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Publication Abstract from PubMed

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.

Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4.,Wang Y, Connors R, Fan P, Wang X, Wang Z, Liu J, Kayser F, Medina JC, Johnstone S, Xu H, Thibault S, Walker N, Conn M, Zhang Y, Liu Q, Grillo MP, Motani A, Coward P, Wang Z Bioorg Med Chem Lett. 2014 Jul 1;24(13):2885-91. doi: 10.1016/j.bmcl.2014.04.089., Epub 2014 May 2. PMID:24835984^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.