Dual‐Functional, Multi‐Targeting GNNQQNY‐AIE Conjugates as Amyloid Probes and Amyloid Modulators via Amyloid Cross‐Seeding Principle
Dual‐Functional, Multi‐Targeting GNNQQNY‐AIE Conjugates as Amyloid Probes and Amyloid Modulators via Amyloid Cross‐Seeding Principle
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DOI：
10.1002/adfm.202208022
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发表时间：
2022-09
影响因子：
19
通讯作者：
Yijing Tang;Dong Zhang;Xiong Gong;Jie Zheng
中科院分区：
文献类型：
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作者：
Yijing Tang;Dong Zhang;Xiong Gong;Jie Zheng
淀粉样蛋白聚集与许多神经退行性疾病相关，包括阿尔茨海默病中的淀粉样蛋白-β (Aβ)、II 型糖尿病中的人胰岛淀粉样多肽 (hIAPP) 以及甲状腺髓样癌中的人降钙素 (hCT)。人们已经做出了巨大的努力来开发不同的诊断和预防策略，以早期检测和干预这些致病蛋白聚集体。然而，传统的设计智慧大多局限于具有单一功能（淀粉样蛋白成像或淀粉样蛋白预防）或单一靶向蛋白（Aβ、hIAPP 或 hCT）的分子。在这里，通过将 GNNQQNY (G7) 淀粉样蛋白片段与三苯基乙烯基苯甲酸 (即 G7-TBA) 的 AIE 荧光分子 (即 G7-TBA) 缀合，证明了淀粉样蛋白聚集诱导发射 (AIE) 活性分子的合理设计策略，使 G7-TBA 作为多靶点、双功能淀粉样蛋白探针和淀粉样蛋白调节剂，用于检测、监测和改变三种不同淀粉样蛋白的淀粉样蛋白聚集（Aβ、hIAPP 和 hCT）。 G7-TBA 探针显示出与淀粉样蛋白聚集体的构象特异性结合亲和力，从淀粉样蛋白单体的“关闭”状态（低荧光）切换到水溶液中富含 β 结构的淀粉样蛋白低聚物和原纤维的“打开”状态（高荧光）。 TBA 探针在表面等离振子共振表面上的进一步表面固定可以增强检测灵敏度和对不同聚集阶段形成的淀粉样蛋白聚集体的结合亲和力。 G7-TBA 作为淀粉样蛋白调节剂，能够加速淀粉样蛋白纤维化，并选择性地保护细胞免受 hIAPP 诱导的毒性。 G7-TBA 独特的淀粉样蛋白检测和调节本质上源自 G7 和淀粉样蛋白聚集体之间通过 β 结构相互作用的交叉播种，这远远超过了商业 ThT 和淀粉样蛋白聚集体之间的结合亲和力。淀粉样蛋白-AIE 缀合物的这种设计概念可以作为生物医学应用的多功能和目标探针和/或调节剂进行进一步探索。
Amyloid protein aggregation is associated with many neurodegenerative diseases, including amyloid‐β (Aβ) in Alzheimer disease, human islet amyloid polypeptide (hIAPP) in type II diabetes, and human calcitonin (hCT) in medullary thyroid carcinoma. Significant efforts have been made to develop different diagnostic and prevention strategies for the early detection and intervention of these disease‐causative protein aggregates. However, conventional design wisdoms are mostly limited to the molecules with either single function (amyloid imaging or amyloid prevention) or single targeting protein (Aβ, hIAPP, or hCT). Here, a rational design strategy of an amyloid‐aggregation‐induced emission (AIE)‐active molecule is demonstrated by conjugating an amyloid fragment of GNNQQNY (G7) with an AIE fluorescent molecule of triphenylvinyl benzoic acid (namely, G7‐TBA), making G7‐TBA as multiple‐target, dual‐function, amyloid probes and amyloid modulators for detecting, monitoring, and altering amyloid aggregation of three different amyloid proteins (Aβ, hIAPP, and hCT). G7‐TBA probe shows conformationally specific binding affinities to amyloid aggregates, switching from an “off” state (low fluorescence) for amyloid monomers to an “on” state (high fluorescence) for β‐structure‐rich amyloid oligomers and fibrils in aqueous solution. Further surface immobilization of TBA probes on surface plasmon resonance surfaces allows to amplify detection sensitivity and binding affinity to amyloid aggregates formed at different aggregation stages. G7‐TBA as amyloid modulator enables acceleration of amyloid fibrillization and selectively protects cells from hIAPP‐induced toxicity. The distinct amyloid detection and modulation of G7‐TBA are essentially derived from the cross‐seeding between G7 and amyloid aggregation via β‐structure interaction, which by far exceed the binding affinity between commercial ThT and amyloid aggregates. Such design concepts of amyloid‐AIE conjugates can be further explored as multiple‐function and target probes and/or modulators for biomedical applications.