Takahashi Tsuyoshi, Mihara Hisakazu
Department of Bioengineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Nagatsuta,Yokohama 226-8501, Japan.
Acc Chem Res. 2008 Oct;41(10):1309-18. doi: 10.1021/ar8000475.
Protein misfolding is related to some fatal diseases including Alzheimer's disease (AD). Amyloid beta-peptide (Abeta) generated from amyloid precursor protein can aggregate into amyloid fibrils, which are known to be a major component of Abeta deposits (senile plaques). The fibril formation of Abeta is typical of a nucleation-dependent process through self-recognition. Moreover, during fibrillization, several metastable intermediates such as soluble oligomers, including Abeta-derived diffusible ligands (ADDLs) and Abeta*56, are produced, which are thought to be the most toxic species to neuronal cells. Therefore, construction of molecules that decrease the Abeta aggregates, including soluble oligomers, protofibrils, and amyloid fibrils, might further our understanding of the mechanism(s) behind fibril formation and enable targeted drug discovery against AD. To this aim, various peptides and peptide derivatives have been constructed using the "Abeta binding element" based on the structural models of Abeta amyloid fibrils and the mechanisms of self-assembly. The central hydrophobic amino acid sequence, LVFF, of Abeta is a key sequence to self-assemble into amyloid fibrils. By combination of this core sequence with a hydrophobic or hydrophilic moiety, such as cholic acid or aminoethoxy ethoxy acetic acid units, respectively, good inhibitors of Abeta aggregation can be designed and synthesized. A peptide, LF, consisting of the sequence Ac-KQKLLLFLEE-NH 2, was designed based on the core sequence of Abeta but with a simplified amino acid sequence. The LF peptide can form amyloid-like fibrils that efficiently coassemble with mature Abeta1-42 fibrils. The LF peptide was also observed to immediately transform the soluble oligomers of Abeta1-42, which are thought to pose toxicity in AD, into amyloid-like fibrils. On the other hand, two Abeta-like beta-strands with a parallel orientation were embedded in green fluorescent protein (GFP), comprised of a beta-barrel structure, to make pseudo-Abeta beta-sheets on its surface. The GFP variant P13H binds to Abeta1-42 and inhibits Abeta1-42 oligomerization effectively in a substoichiometric condition. Thus, molecules capable of binding to Abeta can be designed based on structural similarities with the Abeta molecule. The peptide and protein mimetics based on the structural features of Abeta might lead to the development of drug candidates against AD.
蛋白质错误折叠与包括阿尔茨海默病（AD）在内的一些致命疾病相关。淀粉样前体蛋白产生的淀粉样β肽（Aβ）可聚集成淀粉样纤维，已知其是Aβ沉积物（老年斑）的主要成分。Aβ的纤维形成是通过自我识别的典型成核依赖性过程。此外，在纤维化过程中，会产生几种亚稳态中间体，如可溶性寡聚体，包括Aβ衍生的可扩散配体（ADDLs）和Aβ*56，它们被认为是对神经元细胞毒性最大的物质。因此，构建能够减少Aβ聚集体（包括可溶性寡聚体、原纤维和淀粉样纤维）的分子，可能会加深我们对纤维形成背后机制的理解，并有助于发现针对AD的靶向药物。为了实现这一目标，基于Aβ淀粉样纤维的结构模型和自组装机制，使用“Aβ结合元件”构建了各种肽和肽衍生物。Aβ的中央疏水氨基酸序列LVFF是自组装成淀粉样纤维的关键序列。通过将该核心序列分别与疏水或亲水部分（如胆酸或氨基乙氧基乙氧基乙酸单元）结合，可以设计和合成良好的Aβ聚集抑制剂。一种由序列Ac-KQKLLLFLEE-NH 2组成的肽LF，是基于Aβ的核心序列但具有简化的氨基酸序列设计的。LF肽可以形成与成熟的Aβ1-42纤维有效共组装的淀粉样纤维。还观察到LF肽能立即将被认为在AD中具有毒性的Aβ1-42可溶性寡聚体转化为淀粉样纤维。另一方面，两条平行取向的Aβ样β链被嵌入由β桶结构组成的绿色荧光蛋白（GFP）中，以在其表面形成假Aββ片层。GFP变体P13H在亚化学计量条件下与Aβ1-42结合并有效抑制Aβ1-42寡聚化。因此，可以基于与Aβ分子的结构相似性设计能够与Aβ结合的分子。基于Aβ结构特征的肽和蛋白质模拟物可能会导致开发针对AD的候选药物。
