NEW STRATAGIES FOR FORMATION OF PEPTIDE BETA-SHEETS

多肽和蛋白质的三维结构决定了它们的 生物功能。通常不可能预测这些 结构，而且在控制方面只取得了有限的进展 人造多肽和蛋白质中的结构。测试版的创建- 床单被证明是特别具有挑战性的，因为远程之间的联系 涉及残留物。目前，没有足够的手段来 产生可溶的、多链的B-折叠，这一区域的蛋白质 设计蕴含着巨大的新发现潜力。最新进展 创建蛋白质二级结构的一般策略 将有助于设计出药理上有用的仿制品 具有生物活性的多肽和蛋白质。 这项提案旨在制定三项新战略，以创建 多肽衍生品中的β-薄层。在这些战略中，强制 邻近、分子内氢键和疏水相互作用 共同努力，以诱导形成β-折叠。第一 策略使用寡脲模板将多肽链固定在 邻近性允许形成平行和反平行的β-折叠 由两条或多条多肽组成的。第二种是使用刚性的 β链模拟物，提供氢键功能，可以 在相邻的多肽链中充当形成β-折叠的模板。 第三种是近芳基之间的疏水相互作用。 以加强水溶液中β-链之间的氢键。 这三个策略将通过合成和光谱测试 小模型化合物的研究。这些策略将用于 结合以创建平行和反平行测试页，其中包含 几条多肽链。最后，这些策略将应用于 利用β-折叠基序结合分子受体的研究进展 多肽和对映体选择性裂解多肽的催化剂。 这项研究的主要健康意义在于发展 创造多肽结构的一般策略，而不是 开发特定的药理活性化合物。在……里面 此外，还选择了与生物相关的靶标进行研究。一个 参与形成的β-折叠形成肽的可溶性版本 将制备和表征淀粉样斑块。这个特别的 多肽与II型糖尿病有关；相关多肽包括 与阿尔茨海默氏症和瘙痒病有关。对映体选择性受体 对于D-丙氨酸-D-丙氨酸，新生肽聚糖的末端，将被准备， 以及用D-残基对映体选择性裂解多肽的催化剂 将开发C-末端。这些化合物可能显示出抗生素。 活动。

The three-dimensional structures of peptides and proteins governs their biological functions. It is not generally possible to predict these structures, and only limited progress has been made toward controlling structure in artificial peptides and proteins. The creation of beta- sheets has proven particularly challenging, since contacts between remote residues are involved. At present, there are no adequate means for creating soluble, multiple-stranded B-sheets, and this area of protein design holds tremendous potential for new discoveries. The development of general strategies for the creation of protein secondary structures would facilitate the design of pharmacologically useful mimics of biologically active peptides and proteins. This proposal aims to develop three new strategies for the creation of beta-sheets in peptide derivatives. In these strategies, enforced proximity, intramolecular hydrogen bonding, and hydrophobic interactions work in conjunction to induce the formation of beta-sheets. The first strategy uses an oligourea template to hold strands of peptides in proximity permit the formation of parallel and antiparallel beta-sheets consisting of two or more strands of peptides. The second uses a rigid beta-strand mimetic to provide hydrogen bonding functionality that can act as a template for beta-sheet formation in adjacent peptide strands. The third employs hydrophobic interactions between nearly aromatic groups to buttress hydrogen bonds between beta-strands in aqueous solution. The three strategies will be tested by the synthesis and spectroscopic study of small model compounds. These strategies will be used in conjunction to create parallel and antiparallel beta-sheets containing several peptide strands. Finally, the strategies will be applied to the creation of molecular receptors that use beta-sheet motifs to bind peptides and a catalyst to enantioselectively cleave peptides. The primary health significance of this research is in the development of general strategies for the creation of peptide structure, rather than the development of specific pharmacologically active compounds. In addition, biologically relevant targets have been chosen for study. A soluble version of beta-sheet forming peptide involved in the formation of amyloid plaques will be prepared and characterized. This particular peptide is associated with type II diabetes; related peptides are involved in Alzheimer's disease and scrapie. Enantioselective receptors for D-Ala-D-Ala, the terminus of nascent peptidoglycan, will be prepared, and catalysts to enantioselectively cleave peptides with D-residues at the C-terminus will be developed. These compounds may exhibit antibiotic activity.