Department of Biotechnology, Graduate School of Engineering, Tokyo University of Agriculture & Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
Int J Mol Sci. 2013 Jan 28;14(2):2590-600. doi: 10.3390/ijms14022590.
We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of α-synuclein, amyloid β(1-42) (Aβ(1-42)), and mouse prion protein. Moreover, PQQ-modified α-synuclein and a proteolytic fragment of the PQQ-modified α-synuclein are able to inhibit the amyloid formation of α-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of α-synuclein. We demonstrate that the PQQ-modified α-Syn(36-46) peptide, which is a partial sequence of α-synuclein, prevented α-synuclein amyloid fibril formation but did not inhibit Aβ(1-42) fibril formation. In addition, the α-synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented α-synuclein fibril formation. Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules. Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation.
我们之前曾报道过吡咯并喹啉醌（PQQ）可防止α-突触核蛋白、淀粉样β（1-42）（Aβ（1-42））和鼠朊蛋白的淀粉样形成。此外，PQQ 修饰的α-突触核蛋白和 PQQ 修饰的α-突触核蛋白的蛋白水解片段能够抑制α-突触核蛋白的淀粉样形成。在这里，我们鉴定了作为 PQQ 修饰的α-突触核蛋白特异性肽抑制剂起重要作用的肽序列。我们证明，PQQ 修饰的α-Syn（36-46）肽是α-突触核蛋白的部分序列，可防止α-突触核蛋白淀粉样纤维形成，但不抑制 Aβ（1-42）纤维形成。此外，用其他小分子抑制剂白杨素和表没食子儿茶素没食子酸酯（EGCG）修饰的α-突触核蛋白部分肽也可防止α-突触核蛋白纤维形成。目前报道的醌类淀粉样抑制剂对蛋白质分子没有选择性。因此，我们的研究成果为开发靶向特定淀粉样形成抑制剂提供了新策略：将醌类化合物与参与淀粉样形成的靶蛋白的特定肽序列相结合。
