Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
Department of Chemical, Materials, and Industrial Production Engineering (DICMaPI), University of Naples Federico II, 80125 Naples, Italy.
Inorg Chem. 2023 Jul 3;62(26):10470-10480. doi: 10.1021/acs.inorgchem.3c01522. Epub 2023 Jun 20.
Neurodegenerative diseases are often associated with an uncontrolled amyloid aggregation. Hence, many studies are oriented to discover new compounds that are able to modulate self-recognition mechanisms of proteins involved in the development of these pathologies. Herein, three metal-complexes able to release carbon monoxide (CORMs) were analyzed for their ability to affect the self-aggregation of the amyloidogenic fragment of nucleophosmin 1, corresponding to the second helix of the three-helix bundle located in the C-terminal domain of the protein, i.e., NPM1, peptide. These complexes were two cymantrenes coordinated to the nucleobase adenine () and to the antibiotic ciprofloxacin () and a Re(I)-compound containing 1,10-phenanthroline and 3-CCCHNHCOCHCH-6-bromo-chromone as ligands (). Thioflavin T (ThT) assay, UV-vis absorption and fluorescence spectroscopies, scanning electron microscopy (SEM), and electrospray ionization mass spectrometry (ESI-MS) indicated that the three compounds have different effects on the peptide aggregation. and act as aggregating agents. induces the formation of NPM1 fibers longer and stiffer than that formed by NPM1 alone; irradiation of complexes speeds the formation of fibers that are more flexible and thicker than those found without irradiation. induces the formation of longer fibers, although slightly thinner in diameter. Conversely, acts as an antiaggregating agent. Overall, these results indicate that metal-based CORMs with diverse structural features can have a different effect on the formation of amyloid fibers. A proper choice of ligands attached to metal can allow the development of metal-based drugs with potential application as antiamyloidogenic agents.
神经退行性疾病通常与不受控制的淀粉样蛋白聚集有关。因此，许多研究都致力于发现能够调节参与这些病理发展的蛋白质自我识别机制的新化合物。在此，分析了三种能够释放一氧化碳 (CORM) 的金属配合物，以研究它们影响核磷蛋白 1 淀粉样片段自聚集的能力，该片段对应于位于蛋白质 C 末端结构域的三螺旋束的第二个螺旋，即核磷蛋白 1 肽。这些配合物是两个 cymantrenes 与碱基腺嘌呤 () 和抗生素环丙沙星 () 配位，以及一个含有 1,10-菲咯啉和 3-CCCHNHCOCHCH-6-溴色酮作为配体的 Re(I)-化合物 ()。硫黄素 T (ThT) 测定、紫外-可见吸收光谱、荧光光谱、扫描电子显微镜 (SEM) 和电喷雾电离质谱 (ESI-MS) 表明，这三种化合物对肽聚集有不同的影响。和 作为聚集剂。诱导形成的 NPM1 纤维比单独的 NPM1 形成的纤维更长、更硬；复合物的辐照加速了纤维的形成，形成的纤维比没有辐照时更灵活且更厚。诱导形成更长的纤维，尽管直径略细。相反，作为抗聚集剂。总的来说，这些结果表明，具有不同结构特征的基于金属的 CORM 可以对淀粉样纤维的形成产生不同的影响。与金属连接的配体的适当选择可以允许开发具有作为抗淀粉样形成剂的潜在应用的基于金属的药物。
