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
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: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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