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.
Dalton Trans. 2023 Sep 19;52(36):12677-12685. doi: 10.1039/d3dt02187d.
Platinum (Pt)(II) square planar complexes are well-known anticancer drugs whose Mechanism of Action (MOA) are finely tuned by the polar, hydrophobic and aromatic features of the ligands. In the attempt to translate this tunability to the identification of potential neurodrugs, herein, four Pt(II) complexes were investigated in their ability to modulate the self-aggregation processes of two amyloidogenic models: Sup35p and NPM1 peptides. In particular, phenanthriplatin revealed the most efficient agent in the modulation of amyloid aggregation: through several biophysical assays, as Thioflavin T (ThT), electrospray ionization mass spectrometry (ESI-MS) and ultraviolet-visible (UV-vis) absorption spectroscopy, this complex revealed able to markedly suppress aggregation and to disassemble small soluble aggregates. This effect was due to a direct coordination of phenanthriplatin to the amyloid, with the loss of several ligands and different stoichiometries, by the formation of π-π and π-cation interactions as indicated from molecular dynamic simulations. Presented data support a growing and recent approach concerning the repurposing of metallodrugs as potential novel neurotherapeutics.
铂（II）正方形平面配合物是众所周知的抗癌药物，其作用机制（MOA）通过配体的极性、疏水性和芳香性特征进行精细调节。为了将这种可调节性转化为潜在神经药物的鉴定，本文研究了四个 Pt(II) 配合物在调节两种淀粉样蛋白模型（Sup35p 和 NPM1 肽）的自聚集过程中的能力。特别是，菲咯啉铂显示出在调节淀粉样蛋白聚集方面最有效的试剂：通过几种生物物理测定，如硫黄素 T（ThT）、电喷雾电离质谱（ESI-MS）和紫外可见（UV-vis）吸收光谱，该配合物显示出能够显著抑制聚集并解聚小的可溶性聚集体。这种效果是由于菲咯啉铂与淀粉样蛋白的直接配位，通过形成π-π 和 π-阳离子相互作用，导致几个配体的损失和不同的化学计量比，如分子动力学模拟所示。提出的数据支持了一种越来越多的新兴方法，即将金属药物重新用作潜在的新型神经治疗药物。
