Abe Koichi, Kobayashi Natsuki, Sode Koji, Ikebukuro Kazunori
Department of Biotechnology, Tokyo University of Agriculture and Technology, 2-24-13 Naka-cho, Koganei-shi, Tokyo, 184-8588, Japan.
BMC Bioinformatics. 2007 Nov 16;8:451. doi: 10.1186/1471-2105-8-451.
alpha-Synuclein is a Parkinson's-disease-related protein. It forms aggregates in vivo, and these aggregates cause cell cytotoxicity. Aggregation inhibitors are expected to reduce alpha-synuclein cytotoxicity, and an aggregation accelerator has recently been reported to reduce alpha-synuclein cytotoxicity. Therefore, amyloid aggregation modulating ligands are expected to serve as therapeutic medicines.
We screened peptide ligands against alpha-synuclein by in silico panning, a method which we have proposed previously. In this study, we selected as the target a very hydrophobic region known as the amyloid-core-forming region. Since this region cannot be dissolved in water, it is difficult to carry out the in vitro screening of its peptide ligand. We carried out 6 rounds of in silico panning using a genetic algorithm and a docking simulation. After the in silico panning, we evaluated the top peptides screened in silico by in vitro assay. These peptides were capable of binding to alpha-synuclein.
We demonstrated that it is possible to screen alpha-synuclein-binding peptides by in silico panning. The screened peptides bind to alpha-synuclein, thus affecting the aggregation of alpha-synuclein.
α-突触核蛋白是一种与帕金森病相关的蛋白质。它在体内形成聚集体，这些聚集体会导致细胞毒性。聚集抑制剂有望降低α-突触核蛋白的细胞毒性，最近有报道称一种聚集促进剂也能降低α-突触核蛋白的细胞毒性。因此，淀粉样蛋白聚集调节配体有望成为治疗药物。
我们通过计算机淘选法筛选了针对α-突触核蛋白的肽配体，这是我们之前提出的一种方法。在本研究中，我们选择了一个被称为淀粉样核心形成区域的非常疏水的区域作为靶点。由于该区域不溶于水，因此很难对其肽配体进行体外筛选。我们使用遗传算法和对接模拟进行了6轮计算机淘选。计算机淘选后，我们通过体外试验评估了计算机筛选出的顶级肽。这些肽能够与α-突触核蛋白结合。
我们证明了通过计算机淘选筛选α-突触核蛋白结合肽是可行的。筛选出的肽与α-突触核蛋白结合，从而影响α-突触核蛋白的聚集。
