The discovery of aggregation inhibitors and the elucidation of their mechanism of action are key in the quest to mitigate the toxic consequences of amyloid formation. We have previously characterized the antiamyloidogenic mechanism of action of sodium phtalocyanine tetrasulfonate ([Na₄(H₂PcTS)]) on α-Synuclein (αS), demonstrating that specific aromatic interactions are fundamental for the inhibition of amyloid assembly. Here we studied the influence that metal preferential affinity and peripheral substituents may have on the activity of tetrapyrrolic compounds on αS aggregation. For the first time, our laboratory has extended the studies in the field of the bioinorganic chemistry and biophysics to cellular biology, using a well-established cell-based model to study αS aggregation. The interaction scenario described in our work revealed that both N- and C-terminal regions of αS represent binding interfaces for the studied compounds, a behavior that is mainly driven by the presence of negatively or positively charged substituents located at the periphery of the macrocycle. Binding modes of the tetrapyrrole ligands to αS are determined by the planarity and hydrophobicity of the aromatic ring system in the tetrapyrrolic molecule and/or the preferential affinity of the metal ion conjugated at the center of the macrocyclic ring. The different capability of phthalocyanines and meso-tetra (N-methyl-4-pyridyl) porphine tetrachloride ([H₂PrTPCl₄]) to modulate αS aggregation in vitro was reproduced in cell-based models of αS aggregation, demonstrating unequivocally that the modulation exerted by these compounds on amyloid assembly is a direct consequence of their interaction with the target protein.

中文翻译：

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金属配位和外围取代可调节环状四吡咯对αS聚集的活性：一项基于结构和细胞的研究。

聚集抑制剂的发现及其作用机理的阐明是寻求减轻淀粉样蛋白形成的毒性后果的关键。我们先前已表征了酞菁四磺酸钠（[Na ₄（H ₂PcTS）]）在α-突触核蛋白（αS）上，表明特定的芳香相互作用是抑制淀粉样蛋白组装的基础。在这里，我们研究了金属优先亲和力和外围取代基可能对四吡咯化合物对αS聚集的活性的影响。我们的实验室首次使用已建立的基于细胞的模型研究αS聚集，将生物无机化学和生物物理学领域的研究扩展到细胞生物学。在我们的工作中描述的相互作用情况表明，αS的N端和C端区域均代表所研究化合物的结合界面，这一行为主要是由位于大环外围的带负电荷或带正电荷的取代基驱动的。四吡咯配体与αS的结合方式取决于四吡咯分子中芳环系统的平面性和疏水性和/或共轭在大环中心的金属离子的优先亲和力。酞菁和内消旋四（在基于细胞的αS聚集模型中复制了N-甲基-4-吡啶基）四氯化萘卟啉（[H ₂ PrTPCl ₄ ]），明确表明这些化合物对淀粉样蛋白组装的调控是直接的与靶蛋白相互作用的结果。