Department of Chemistry and ‡ Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
J Am Chem Soc. 2017 Mar 29;139(12):4298-4301. doi: 10.1021/jacs.7b00289. Epub 2017 Mar 16.
Amyloid aggregation and deposition are associated with many intractable human diseases. Although the inhibition of amyloid protein aggregation has been well-studied, the disaggregation and dissolution of existing amyloid fibrils is less known. Taking a fibrillar assembly of amyloid β (Aβ) peptide as the model system, here we report multivalent polymer-peptide conjugates (mPPCs) that disassemble preformed Aβ fibrils into dispersible sub-100 nm structures. Atomic force microscopy and dynamic light scattering studies show that the disassembly rate of preformed Aβ fibrils is controlled by the molecular weight of mPPCs. Rate equations on fibril disappearance are deduced from a simple model, which indicate that the disassembly reaction is first-order in the concentration of Aβ fibrils and a pseudo-first-order reaction in the concentration of peptide moieties on mPPCs, respectively. We eliminate the possibility that the disassembly occurs by the association between mPPCs and Aβ monomer/oligomers based on circular dichroism and Thioflavin T fluorescence assays. It is mostly likely that the mPPCs disassemble Aβ fibrils through a direct interaction. The mPPCs may thus offer a general macromolecular design concept that breaks down existing amyloid fibrils in a predictable fashion.
淀粉样蛋白的聚集和沉积与许多难以治愈的人类疾病有关。尽管抑制淀粉样蛋白聚集的研究已经很充分，但对于现有淀粉样纤维的解聚和溶解知之甚少。在这里，我们以淀粉样 β (Aβ) 肽的纤维状聚集物作为模型系统，报告了多价聚合物-肽缀合物 (mPPC)，它可以将预先形成的 Aβ 纤维解聚成可分散的小于 100nm 的结构。原子力显微镜和动态光散射研究表明，预先形成的 Aβ 纤维的解聚速率由 mPPC 的分子量控制。从一个简单的模型推导出关于纤维消失的速率方程，表明该解聚反应在 Aβ 纤维的浓度下是一级反应，在 mPPC 上的肽部分的浓度下是拟一级反应。我们根据圆二色性和硫黄素 T 荧光测定排除了 mPPC 与 Aβ 单体/低聚物之间的缔合导致解聚的可能性。最有可能的是，mPPC 通过与 Aβ 纤维的直接相互作用来解聚 Aβ 纤维。因此，mPPC 可能提供了一种通用的大分子设计概念，可以以可预测的方式分解现有的淀粉样纤维。
