Conformational-specific self-assembled peptides as dual-mode, multi-target inhibitors and detectors for different amyloid proteins
Conformational-specific self-assembled peptides as dual-mode, multi-target inhibitors and detectors for different amyloid proteins
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DOI：
10.1039/d1tb02775a
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发表时间：
2022-01-31
影响因子：
7
通讯作者：
Zheng，Jie
中科院分区：
文献类型：
--
作者：
Ren，Baiping;Tang，Yijing;Zheng，Jie
预防和检测错误折叠的淀粉样蛋白及其富含β结构的聚集体是治疗和诊断阿尔茨海默病(AD)和II型糖尿病(T2D)等神经退行性疾病的两种有前途但不同的(前)临床策略。传统的策略阻止设计同时具有淀粉样蛋白抑制和检测功能的新药物分子。在这里，我们提出了一种“类似-作用-类似”的设计原则来重新设计一系列新的自组装肽(SAP)，使它们能够与构象相似的β-Sheet基序Aβ(与AD相关)和hIAPP(与T2D相关)特异地相互作用。来自硫代黄素、原子力显微镜、圆二色谱和细胞分析的集体体外实验数据表明，SAP具有两个综合功能：(I)淀粉样蛋白抑制可阻止A-β和hIAPP聚集34-61%，并将其诱导的细胞毒性降低7.6-35.4%；(Ii)淀粉样蛋白传感使用基于SAP的纸质传感器和SPR传感器早期检测有毒的A-β和hIAPP聚集体。SAP中淀粉样蛋白抑制和检测的存在源于淀粉样蛋白聚集体和SAP之间的强烈分子相互作用，从而为扩展SAP和其他具有淀粉样蛋白抑制和检测功能的设计的新治疗潜力提供了新的多靶点模型。
Prevention and detection of misfolded amyloid proteins and their β-structure-rich aggregates are the two promising but different (pre)clinical strategies to treat and diagnose neurodegenerative diseases including Alzheimer's diseases (AD) and type II diabetes (T2D). Conventional strategies prevent the design of new pharmaceutical molecules with both amyloid inhibition and detection functions. Here, we propose a “like-interacts-like” design principle to de novo design a series of new self-assembling peptides (SAPs), enabling them to specifically and strongly interact with conformationally similar β-sheet motifs of Aβ (association with AD) and hIAPP (association with T2D). Collective in vitro experimental data from thioflavin (ThT), atomic force microscopy (AFM), circular dichroism (CD), and cell assay demonstrate that SAPs possess two integrated functions of (i) amyloid inhibition for preventing both Aβ and hIAPP aggregation by 34–61% and reducing their induced cytotoxicity by 7.6–35.4% and (ii) amyloid sensing for early detection of toxic Aβ and hIAPP aggregates using in-house SAP-based paper sensors and SPR sensors. The presence of both amyloid inhibition and detection in SAPs stems from strong molecular interactions between amyloid aggregates and SAPs, thus providing a new multi-target model for expanding the new therapeutic potentials of SAPs and other designs with built-in amyloid inhibition and detection functions.