van Dongen Mallory A, Silpe Justin E, Dougherty Casey A, Kanduluru Ananda Kumar, Choi Seok Ki, Orr Bradford G, Low Philip S, Banaszak Holl Mark M
Department of Chemistry and ⊥Department of Physics, ‡Program in Macromolecular Sciences and Engineering, and §Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan , Ann Arbor, Michigan 48019, United States.
Mol Pharm. 2014 May 5;11(5):1696-706. doi: 10.1021/mp5000967. Epub 2014 Apr 11.
Multivalent conjugation of folic acid has been employed to target cells overexpressing folate receptors. Such polymer conjugates have been previously demonstrated to have high avidity to folate binding protein. However, the lack of a monovalent folic acid-polymer material has prevented a full binding analysis of these conjugates, as multivalent binding mechanisms and polymer-mass mechanisms are convoluted in samples with broad distributions of folic acid-to-dendrimer ratios. In this work, the synthesis of a monovalent folic acid-dendrimer conjugate allowed the elucidation of the mechanism for increased binding between the folic acid-polymer conjugate and a folate binding protein surface. The increased avidity is due to a folate-keyed interaction between the dendrimer and protein surfaces that fits into the general framework of slow-onset, tight-binding mechanisms of ligand/protein interactions.
叶酸的多价共轭已被用于靶向过表达叶酸受体的细胞。此类聚合物共轭物此前已被证明对叶酸结合蛋白具有高亲和力。然而，缺乏单价叶酸 - 聚合物材料阻碍了对这些共轭物的全面结合分析，因为在叶酸与树枝状聚合物比例分布广泛的样品中，多价结合机制和聚合物质量机制相互交织。在这项工作中，单价叶酸 - 树枝状聚合物共轭物的合成使得能够阐明叶酸 - 聚合物共轭物与叶酸结合蛋白表面之间结合增加的机制。亲和力的增加归因于树枝状聚合物与蛋白质表面之间的叶酸键合相互作用，这符合配体/蛋白质相互作用的慢起始、紧密结合机制的一般框架。
