BETA-SHEET MIMICS FROM CONSTRAINED DIPEPTIDE UNITS

描述：(改编自应用程序)。一种新型的限制性二肽 单位将被合成和寡聚，以测试产生的多肽 将有很高的倾向形成延长的构象链。这些 假定的延伸构象链应预先组织为具有高度 仅沿着链的一个边缘的合作氢键结构域。这些 研究人员将测试这些多肽是否通过氢键形成同源二聚体 在含水缓冲液中以浓度依赖的方式形成结构域。与自然不同 多肽，没有进一步的氢键介导的齐聚是可能的，因为 受限制的二肽单元在所有其他氨基酸中都缺乏酰胺N-H键。 结构(平行和/或反平行的B-折叠二聚体模型)和 这些多肽均二聚体的聚集特性将被研究以 验证这些假设。三种不同限制性二肽的作用 单位和不同的氨基酸侧链、肽序列和肽长度 关于均二聚平衡的研究将指导理性 优先结合替代物的延伸构象链的设计 氢键位置。通过模仿已知的淀粉样蛋白B肽序列{L-40} (A-β)纤维/原纤维蛋白抑制剂，它们将促进它们之间的结合 延伸的构象链和纤维/原纤维的生长边缘 这可能会导致阿尔茨海默氏症(AD)。调查人员 假设这些延长的构象链可以覆盖生长 B片富含纤维/原纤维，并抑制或逆转不受控制的 AD的体外聚集。目前有争议的是原纤维还是 原纤维或其他物质才是真正的细胞毒性物质。因此， 他们将直接测量Extended的细胞保护活性 使用已建立的体外分析方法构建构象链。

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.