Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide.
Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide.
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DOI：
10.1021/ja210588m
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发表时间：
2012-04-18
影响因子：
15
通讯作者：
Mirica, Liviu M.
中科院分区：
文献类型：
--
作者：
Sharma, Anuj K.;Pavlova, Stephanie T.;Kim, Jaekwang;Finkelstein, Darren;Hawco, Nicholas J.;Rath, Nigam P.;Kim, Jungsu;Mirica, Liviu M.
铜、锌离子与β淀粉样蛋白（Aβ）的异常相互作用在阿尔茨海默病（AD）的发病机制中起重要作用。使用化学试剂破坏这些金属-肽相互作用作为对抗这种不治之症的治疗策略具有相当大的希望。本文报道了两种含有淀粉样蛋白结合和金属螯合分子基序的双功能化合物（BFC）L1和L2。L1和L2对Cu 2+和Zn 2+都表现出高稳定常数，因此是这些金属离子的良好螯合剂。此外，L1和L2对Aβ种类显示出强亲和力。通过ThT荧光、非变性凝胶电泳/蛋白质印迹和透射电子显微镜（TEM）观察到，这两种化合物都是金属介导的Aβ42肽聚集的有效抑制剂，并促进淀粉样纤维的解聚。有趣的是，在存在金属离子和BFC的情况下，可溶性Aβ42寡聚体的形成导致细胞毒性增加。这些结果表明，对于Aβ42肽-与Aβ40肽相反，由于形成神经毒性可溶性Aβ42寡聚体，先前采用的抑制Aβ聚集和促进淀粉样蛋白原纤维解聚的策略可能不是开发潜在AD治疗剂的最佳策略。
Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer’s disease (AD). Disruption of these metal–peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu2+ and Zn2+ and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal–mediated aggregation of the Aβ42 peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ42 oligomers in presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ42 peptide – in contrast to the Aβ40 peptide, the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ42 oligomers.
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影响因子：
20.6
作者：
Alderighi, L;Gans, P;Vacca, A
通讯作者：
Vacca, A
影响因子：
--
作者：
Braymer JJ;Detoma AS;Choi JS;Ko KS;Lim MH
通讯作者：
Lim MH
影响因子：
15
作者：
Folk DS;Franz KJ
通讯作者：
Franz KJ
影响因子：
2.3
作者：
De Buysser, K;Herman, GG;Van Driessche, I
通讯作者：
Van Driessche, I
DOI：
10.1039/dt9840001349
发表时间：
1984-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-DALTON TRANSACTIONS
影响因子：
--
作者：
ADDISON, AW;RAO, TN;VERSCHOOR, GC
通讯作者：
VERSCHOOR, GC