The deposition of human islet amyloid polypeptide (hIAPP) is considered as a causative factor of type 2 diabetes mellitus (T2DM). Developing effective inhibitors against the fibril formation of hIAPP is a potential way to treat T2DM. Recent studies indicate that various metal complexes including homo-binuclear Ru complexes can inhibit hIAPP aggregation. Hetero-multinuclear PtRu metal complexes exhibit multiple bioactivities, but their roles in reversing amyloidosis remain unclear. In this work, we synthesized and identified a new hetero-binuclear PtRu metal complex Na{[RuCl₄(DMSO-S)](bpy)[Pt(DMSO-S)Cl₂]} (bpy: 4,4′-bipyridyl). We studied the inhibitory effect of the compound on hIAPP aggregation together with K{[RuCl₄(DMSO-S)](pyz)[Pt (DMSO-S)Cl₂]} (pyz: pyrazine) through diverse biophysical methods. Results showed that two PtRu metal complexes can remarkably reverse hIAPP aggregation and scatter the fibrils into nanoscale particles. Thermodynamic and spectrometric studies revealed that the binding of metal complexes with hIAPP was a spontaneous, enthalpy-driven process resulting from the predominant hydrophobic interaction and metal coordination. Two hetero-binuclear PtRu metal complexes showed stronger binding affinity and better inhibitory effects against peptide fibril formation than homo-binuclear Ru complexes and corresponding mononuclear Ru complexes. The compounds also regulated the peptide-induced cytotoxicity against Insulinoma β-cells and significantly increased the cell viability. This work shed light on a potential strategy for designing hetero-multinuclear metal complexes against amyloidosis-related diseases.

人胰岛淀粉样多肽（hIAPP）的沉积被认为是2型糖尿病（T2DM）的病因。开发针对hIAPP的原纤维形成的有效抑制剂是治疗T2DM的潜在方法。最近的研究表明，包括同核双核Ru配合物在内的各种金属配合物均可以抑制hIAPP聚集。杂多核Pt Ru金属配合物具有多种生物活性，但它们在逆转淀粉样变性中的作用仍不清楚。在这项工作中，我们合成并鉴定了新的杂双核Pt Ru金属配合物Na {[RuCl ₄（DMSO-S）]（bpy）[Pt（DMSO-S）Cl ₂ ]}（bpy：4,4'-联吡啶）。我们研究了该化合物与K {[RuCl ₄（DMSO-S）]（pyz）[Pt（DMSO-S）Cl ₂ ]}（pyz：吡嗪）通过多种生物物理方法。结果表明，两种Pt Ru金属配合物可以显着逆转hIAPP聚集并将原纤维分散成纳米级颗粒。热力学和光谱学研究表明，金属配合物与hIAPP的结合是自发的，由焓驱动的过程，这是由主要的疏水相互作用和金属配位导致的。两个异双核铂钌金属配合物比同核双核钌配合物和相应的单核钌配合物表现出更强的结合亲和力和对肽原纤维形成的更好抑制作用。这些化合物还调节了肽诱导的针对胰岛素瘤β细胞的细胞毒性，并显着提高了细胞活力。这项工作阐明了设计针对淀粉样变性相关疾病的杂多核金属配合物的潜在策略。