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    Fenretinide Derivatives Act as Disrupters of Interactions of Serum Retinol Binding Protein (sRBP) with Transthyretin and the sRBP Receptor


    Campos-Sandoval, Jose Angel and Redondo, Clara and Kinsella, Gemma K. and Pal, Akos and Jones, Geraint and Eyre, Gwen S. and Hirst, Simon C, and Findlay, John B. C. (2011) Fenretinide Derivatives Act as Disrupters of Interactions of Serum Retinol Binding Protein (sRBP) with Transthyretin and the sRBP Receptor. Journal of Medicinal Chemistry, 54. pp. 4378-4387. ISSN 0022-2623

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    Abstract

    Serum retinol binding protein (sRBP) is released from the liver as a complex with transthyretin (TTR), a process under the control of dietary retinol. Elevated levels of sRBP may be involved in inhibiting cellular responses to insulin and in generating first insulin resistance and then type 2 diabetes, offering a new target for therapeutic attack for these conditions. A series of retinoid analogues were synthesized and examined for their binding to sRBP and their ability to disrupt the sRBP-TTR and sRBP-sRBP receptor interactions. A number inhibit the sRBP-TTR and sRBP-sRBP receptor interactions as well as or better than Fenretinide (FEN), presenting a potential novel dual mechanism of action and perhaps offering a new therapeutic intervention against type 2 diabetes and its development. Shortening the chain length of the FEN derivative substantially abolished binding to sRBP, indicating that the strength of the interaction lies in the polyene chain region. Differences in potency against the sRBP-TTR and sRBP-sRBP receptor interactions suggest variant effects of the compounds on the two loops of sRBP guarding the entrance of the binding pocket that are responsible for these two protein-protein interactions.

    Item Type: Article
    Keywords: Fenretinide; Derivatives; Disrupters; Interactions; Serum Retinol Binding Protein; sRBP; Transthyretin; Receptor;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 5431
    Identification Number: dx.doi.org/10.1021/jm200256g
    Depositing User: Gemma Kinsella
    Date Deposited: 29 Sep 2014 15:13
    Journal or Publication Title: Journal of Medicinal Chemistry
    Publisher: ACS Publications
    Refereed: Yes
    URI:

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