Inhibition of Beta-Amyloid Peptide Aggregation by Multifunctional Carbazole-Based Fluorophores
Inhibition of Beta-Amyloid Peptide Aggregation by Multifunctional Carbazole-Based Fluorophores
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DOI：
10.1002/anie.201104150
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Wong, Man Shing
中科院分区：
文献类型：
--
作者：
Yang, Wanggui;Wong, Yi;Wong, Man Shing
阿尔茨海默病（AD）影响全球超过2400万人，导致痴呆、认知障碍和记忆丧失。[1]一般认为，由淀粉样前体蛋白裂解形成的40和42个残基的β淀粉样（Aβ）肽在AD发病机制中起关键作用，其中单体Aβ肽通过可溶性寡聚体中间体聚集成不溶性斑块相关淀粉样纤维，将诱导级联反应，最终导致神经元细胞死亡。[2]Aβ的原纤维形成是一个两阶段的过程，包括成核和延伸阶段，在此期间，Aβ肽经历构象转变，从主要的非结构化形式转变为富含β-片层的结构，该结构通过端对端退火和沃尔什及其同事提出的侧向缔合机制沿原纤维的长轴沿着堆叠。[3]虽然尚未出现解释致病性寡聚体组装的共识机制，但开发干扰Aβ肽聚集的脑穿透剂，从而抑制神经毒性寡聚体和原纤维的形成，是治疗AD的有吸引力的主要方法。多年来，已经进行了许多努力来开发有效的原纤维抑制剂和β-折叠破坏剂，其可以防止Aβ单体聚集成低聚物和原纤维构象。[4]例如，scyllo cyclohexanehexol已被开发为Aβ聚集抑制剂，目前正在进行II期临床试验。[4b]多酚和抗氧化剂也被报道可以抑制Aβ纤维形成，其中一些目前正在进行临床试验。[5]各种尺寸和疏水性的聚合物纳米颗粒已被用于将Aβ肽吸附到颗粒表面上以控制其原纤维形成动力学。[6]我们之前的工作已经证明，配体功能化的量子点可以通过阻断种子原纤维或单体上的活性位点来淬灭Aβ（1-40）肽的成核和延伸。[7]除了纳米材料，过渡金属络合物，如铂（II），[8]双核钌（II）铂（II），[9]铱（III）和铑（III）溶剂合物[10]已被用作通过与肽的氨基酸残基形成配位键的Aβ聚集的有效抑制剂。为了在临床上有用，这些抑制剂或β-破坏剂还必须具有血脑屏障（BBB）渗透性、低神经毒性和高体内稳定性。然而，这些关键性质尚未在这些抑制剂或β-破坏剂中得到证实。最近，咔唑基菁荧光团已被证明是双链DNA的高灵敏度荧光发光探针和双光子激发生物成像的双光子吸收染料。[11]最近，已经发现单花青荧光团也与Aβ肽结合，伴随着强荧光增强（> 80倍）。这一观察结果为我们开发新的功能分子提供了一个先导结构，用于直接成像Aβ纤维形成的动力学，更重要的是，用于抑制Aβ肽的聚集。本文报道了一系列新的咔唑基菁荧光团的结构-活性研究，这些荧光团在与Aβ肽和原纤维结合时表现出强烈的荧光增强。使用各种官能化的吡啶鎓或喹啉鎓接受部分，这些花青染料的功能性质（包括生物物理性质、Aβ结合性质、细胞毒性性质和BBB渗透性性质）可以被修饰和微调。其中一种荧光团，即...
Alzheimer s disease (AD) affects more than 24million people worldwide, leading to dementia, cognitive impairment and memory loss.[1] It is commonly accepted that betaamyloid (Aβ) peptides of 40 and 42 residues formed from the cleavage of amyloid precursor protein play a key role in AD pathogenesis where the aggregation of monomeric Aβ peptides to insoluble plaque-associated amyloid fibrils via soluble oligomeric intermediates would induce a cascade of events that eventually lead to the death of neuronal cells.[2] The fibrillogenesis of Aβ is a two-phase process, involving nucleation and elongation phases, during which the Aβ peptides undergo conformational transition from predominantly unstructured form to a β-sheet-rich structure which stacks along the long axis of the fibrils through end-to-end annealing and the lateral association mechanism proposed by Walsh and co-workers.[3] Although a consensus mechanism to explain the pathogenic oligomeric assembly has yet to emerge, the development of a brain-penetrating agent that interferes with the aggregation of the Aβ peptides, thus inhibiting the formation of the neurotoxic oligomers and fibrils, is an attractive primary approach to the treatment of AD. Over the years, there have been numerous efforts to develop effective fibril inhibitors and β-sheet breakers that can prevent the aggregation of Aβ monomers into oligomeric and fibrillar conformations.[4] For instance, scyllo cyclohexanehexol has been developed as an Aβ-aggregation inhibitor and is currently under phase II clinical trial.[4b] Polyphenols and antioxidants have also been reported to inhibit Aβ fibrillogenesis and some are currently under clinical trials.[5] Polymeric nanoparticles of various sizes and hydrophobicities have been used to adsorb the Aβ peptide onto the particle surface to control its fibrillogenesis kinetics.[6] Our previous work has demonstrated that ligand-functionalized quantum dots can quench both the nucleation and elongation of the Aβ (1–40) peptide by blocking active sites on the seed fibrils or monomers.[7] In addition to nanomaterials, transition-metal complexes, such as platinum (II),[8] binuclear ruthenium (II) platinum (II),[9] iridium (III) and rhodium (III) solvato [10] complexes have been utilized as potent inhibitors of Aβ aggregation by the formation of coordinative bond with amino acid residues of the peptides. To be clinically useful, these inhibitors or β-breakers must also have blood–brain barrier (BBB) permeability, low neurotoxicity, and high in vivo stability. However, these crucial properties have yet to be demonstrated in these inhibitors or β-breakers. Recently, carbazole-based cyanine fluorophores have been shown to be a highly sensitive fluorescent light-up probe for double-stranded DNA and two-photon absorption dyes for two-photon excited bioimaging.[11] More recently, the mono-cyanine fluorophores have been found to bind to the Aβ peptide as well, concomitant with strong fluorescence enhancement (> 80 fold). This observation has provided us with a lead structure to develop novel functional molecules for a direct imaging of the dynamics of Aβ fibrillogenesis and, more importantly, for inhibiting the aggregation of Aβ peptides. Herein, a structure–activity investigation of a novel series of carbazole-based cyanine fluorophores that exhibit strong fluorescence enhancement upon binding with Aβ peptides and fibrils is reported. Using variously functionalized pyridinium or quinolinium accepting moieties, the functional properties, which include photophysical, Aβ-binding, cytotoxic, and BBB permeability properties, of these cyanine dyes can be modified and fine-tuned. One of these fluorophores, namely …