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: 10201680
• 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/10201680
• 关键词: Amides; Amino Acids; Biological; Biological Process; 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.

制备均一糖蛋白的化学方法 评价 摘要-我们的长期目标是揭示细胞和传染性疾病的未知功能， 朊病毒蛋白质通过询问单个同质朊病毒糖型。我们的目标是 开发一类利用应变分子的有效肽基偶联方案，例如β- 内酯和β-硫代内酯，用于构建以前无法实现的目标，如环状 四肽和膜朊病毒蛋白。我们的中心假设，来自我们发表的 结果和初步研究如下所述，是化学合成可以提供PrPC 和具有高构象保真度的PrPSc菌株，这使得朊病毒生物学研究能够被 在询问合成的均质glyco-PrPs时，以忠实的准确度进行。的 修饰蛋白质构建体的灵活性取代了以前无法获得的评估朊病毒的工具 疾病拟定研究目标的基本原理是β-硫代内酯和β-内酯 环酯应变的释放使得前所未有的快速酰胺键构建成为可能， 两个氨基酸残基。此外，环丁烯环的近平面几何形状将 通过防止恶唑酮的形成而产生所需的肽基加合物而没有差向异构化。 一种类似的方法可以应用于构建同源膜糖蛋白， β-硫内酯促进蛋白质连接。我们计划测试我们的中心假设，因此， 通过以下目标实现本申请的目标：1.设计和扩展 可用于肽合成而无需差向异构化的受限酯的范围。2. 同质细胞朊病毒糖蛋白及其同源物的合成。3.生物学功能和 制备的肽和蛋白的活性研究。