کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10591848 | 981767 | 2014 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
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چکیده انگلیسی
Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 13, 1 July 2014, Pages 2885-2891
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 13, 1 July 2014, Pages 2885-2891
نویسندگان
Yingcai Wang, Richard Connors, Pingchen Fan, Xiaodong Wang, Zhongyu Wang, Jiwen Liu, Frank Kayser, Julio C. Medina, Sheree Johnstone, Haoda Xu, Stephen Thibault, Nigel Walker, Marion Conn, Ying Zhang, Qingxiang Liu, Mark P. Grillo, Alykhan Motani,