作为Aβ自组装调节器的α-螺旋模拟剂
Sunil Kumar1, Andrew D Hamilton1
1Department of Chemistry, New York University , New York, New York 10003, United States.
Journal of the American Chemical Society
|March 9, 2017
概括
一种新型化合物ADH-41有效地预防阿尔茨海默病 (AD) 粉样β (Aβ) 纤维化和神经毒性寡合体的形成. 这种α-螺旋模拟器专门针对Aβ,为阿尔茨海默病提供了有前途的治疗策略.
科学领域:
- 神经科学
- 生物化学
- 药物发现
背景情况:
- 阿尔茨海默病 (AD) 的特征是粉样质斑块,主要由Aβ42组成.
- 可溶性Aβ寡合体被确定为驱动AD病理的关键神经毒性物种.
- 在某些环境中,Aβ42采用α螺旋形状,具有潜在的治疗目标.
研究的目的:
- 设计和识别针对Aβ (Aβ13-26) 中心α螺旋的α螺旋模拟器.
- 评估已识别的化合物在抑制Aβ纤维化和寡合化的有效性.
- 研究强效抑制剂的特异性和作用机制.
主要方法:
- 基于寡胺的α-螺旋模拟剂的设计和合成.
- 粉样组合动力学的抑制试验.
- 使用传输电子显微镜 (TEM) 和原子力显微镜 (AFM) 的结构分析.
- 生物化学测定包括Dot blot和ELISA用于Aβ寡合物的检测.
- 针对小岛氨基聚 (IAPP) 的特异性测试.
- 光谱研究 (NMR,CD) 和结合亲和度测量 (热量测量,光定位).
主要成果:
- 一种三胺,ADH-41,被确定为Aβ纤维化的强大对手.
- 根据TEM和AFM的证实,ADH-41抑制了亚胆量计剂量的Aβ聚合.
- 斑点测试和ELISA测试显示ADH-41抑制了神经毒性Aβ寡合体的形成.
- 显示ADH-41的序列和结构特异性抑制,对IAPP聚合没有影响.
- 谱学研究证实ADH-41在Aβ中诱导α-,具有低微分子范围的结合亲和力.
- 通过促进纤维无能结构,ADH-41抑制了种子催化Aβ聚合.
结论:
- ADH-41是一种高度有效的Aβ纤维化和神经毒性寡合体形成的抑制剂.
- 该化合物以特定序列和结构的方式作用,向Aβ的α-螺旋子域.
- ADH-41通过将Aβ引导到路径之外的结构来显示其作为治疗剂的潜力.
- 目前正在进行更多基于细胞的测定,以评估ADH-41的体内疗效.
相关概念视频
Amyloid Fibrils
12.4K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
12.4K
Amyloid Fibrils
6.8K
6.8K
Protein Folding
12.0K
Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
12.0K
Protein Complex Assembly
17.0K
Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types. Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Many viruses self-assemble into a fully functional unit using the infected host cell to...
17.0K
Molecular Chaperones and Protein Folding
20.6K
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
The...
20.6K


