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Binding interactions of agents that alter alpha-synuclein aggregation

机译：改变α-突触核蛋白聚集的药剂的结合相互作用

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Further examination of peptides with well-folded antiparallel beta strands as inhibitors of amyloid formation from alpha-synuclein has resulted in more potent inhibitors. Several of these had multiple Tyr residues and represent a new lead for inhibitor design by small peptides that do not divert alpha-synuclein to non-amyloid aggregate formation. The most potent inhibitor obtained in this study is a backbone cyclized version of a previously studied beta hairpin, designated as WW2, with a cross-strand Trp/Trp cluster. The cyclization was accomplished by adding a D-Pro-L-Pro turn locus across strand termini. At a 2 : 1 peptide to alpha-synuclein ratio, cyclo-WW2 displays complete inhibition of beta-structure formation. Trp-bearing antiparallel beta-sheets held together by a disulphide bond are also potent inhibitors. N-15 HSQC spectra of alpha-synuclein provided new mechanistic details. The time course of N-15 HSQC spectral changes observed during beta-oligomer formation has revealed which segments of the structure become part of the rigid core of an oligomer at early stages of amyloidogenesis and that the C-terminus remains fully flexible throughout the process. All of the effective peptide inhibitors display binding-associated titration shifts in N-15 HSQC spectra of alpha-synuclein in the C-terminal Q109-E137 segment. Cyclo-WW2, the most potent inhibitor, also displays titration shifts in the G41-T54 span of alpha-synuclein, an additional binding site. The earliest aggregation event appears to be centered about H50 which is also a binding site for our most potent inhibitor.
机译：进一步检查具有良好折叠的反平行β链作为α-突触核蛋白的淀粉样蛋白形成的抑制剂的肽导致更有效的抑制剂。其中几种具有多个Tyr残留物，并通过不将α-突触核蛋蛋白与非淀粉样蛋白聚集体形成的小肽代表抑制剂设计的新铅。本研究中获得的最有效的抑制剂是先前研究的β发夹的骨干循环版，其指定为WW2，具有跨链TRP / TRP簇。通过在跨链末端添加D-Pro-L-Pro转向基因座来实现环化。在2：1肽至α-突触核蛋白比中，Cyclo-WW2显示完全抑制β结构的形成。通过二硫键保持在一起的TRP的反平行β-片也是有效的抑制剂。 α-突触核蛋白的N-15 HSQC光谱提供了新的机制细节。在β-低聚物形成期间观察到的N-15 HSQC光谱变化的时间过程揭示了该结构的哪个区段成为淀粉片过生的早期阶段的低聚物的刚性芯的一部分，并且C末端在整个过程中保持完全灵活。所有有效的肽抑制剂显示在C末端Q109-E137区段中α-突触核蛋白的N-15 HSQC光谱中的结合相关滴定偏移。 Cyclo-WW2是最有效的抑制剂，也显示出α-突触核蛋白的G41-T54跨度中的滴定移位，另外的结合位点。最早的聚合事件似乎以H50为中心，这也是我们最有效抑制剂的结合位点。

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  • 来源
    《RSC Advances》 |2015年第15期|共14页
  • 作者

    Sivanesam K.; Byrne A.; Bisaglia M.; Bubacco L.; Andersen N.;

  • 作者单位

    Univ Washington Dept Chem Seattle WA 98195 USA;

    Univ Washington Dept Chem Seattle WA 98195 USA;

    Univ Padua Dept Biol I-35121 Padua Italy;

    Univ Padua Dept Biol I-35121 Padua Italy;

    Univ Washington Dept Chem Seattle WA 98195 USA;

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  • 正文语种 eng
  • 中图分类 化学;
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