Institute of Organic Chemistry, Johannes Gutenberg-University, Duesbergweg 10-14, 55128, Mainz, Germany.
Sanofi-Aventis, Deutschland, GmbH, R&D, IDD, Industriepark Höchst, 65926, Frankfurt am Main, Germany.
Angew Chem Int Ed Engl. 2018 Jan 22;57(4):1044-1048. doi: 10.1002/anie.201710437. Epub 2017 Dec 27.
A single high-affinity fatty acid binding site in the important human transport protein serum albumin (HSA) is identified and characterized using an NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl)-C fatty acid. This ligand exhibits a 1:1 binding stoichiometry in its HSA complex with high site-specificity. The complex dissociation constant is determined by titration experiments as well as radioactive equilibrium dialysis. Competition experiments with the known HSA-binding drugs warfarin and ibuprofen confirm the new binding site to be different from Sudlow-sites I and II. These binding studies are extended to other albumin binders and fatty acid derivatives. Furthermore an X-ray crystal structure allows locating the binding site in HSA subdomain IIA. The knowledge about this novel HSA site will be important for drug depot development and for understanding drug-protein interaction, which are important prerequisites for modulation of drug pharmacokinetics.
一个单高亲和力的脂肪酸结合位点在重要的人血白蛋白（HSA）运输蛋白被鉴定和特征使用 NBD（7-硝基苯-2-恶唑-1,3-二唑-4-基）-C 脂肪酸。这种配体在其 HSA 复合物中表现出 1:1 的结合化学计量比，具有高特异性。复合物解离常数通过滴定实验以及放射性平衡透析来确定。与已知的 HSA 结合药物华法林和布洛芬的竞争实验证实了新的结合位点与 Sudlow 位点 I 和 II 不同。这些结合研究扩展到其他白蛋白结合物和脂肪酸衍生物。此外，X 射线晶体结构允许在 HSA 亚结构域 IIA 中定位结合位点。关于这个新的 HSA 位点的知识对于药物库的开发和理解药物-蛋白质相互作用是非常重要的，这是调节药物药代动力学的重要前提。
