Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation

IF 4.1 2区 化学 Q2 POLYMER SCIENCE Chinese Journal of Polymer Science Pub Date : 2024-08-20 DOI:10.1007/s10118-024-3169-6
Hui Wang, Lin-Lin Xu, Lin-Qi Shi, Ru-Jiang Ma
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Abstract

Amyloidosis is characterized by the deposition of fibrillar aggregates, with a specific peptide or protein as the primary component, in affected tissues or organs. Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis. In this study, a nanochaperone (nChap-NA) was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones. The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA), which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn) moieties and hydrophilic PEG chains. The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn) synergistically work together to effectively trap the amyloid monomer and block its fibrillation site. Insulin and human islet amyloid polypeptide (hIAPP) were used as model proteins to investigate the nanochaperone’s inhibition of amyloid misfolding and fibrillation. It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP, and effectively inhibit their fibrillation. In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation. This study may provide a promising strategy for the prophylactic treatment of amyloidosis.

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基于疏水相互作用和配位的纳米伴侣抑制蛋白质错误折叠和纤维化
淀粉样变性的特征是在受影响的组织或器官中沉积以特定肽或蛋白质为主要成分的纤维状聚集体。淀粉样蛋白纤维的过度增殖和沉积会导致机体功能失调,造成与淀粉样变性相关的致命病理结果。本研究开发了一种纳米伴侣(nChap-NA),通过模拟天然分子伴侣的功能来抑制蛋白质的错误折叠和纤维化。这种纳米伴侣素是由 PEG-b-PCL 和 PCL-b-P(NIPAM-co-AANTA) 两种嵌段共聚物自组装制备而成的,它们具有一个相分离的表面,由带有配位 NTA(Zn) 分子的疏水 PNIPAM 微域和亲水 PEG 链组成。PNIPAM 微域的疏水作用和 NTA(Zn)的配位协同作用,可有效捕获淀粉样单体并阻断其纤维化部位。以胰岛素和人胰岛淀粉样多肽(hIAPP)为模型蛋白,研究了纳米伴侣对淀粉样蛋白错误折叠和纤维化的抑制作用。研究证明,纳米伴侣能稳定被困胰岛素和 hIAPP 的自然构象,并有效抑制其纤维化。体内研究表明,纳米伴侣能有效保持胰岛素的生物活性,并降低 hIAPP 聚合引起的细胞毒性。这项研究为淀粉样变性的预防性治疗提供了一种可行的策略。
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来源期刊
Chinese Journal of Polymer Science
Chinese Journal of Polymer Science 化学-高分子科学
CiteScore
7.10
自引率
11.60%
发文量
218
审稿时长
6.0 months
期刊介绍: Chinese Journal of Polymer Science (CJPS) is a monthly journal published in English and sponsored by the Chinese Chemical Society and the Institute of Chemistry, Chinese Academy of Sciences. CJPS is edited by a distinguished Editorial Board headed by Professor Qi-Feng Zhou and supported by an International Advisory Board in which many famous active polymer scientists all over the world are included. The journal was first published in 1983 under the title Polymer Communications and has the current name since 1985. CJPS is a peer-reviewed journal dedicated to the timely publication of original research ideas and results in the field of polymer science. The issues may carry regular papers, rapid communications and notes as well as feature articles. As a leading polymer journal in China published in English, CJPS reflects the new achievements obtained in various laboratories of China, CJPS also includes papers submitted by scientists of different countries and regions outside of China, reflecting the international nature of the journal.
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