Institute of Biopharmaceutical Research, Liaocheng University, Liaocheng, Shandong 252000, China.
Department of Chemistry, University of Massachusetts Lowell, 1 University Avenue, Lowell, Massachusetts 01854, United States.
Biomacromolecules. 2021 May 10;22(5):1910-1920. doi: 10.1021/acs.biomac.0c01802. Epub 2021 Apr 12.
Misfolding proteins could form oligomers or amyloid fibers, which can cause a variety of amyloid-associated diseases. Thus, the inhibition of protein misfolding and fibrillation is a promising way to prevent and treat these diseases. Captopril (CAP) is an angiotensin-converting enzyme inhibitor (ACEI) that is widely used to treat diseases such as hypertension and heart failure. In this study, we found that CAP inhibits human lysozyme (HL) fibrillation through the combination techniques of biophysics and biochemistry. The data obtained by thioflavin-T (ThT) and Congo red (CR) assays showed that CAP hindered the aggregation of HL amyloid fibrils by reducing the β-sheet structure of HL amyloid, with an IC value of 34.75 ± 1.23 μM. Meanwhile, the particle size of HL amyloid decreased sharply in a concentration-dependent approach after CAP treatment. According to the visualization of atomic force microscopy (AFM) and transmission electron microscopy (TEM), we verified that in the presence of CAP, the needle-like fibers of HL amyloid were significantly reduced. In addition, CAP incubation dramatically improved the cell survival rate exposed to HL fibers. Our studies also revealed that CAP could form hydrogen bonds with amino acid residues of Glu 35 and Ala 108 in the binding pocket of HL, which help in maintaining the α-helical structure of HL and then prevent the formation of amyloid fibrillation. It can be concluded that CAP has antiamyloidogenic activity and a protective effect on HL amyloid cytotoxicity.
错误折叠的蛋白质可能会形成寡聚物或淀粉样纤维，从而导致多种淀粉样相关疾病。因此，抑制蛋白质错误折叠和纤维化是预防和治疗这些疾病的一种有前途的方法。卡托普利 (CAP) 是一种血管紧张素转换酶抑制剂 (ACEI)，广泛用于治疗高血压和心力衰竭等疾病。在这项研究中，我们发现 CAP 通过生物物理和生物化学结合技术抑制人溶菌酶 (HL) 的纤维化。通过硫黄素-T (ThT) 和刚果红 (CR) 测定获得的数据表明，CAP 通过减少 HL 淀粉样纤维的 β-折叠结构来抑制 HL 淀粉样聚集物的聚集，IC 值为 34.75 ± 1.23 μM。同时，HL 淀粉样纤维的粒径在 CAP 处理后呈浓度依赖性急剧下降。根据原子力显微镜 (AFM) 和透射电子显微镜 (TEM) 的可视化，我们验证了在 CAP 的存在下，HL 淀粉样的针状纤维明显减少。此外，CAP 孵育可显著提高暴露于 HL 纤维的细胞存活率。我们的研究还表明，CAP 可以与 HL 结合口袋中 Glu 35 和 Ala 108 氨基酸残基形成氢键，有助于维持 HL 的α-螺旋结构，从而防止淀粉样纤维形成。可以得出结论，CAP 具有抗淀粉样变性活性和对 HL 淀粉样纤维细胞毒性的保护作用。
