Peroxynitrite scavenger FeTPPS effectively inhibits hIAPP aggregation and protects against amyloid induced cytotoxicity
Peroxynitrite scavenger FeTPPS effectively inhibits hIAPP aggregation and protects against amyloid induced cytotoxicity
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过氧亚硝酸盐清除剂 FeTPPS 有效抑制 hIAPP 聚集并防止淀粉样蛋白诱导的细胞毒性
DOI：
10.1016/j.ijbiomac.2020.06.034
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发表时间：
2020
影响因子：
8.2
通讯作者：
Gao Zhonghong
中科院分区：
文献类型：
--
作者：
Zhang Pengfei;Zeng Lizhen;Gao Wanxia;Li Hailing;Gao Zhonghong
2 型糖尿病 (T2D) 与胰腺 β 细胞功能障碍有关，氧化应激或/和人胰岛淀粉样多肽 (hIAPP) 的聚集可诱导胰腺 β 细胞功能障碍。因此，ONOO−和hIAPP成为T2D治疗的重要靶点。此前，我们发现血红素可能是 hIAPP 聚集的有效抑制剂。然而，血红素通过氧化应激对细胞、组织和器官产生严重的毒性作用，这阻碍了它作为治疗 T2D 的潜在候选药物。 5,10,15,20-四(4-磺基苯基)卟啉三氯化铁(FeTPPS)是一种水溶性血红素衍生物，被认为是一种高效的ONOO−分解催化剂，据报道在包括T2D在内的ONOO−相关疾病中具有巨大的治疗潜力。在这里，我们探讨了 FeTPPS 作为 hIAPP 聚集抑制剂的潜力以及对 hIAPP 聚集的细胞毒性的保护作用。研究发现，FeTPPS 和 hIAPP 之间的相互作用通过稳定 hIAPP 单体和将长原纤维分解成小的寡聚体，显着影响 hIAPP 纤维颤动。此外，与血红素不同，添加 FeTPPS 完全逆转了 hIAPP 诱导的细胞毒性和 ROS 水平，这与其强抑制活性一致。这些结果表明 FeTPPS 可能是治疗 T2D 的有前途的药物。
Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, which can be induced by oxidative stress or/and the aggregation of human islet amyloid polypeptide (hIAPP). Therefore, ONOO−and hIAPP become the crucial targets of T2D treatment. Previously, we found heme could be an effective inhibitor of hIAPP aggregation. However, heme causes serious toxic effects on cells, tissues and organs through oxidative stress, which block it as a potential drug candidate for T2D treatment. 5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron(III) chloride (FeTPPS), a water-soluble derivative of heme, is recognized as a high-efficient ONOO−decomposition catalyst, which is reported to have a great therapeutic potential in ONOO−-related diseases, including T2D. Here, we explored the potentiality of FeTPPS to be an inhibitor of hIAPP aggregation and the protective effects on cytotoxicity of hIAPP aggregation. It was found that the interaction between FeTPPS and hIAPP remarkably affected hIAPP fibrillation by both stabilizing hIAPP monomers and disaggregating the long fibrils into small oligomeric species. Furthermore, unlike heme, the addition of FeTPPS completely reversed the cytotoxicity and ROS level induced by hIAPP, which was consistent with its strong inhibitory activity. These results implied that FeTPPS could be a promising agent for the treatment of T2D.