The Marie Curie Laboratory for Membrane Proteins, Department of Biology, National University of Ireland, Maynooth, County Kildare, Ireland.
J Med Chem. 2011 Jul 14;54(13):4378-87. doi: 10.1021/jm200256g. Epub 2011 Jun 7.
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.
血清视黄醇结合蛋白（sRBP）与转甲状腺素蛋白（TTR）形成复合物从肝脏中释放出来，这一过程受膳食视黄醇的控制。sRBP 水平升高可能参与抑制细胞对胰岛素的反应，并导致胰岛素抵抗和 2 型糖尿病，为这些疾病提供了新的治疗靶点。合成了一系列类视黄醇，并研究了它们与 sRBP 的结合能力以及它们破坏 sRBP-TTR 和 sRBP-sRBP 受体相互作用的能力。一些化合物能抑制 sRBP-TTR 和 sRBP-sRBP 受体相互作用，其效果与 Fenretinide（FEN）相当，甚至更好，这提出了一种潜在的新型双重作用机制，并可能为 2 型糖尿病及其发展提供新的治疗干预。FEN 衍生物的链长大大缩短，与 sRBP 的结合几乎完全被废除，这表明相互作用的强度在于多烯链区。对 sRBP-TTR 和 sRBP-sRBP 受体相互作用的效力差异表明，这些化合物对负责这两种蛋白质-蛋白质相互作用的 sRBP 两个环的影响不同。
