School of Chemistry and Chemical Engineering, Key Laboratory of Jiangxi Province for Special Optoelectronic Artificial Crystal Materials, Jinggangshan University, Ji'an, Jiangxi 343009, P. R. China.
Department of Experimental Medical Science, Faculty of Medicine, Lund University, 22100, Lund, Sweden.
Dalton Trans. 2024 Oct 22;53(41):17036-17049. doi: 10.1039/d4dt02214a.
Human calcitonin (hCT) is an endogenous polypeptide commonly employed in treating bone resorption-related illnesses, but its clinical application is limited due to its high aggregation tendency. Metalloporphyrins are effective in suppressing amyloid fibrillation, positioning them as potential drug candidates for amyloidogenic disorders like Alzheimer's and type 2 diabetes. In this work, we investigated the effects of Fe(III) -tetra(4-sulfonatophenyl)porphine chloride (FeTPPS), a highly efficient ONOO decomposition catalyst, on hCT aggregation. Our findings reveal that FeTPPS effectively precludes hCT fibrillation by stabilizing the monomers and delaying the structural transition from α-helix bundles to β-sheet-rich aggregates. The macrocyclic ring of FeTPPS plays a significant role in disrupting hCT self-associations. Among various porphyrin analogs, those with an iron center and negatively charged peripheral substituents exhibit a stronger inhibitory effect on hCT aggregation. Spectroscopic analyses and computational simulations indicate that FeTPPS binds to hCT's core aggregation region complexation with His20 in a 1 : 1 molar ratio. Hydrophobic interaction, hydrogen bonding, and π-π stacking with the residues involving Tyr12, Phe19, and Ala26 also contribute to the interactions. Collectively, our study provides a promising approach for developing novel hCT drug formulations and offers theoretical guidance for designing metalloporphyrin-based inhibitors for various amyloidosis conditions.
人降钙素 (hCT) 是一种内源性多肽，常用于治疗与骨吸收相关的疾病，但由于其高度聚集倾向，其临床应用受到限制。金属卟啉在抑制淀粉样纤维形成方面非常有效，因此它们可能成为治疗阿尔茨海默病和 2 型糖尿病等淀粉样变性疾病的潜在药物候选物。在这项工作中，我们研究了 Fe(III)-四(4-磺基苯基)卟啉氯化物 (FeTPPS) 的作用，FeTPPS 是一种高效的 ONOO 分解催化剂，对 hCT 聚集的影响。我们的研究结果表明，FeTPPS 通过稳定单体和延迟从 α-螺旋束到富含 β-折叠的聚集物的结构转变，有效地阻止了 hCT 的纤维形成。FeTPPS 的大环在破坏 hCT 自组装中起着重要作用。在各种卟啉类似物中，那些具有铁中心和带负电荷的外围取代基的卟啉类似物对 hCT 聚集的抑制作用更强。光谱分析和计算模拟表明，FeTPPS 与 hCT 的核心聚集区域结合，与 His20 以 1:1 的摩尔比形成复合物。与 Tyr12、Phe19 和 Ala26 等残基的疏水相互作用、氢键和 π-π 堆积也有助于相互作用。总的来说，我们的研究为开发新型 hCT 药物制剂提供了一种有前途的方法，并为设计基于金属卟啉的各种淀粉样变性抑制剂提供了理论指导。
