Heme prevents highly amyloidogenic human calcitonin (hCT) aggregation: A potential new strategy for the clinical reuse of hCT
Heme prevents highly amyloidogenic human calcitonin (hCT) aggregation: A potential new strategy for the clinical reuse of hCT
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血红素可防止高度淀粉样蛋白生成的人降钙素 (hCT) 聚集：hCT 临床再利用的潜在新策略
DOI：
10.1016/j.jinorgbio.2019.03.026
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发表时间：
2019
影响因子：
3.9
通讯作者：
Gao Zhonghong
中科院分区：
文献类型：
--
作者：
Ye Huixian;Zhou Jun;Li Hailing;Gao Zhonghong
不可逆的聚集可以极大地限制基于肽的药物的生物利用度和治疗活性。因此，肽原纤化是生物技术药物开发的一个很好的挑战。人降钙素（hCT）是这样一种肽激素，已知其具有低钙作用，但由于高聚集倾向而具有有限的药学潜力。因此，hCT不是临床实践中广泛使用的制剂。尽管如此，当纤颤被有效抑制时，hCT似乎仍然是临床治疗的理想靶点，因为hCT的替代品可以刺激患者中不期望的免疫应答并引起副作用。有趣的是，血红素是许多生命的重要组成部分，并已显示出对一些淀粉样蛋白生成肽聚集的强烈抑制作用。在这里，我们证明它可能是一个最合适的，安全的，生物相容性的小分子抑制剂对hCT聚集，从而提高其活性时，指导药物肽在临床治疗。在这项工作中，我们发现血红素能够可逆地与hCT结合，形成具有中等结合常数（9.17 × 106 M −1）的血红素-hCT复合物，并显著抑制hCT的聚集，这可能是通过血红素与其结合实现的，阻断了hCT原纤维聚集所必需的β-折叠结构组装。同时，血红素-hCT复合物在24 h孵育时间后在降低小鼠血钙水平方面显示出比hCT本身增强的生物活性。本研究可能为野生型hCT在临床治疗中的再利用提供新的策略。
Irreversible aggregation can extremely limit the bioavailability and therapeutic activity of peptide-based drugs. Thus, peptide fibrillation is an excellent challenge for biotechnological drug development. Human calcitonin (hCT) is such a peptide hormone known for its hypocalcaemic effect but has limited pharmaceutical potential due to a high tendency to aggregate. hCT is therefore not widely used preparation in clinical practice. Nonetheless, hCT seems to be still an ideal target for clinical therapy when fibrillation is effectively inhibited, because the alternatives of hCT can stimulate undesirable immune responses in patients and cause side effects. Interestingly, heme is an essential component for many livings and has been shown a strong inhibitory effect on some amyloidogenic peptides aggregation. Here we demonstrate that it may be a most suitable, safe, biocompatible small molecule inhibitor on hCT aggregation, and thereby improving its activity when guiding the drug peptide in clinical therapeutics. In this work, we found that heme was able to reversibly bind with hCT to form a heme-hCT complex with a moderate binding constant (9.17 × 106M−1) and significantly suppress the aggregation of hCT probably accomplished by heme binding to it, blocking the β-sheet structure assembly which is essential in hCT fibril aggregation. Meanwhile, the heme-hCT complexes showed enhanced bioactivity compared to hCT itself after a 24 h incubation time in reducing blood calcium levels in mice. This study may develop a new strategy to reuse the wild-type hCT in clinical therapeutics.