BETA-SHEET MIMICS FROM CONSTRAINED DIPEPTIDE UNITS

描述：（改编自应用程序）。 新型约束二肽 单元将被合成并寡聚化以测试所得肽是否 将具有形成延伸构象链的高倾向性。 这些 假定的延伸构象链应该被预先组织成具有高度的 协作氢键域沿着仅一个边缘的链。 这些 研究人员将测试这些肽是否通过它们的H键形成同源二聚体 结构域以浓度依赖性方式在水性缓冲液中。 与天然 肽，没有进一步的H-键介导的寡聚化是可能的，因为 受约束的二肽单元在每隔一个氨基酸中缺少酰胺N-H键。 结构（平行和/或反平行B折叠二聚体模型）和 将研究这些肽同源二聚体的聚集特性， 验证这些假设。 三种不同的限制性二肽 单元和不同的氨基酸侧链、肽序列和肽长度 对同二聚平衡的研究，以指导合理的 优先结合替代物的延伸构象链的设计 氢键位点 通过模拟已知的淀粉样蛋白B肽{1 -40}的序列， （A-BETA）β-淀粉样蛋白/原纤维抑制剂，它们将促进这些蛋白之间的结合。 延伸的构象链和原纤维/原纤维的生长边缘 可能导致阿尔茨海默氏症（AD）的疾病。 调查人员 假设这些延伸的构象链可以限制 b-片层丰富的原纤维/原纤维，并抑制或逆转不受控制的 体外聚集AD。 目前有争议的是， 原纤维或其他物质才是真正的细胞毒性物质。 因此，我们认为， 他们将直接测量细胞保护活性的延长， 使用已建立的体外测定法测定构象链。

DESCRIPTION: (Adapted from the Application). Novel constrained dipeptide units will be synthesized and oligomerized to test if the resulting peptides will have a high propensity to form extended conformation strands. These putative extended conformation strands should be pre-organized to have highly cooperative H-bonding domains along only one edge of the strand. These investigators will test if these peptides form homodimers via their H-bonding domains in a concentration dependent manner in aqueous buffer. Unlike natural peptides, no further H-bond mediated oligomerization is possible because the constrained dipeptide units lack amide N-H bonds in every other amino acid. The structure (parallel and/or antiparallel B-sheet dimer models) and the aggregation characteristics of these peptide homodimers will be studied to verify these hypotheses. The effect of three different constrained dipeptide units and varying amino acid side chains, peptide sequence, and peptide length on the homodimerization equilibrium will be studied to guide the rational design of extended conformation strands that preferentially bind alternative H-bonding sites. By mimicking the sequences of known amyloid B-peptide{l-40} (A-BETA) fibri/protofibril inhibitors, they will promote binding between these extended conformation strands and the growing edge of the fibrils/protofibrils that supposedly lead to Alzheimer's disease (AD). The investigators hypothesize that these extended conformation strands can cap off growing b-sheet rich fibrils/protofibrils and inhibit or reverse the uncontrolled aggregation of AD in vitro. It is currently disputed whether fibrils or protofibrils or something else are the actual cytotoxic species. Therefore, they will directly measure the cytoprotective activity of extended conformation strands using an established assay in vitro.