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Supramolecular Assembly of Peptides Derived from Amyloid-beta (Abeta) and Development of Peptide Antibiotics

机译:淀粉样β(Abeta)衍生的肽的超分子组装和肽抗生素的发展。

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摘要

Soluble oligomers of amyloid-beta (Abeta) have been implicated as the culprit for neurodegeneration in Alzheimer's disease. Familial mutations of Abeta can lead to early-onset Alzheimer's disease. Structures of fibrils formed by wild-type Abeta and Abeta familial mutants differ. Structural elucidation of Abeta oligomers containing Abeta familial mutations may further our understanding of the disease. High resolution structures of Abeta oligomers can provide useful information for medicinal chemists to design therapeutics to treat Alzheimer's disease. The first chapter of this dissertation describes the X-ray crystallographic structures of two macrocyclic beta-sheets containing Abeta familial mutations. The oligomeric structures of these two macrocyclic beta-sheets are slightly different than the structure from the macrocyclic beta-sheet containing the wild-type Abeta sequence. Preliminary results of cytotoxicity studies showed that some Abeta familial mutants are more toxic toward neuronal cells than the wild-type Abeta. The findings of this chapter are significant, because the newly elucidated chemical models of Abeta oligomers containing Abeta familial mutations can potentially provide insights to early-onset Alzheimer's disease. Supramolecular assemblies of Abeta are interesting to investigate, because they are central in Alzheimer's disease.;They also act as a good starting point to study molecular recognition of peptides and fabrication of nanostructures. The second chapter of this dissertation describes the X-ray crystallographic structure of an Abeta-inspired macrocyclic beta-sheet that forms a giant double-walled nanotube. Monomers of the macrocyclic beta-sheet adopt two different conformations. The size of the nanotube rivals the size and complexity of the largest tubular biomolecular assemblies, such as microtubules. The findings of this chapter are significant, because a peptide nanotube of this size cannot currently be predicted from the Abeta16--22 sequence.;Structural chemists are interested in understanding the rules that govern molecular recognition and self-assembly of peptides. Currently, it is difficult to predict self-assembly of peptides, and the resulting oligomeric structures. The third chapter of this dissertation describes a different X-ray crystallographic structure formed from an analogue of the macrocyclic beta-sheet that yielded the peptide nanotube. The new macrocyclic beta-sheet has the same peptide sequence with a different beta-turn stabilizer. Changing the beta-turn stabilizer eliminates some existing molecular interactions. As a result, the new structure is very different than the peptide nanotube. The structural difference is yet another example that self-assembly of peptides cannot be reliably predicted. The findings of this chapter are significant, because they demonstrate that simple peptide modifications can induce an alternative supramolecular assembly from the same Abeta peptide sequence.;Teixobactin is a promising recently discovered antibiotic. The undecapeptide contains a 13-membered macrolactone ring and a non-proteinogenic amino acid allo-enduracididine. Teixobactin can kill drug-resistant Gram-positive bacteria without acquiring antibiotic resistance. Teixobactin binds to bacterial cell wall precursors such as lipid II and inhibits bacterial cell wall biosynthesis, which leads to cell lysis. The fourth and last part of this dissertation describes an alanine scan of Lys10-teixobactin. This traditional structure-activity-relationship study revealed that the cationic allo-enduracididine is not necessary for activity. The solubility, cytotoxicity, and hemolytic activities of these alanine scan analogues were evaluated. Reduced aqueous solubility correlates with better antibiotic activity. The alanine scan analogues are non-cytotoxic and non-hemolytic. The findings of this chapter are significant, because the results from the alanine scan of a teixobactin analogue provides a solid foundation to guide future teixobactin analogue design.
机译:淀粉样β(Abeta)的可溶性寡聚体被认为是阿尔茨海默氏病神经退行性变的元凶。 Abeta的家族性突变可导致早发型阿尔茨海默氏病。由野生型Abeta和Abeta家族突变体形成的原纤维结构不同。含有Abeta家族性突变的Abeta低聚物的结构解析可能会进一步加深我们对该疾病的了解。 Abeta低聚物的高分辨率结构可为药物化学家设计治疗Alzheimer病的疗法提供有用的信息。本文的第一章描述了两个含有Abeta家族突变的大环β-折叠的X射线晶体结构。这两个大环β-折叠的寡聚结构与包含野生型Abeta序列的大环β-折叠的结构略有不同。细胞毒性研究的初步结果表明,某些Abeta家族突变体对神经元细胞的毒性比野生型Abeta更强。本章的发现意义重大,因为新近阐明的含有Abeta家族性突变的Abeta低聚物的化学模型可以为早期发作的阿尔茨海默氏病提供潜在的见识。 Abeta的超分子组装是有趣的研究,因为它们在阿尔茨海默氏病中很重要。;它们也是研究肽的分子识别和纳米结构制造的良好起点。本论文的第二章描述了形成巨大的双壁纳米管的Abeta启发的大环β片的X射线晶体学结构。大环β-折叠的单体采用两种不同的构象。纳米管的尺寸可与最大的管状生物分子组件(例如微管)的尺寸和复杂性相媲美。本章的发现意义重大,因为目前尚无法从Abeta16--22序列中预测出这种大小的肽纳米管。结构化学家对理解控制肽的分子识别和自组装的规则感兴趣。当前,难以预测肽的自组装以及由此产生的寡聚结构。本论文的第三章描述了由产生肽纳米管的大环β-折叠的类似物形成的不同的X射线晶体学结构。新的大环β-折叠具有相同的肽序列和不同的β-转角稳定剂。更改β转角稳定剂可消除一些现有的分子相互作用。结果,新结构与肽纳米管有很大不同。结构差异是不能可靠地预测肽的自组装的另一个例子。本章的发现意义重大,因为它们表明简单的肽修饰可以从相同的Abeta肽序列诱导出超分子组装。; Teixobactin是一种有前途的新近发现的抗生素。十一肽包含一个13元的大内酯环和一个非蛋白氨基酸的同种内酰胺基。 Teixobactin可以杀死耐药的革兰氏阳性细菌,而无需获得抗生素耐药性。 Teixobactin与细菌细胞壁前体(如脂质II)结合,并抑制细菌细胞壁的生物合成,从而导致细胞裂解。本论文的第四部分和最后一部分描述了Lys10-teixobactin的丙氨酸扫描。这项传统的结构-活性-关系研究表明,阳离子同种异体-神经氨酸不一定是必需的。评估了这些丙氨酸扫描类似物的溶解度,细胞毒性和溶血活性。降低的水溶性与更好的抗生素活性有关。丙氨酸扫描类似物是无细胞毒性和非溶血性的。本章的发现意义重大,因为teixobactin类似物的丙氨酸扫描结果为指导将来的teixobactin类似物设计提供了坚实的基础。

著录项

  • 作者

    Chen, Kevin Hsinwen.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Organic chemistry.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 197 p.
  • 总页数 197
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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