Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.
Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.
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DOI：
10.1021/ja405239v
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发表时间：
2013-11-06
影响因子：
15
通讯作者：
Ran C
中科院分区：
文献类型：
--
作者：
Zhang X;Tian Y;Li Z;Tian X;Sun H;Liu H;Moore A;Ran C
在这篇文章中，我们首先设计并合成了基于姜黄素的近红外（NIR）荧光成像探针，用于检测可溶性和不溶性淀粉样蛋白β（Aβ）物种，然后设计并合成了一种抑制剂，可以减弱铜诱导的Aβ交联。根据本课题组的研究结果，结合Aβ13-20（HHQKLVFF）片段的疏水/亲水特性和Aβ13-20肽段可能存在的立体位阻相容性，设计并合成了CRANAD-58近红外成像探针。正如预期的那样，CRANAD-58在体外与可溶性和不溶性Aβ物质混合后显示出显著的荧光性质变化。体内近红外成像显示，CRANAD-58能够区分4个月大的转基因和野生型小鼠，该年龄缺乏明显可见的Aβ斑块，Aβ可能处于可溶性形式。在本报告中，根据我们对CRANAD-58与Aβ相互作用机制的有限研究，我们还设计了CRANAD-17来减弱铜诱导的Aβ42交联。众所周知，铜与Aβ肽组氨酸-13和14（H13，H14）上的咪唑配位可以引发Aβ的共价交联。在CRANAD-17中，使用姜黄素支架作为锚定部分，将设计的化合物引导到Aβ的H13和H14附近，并掺入咪唑环以与H13/H14竞争铜结合。SDS-PAGE凝胶电泳和Western blot结果表明，CRANAD-17能够抑制铜诱导的Aβ42交联。这提高了CRANAD-17被考虑用于AD治疗的可能性。
In this article, we first designed and synthesized curcumin-based near infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species, and then an inhibitor that could attenuate crosslinking of Aβ induced by copper. According to our previous results and the possible structural stereo-hindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13–20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild type mice as young as 4-months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. In this report, according to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the crosslinking of Aβ42 induced by copper. It is well known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent crosslinking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.