Department of Medicine, Columbia University, 630 W. 168th St., Box 84, New York, NY, 10032, USA.
Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
Chemistry. 2018 Jul 25;24(42):10646-10652. doi: 10.1002/chem.201801388. Epub 2018 Jul 4.
High-relaxivity protein-complexes of Gd are being pursued as MRI contrast agents in hope that they can be used at much lower doses that would minimize toxic-side effects of Gd release from traditional contrast agents. We construct here a new type of protein-based MRI contrast agent, a proteinaceous cage based on a stable insulin hexamer in which Gd is captured inside a water filled cavity. The macromolecular structure and the large number of "free" Gd coordination sites available for water binding lead to exceptionally high relaxivities per one Gd ion. The Gd slowly diffuses out of this cage, but this diffusion can be prevented by addition of ligands that bind to the hexamer. The ligands that trigger structural changes in the hexamer, SCN , Cl and phenols, modulate relaxivities through an outside-in signaling that is allosterically transduced through the protein cage. Contrast-o-phores based on protein-caged metal ions have potential to become clinical contrast agents with environmentally-sensitive properties.
我们正在探索具有高弛豫率的 Gd 蛋白复合物，希望将其用作磁共振成像 (MRI) 造影剂，以降低传统造影剂 Gd 释放所带来的毒性副作用。在这里，我们构建了一种新型基于蛋白质的 MRI 造影剂，这是一种基于稳定胰岛素六聚体的蛋白笼，其中 Gd 被捕获在充满水的空腔内。这种大分子结构和大量可用于结合水分子的“游离”Gd 配位位点导致每个 Gd 离子的弛豫率非常高。Gd 会从笼中缓慢扩散出来，但通过添加与六聚体结合的配体可以阻止这种扩散。触发六聚体结构变化的配体，如 SCN 、Cl 和酚类，通过通过蛋白笼变构传递的外-内信号来调节弛豫率。基于蛋白笼化金属离子的造影剂有可能成为具有环境敏感性的临床造影剂。
