控制aβ42的金属介导聚合的双功能化合物
Anuj K Sharma1, Stephanie T Pavlova, Jaekwang Kim
1Department of Chemistry, Washington University, One Brookings Drive, St. Louis, Missouri 63130-4899, USA.
Journal of the American Chemical Society
|March 29, 2012
概括
新的双功能化合物 (BFC) 在破坏与阿尔茨海默病 (AD) 相关的金属相互作用方面表现有前途. 然而,矛盾的是,它们通过形成可溶性粉样β (Aβ) 寡合体来增加神经毒性.
科学领域:
- 神经科学是一个神经科学.
- 生物化学 生物化学
- 药用化学 医学化学
背景情况:
- 铜 (Cu) 和 (Zn) 离子和粉样β (Aβ) 之间的异常相互作用与阿尔茨海默氏症 (AD) 病原发生有关.
- 针对这些金属相互作用与化学剂是阿尔茨海默病的有希望的治疗策略.
研究的目的:
- 合成和评估两种新型双功能化合物 (BFCs),L1和L2,旨在结合粉样蛋白和金属离子.
- 研究这些BFCs在抑制金属介导的Aβ聚合和促进粉样纤维分离方面的有效性.
主要方法:
- 合成双功能化合物 (BFCs) L1 和 L2.
- 对Cu(2+) 和Zn(2+) 的金属结合稳定常数的评估.
- 使用ThT光,原生凝电泳/西式涂抹和传输电子显微镜 (TEM) 评估Aβ结合亲和力和抑制Aβ(42) 聚合.
- 细胞毒性测定用于评估BFC和金属离子对Aβ物种的影响.
主要成果:
- L1和L2对Cu(2+) 和Zn(2+) 显示出高稳定常数,表明有效的金属化.
- 这两种BFC都对Aβ物种表现出强烈的亲和力,并且有效地抑制了Aβ的金属介导聚合.
- BFCs促进了预先形成的粉样纤维的分解.
- 一个值得注意的发现是,在金属离子和BFCs的存在下,可溶性Aβ(42) 寡合体的形成导致细胞毒性增加.
结论:
- 开发的双功能化合物 (BFC) 有效化铜和离子,并与粉样β相互作用.
- 虽然BFCs抑制Aβ聚合和分解纤维,但它们可以通过形成可溶性Aβ42) 寡合体,矛盾地增加神经毒性.
- 这表明,仅仅专注于抑制聚合和促进分离的策略可能不是开发针对Aβ的阿尔茨海默病治疗方法的最佳选择.
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