The chemical approach towards homogenous glycoprotein preparation and evaluation

均质糖蛋白制备和评价的化学方法

• 批准号: 10413931
• 负责人: Qiang Zhang
• 金额: $ 36.56万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413931
• 关键词: Amides; Amino Acids; Biological; Biological Process; Biological Products; Cell physiology; Chemicals; Coupling; Cyclic Peptides; Esters; Evaluation; Geometry; Glycoproteins; Goals; Individual; Investigation; Lactones; Ligation; Membrane; Membrane Glycoproteins; Molecular Conformation; Oxazolone; Peptide Synthesis; Peptides; Periodicity; Pharmacologic Substance; PrP; PrPSc Proteins; Preparation; Prion Diseases; Prions; Proteins; Protocols documentation; Public Health; Publishing; Research; Testing; adduct; chemical synthesis; design; epimerization; flexibility; prevent; protein function; tool

The chemical approach towards homogenous glycoprotein preparation and evaluation ABSTRACT – Our long-term goal is to uncover the unknown function of cellular and infectious prion protein by interrogating individual homogenous prion glycoform. The objective here, is to develop a class of efficient peptidyl coupling protocols utilizing strained molecules, such as β- lactone and β-thiolactone, for the construction of previously unattainable targets such as cyclic tetrapeptides and membrane prion protein. Our central hypothesis, derived from our published results and preliminary studies described below, is that chemical synthesis can provide the PrPC and PrPSc strains with high conformational fidelity, which allows prion biological studies to be carried out with faithful accuracy when interrogating synthetic homogenous glyco-PrPs. The flexibility of modifying protein construct furnishes previously unavailable tool for evaluation prion disease. The rationale for the proposed research objectives is that the β-thiolactone and β-lactone release of cyclic ester strain enables unprecedented rapid amide bond construction and connects two amino acid residues. Furthermore, the near-planar geometry of the cyclobutene ring will generate desired peptidyl adducts without epimerization by preventing the oxazolone formation. An analogous approach could be applied to construct homogenous membrane glycoproteins from β-thiolactone promoted protein ligation. We plan to test our central hypothesis and, thereby, accomplish the objectives of this application via the following goals: 1. Design and expansion of the range of constrained esters that can be utilized for peptide synthesis without epimerization. 2. Synthesis of homogeneous cellular prion glycoproteins and congeners. 3. Biological function and activities investigation of prepared peptide and proteins.

均质糖蛋白制备的化学方法和 评估 摘要 - 我们的长期目标是发现细胞和感染性的未知功能 prion蛋白通过询问个体同质prion糖型。这里的目的是 开发利用紧张分子（例如β-）的一类有效肽基偶联方案 内酯和β-硫代酮，用于构建先前无法实现的靶标，例如环状靶标 四肽和膜prion蛋白。我们的中心假设，源自我们已发表的 结果和初步研究下面描述的是化学合成可以提供PRPC 以及具有高构象忠诚度的PRPSC条纹，这使prion生物学研究成为 询问合成同质的GlycoPRP时，以忠实的准确性进行。 修改蛋白质构建体的灵活性提供了以前无法获得的评估工具 疾病。拟议的研究目标的理由是β-硫代酮和β-内酯 释放环状酯应变可以实现前所未有的快速酰胺键构建并连接 两个氨基酸残基。此外，环丁烯环的接近平面几何形状将 通过防止恶唑龙形成产生所需的肽基合力而无需发作。 可以采用类似方法来构建来自 β-硫代酮促进了蛋白质连接。我们计划检验我们的中心假设，从而 通过以下目标实现此应用程序的目标：1。设计和扩展 可以用于肽合成而无需发作的约束酯的范围。 2。 均质细胞prion糖蛋白和同类物的合成。 3。生物功能和 活动准备的胡椒和蛋白质的投资。