Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
PLoS One. 2012;7(7):e39485. doi: 10.1371/journal.pone.0039485. Epub 2012 Jul 30.
Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge.
Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration.
The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target.
非天然自组织仿生聚合物（foldamers）作为生物分子识别和抑制的有前途的材料而出现。我们的目标是构建多价 foldamer-树状聚合物缀合物，通过其螺旋 foldamer 触手高亲和力地包裹毒性突触的β-淀粉样蛋白（Aβ）寡聚物。寡聚 Aβ 物种在阿尔茨海默病中起关键作用，因此识别和直接抑制这个难以成药的靶标是当前的巨大挑战。
具有设计的二级结构和侧链化学模式的短螺旋β-肽 foldamers 被用作潜在的识别片段，并通过 NMR 方法（饱和转移差异和转移核 Overhauser 效应）测试它们与靶标的结合。在 µM 区域表现出结合的螺旋体与四价 G0-PAMAM 树状聚合物偶联。体外生物物理（等温滴定量热法、动态光散射、透射电子显微镜和尺寸排阻色谱）和生化测试（ELISA 和点印迹）表明 foldamer 缀合物与 Aβ 寡聚物之间的紧密结合。此外，还发现与 Aβ 寡聚物的低分子量部分具有选择性的低 nM 相互作用。离体电生理实验表明，该新材料以亚微摩尔浓度在小鼠海马切片中从毒性 Aβ 寡聚物中挽救长时程增强。
foldamer 方法、基于片段的方法和多价设计的结合为具有特定分子识别能力的非天然蛋白质模拟物提供了一条途径，并且已经产生了针对极其困难的靶标的抑制剂。
