-388. https://doi.org/10.1002/psc.980
    5. F. Fernandes, L.M.S. Loura, A. Fedorov, N. Dixon, T.P. Kee, M. Prieto, M.A. Hemminga. Binding assays of inhibitors towards selected V-ATPase domains. Biochimica et Biophysica Acta (BBA) - Biomembranes 2006, 1758 (11) , 1777-1786. https://doi.org/10.1016/j.bbamem.2006.07.006

    Biochemistry

    Cite this: Biochemistry 2006, 45, 16, 5271–5279
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi0522753
    Published April 5, 2006
    Copyright © 2006 American Chemical Society

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