CAREER: Bioorganic Research at USM. Development of Novel Somatostatin and Neurotensin Analogues

职业：USM 生物有机研究。

• 批准号: 0844478
• 负责人: Douglas Masterson
• 金额: $ 82.5万
• 依托单位: University of Southern Mississippi
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0844478&HistoricalAwards=false
• 关键词: CAREER; Bioorganic; Research; USM.; Development

Amino acids are the building blocks of life and are used in biology to prepare important materials of various types (i.e. proteins, peptides, hormones, etc). Small peptides have shown to be biologically active and can be used in a variety of situations. However, small peptides are frequently degraded by the presence of endogenous enzymes ultimately reducing their ability to achieve their biological function in an efficient manner. Unnatural amino acids, i.e. amino acids that are either not found or only rarely found in nature, have shown an ability to impart stability to small peptides towards enzymatic degradation. The Masterson Research Group (MRG) is particularly interested in two small peptides (Somatostatin and Neurotensin), which show a wide range of biological activity. The MRG has developed techniques that allow for the preparation of a variety of unnatural amino acids from a common synthetic intermediate. The synthetic strategy developed by the MRG allows for the parallel preparation of a variety of unnatural amino acids of importance to Somatostatin and Neurotensin. The unnatural amino acids will be used to replace specific amino acids in Somatostatin and Neurotensin. The peptide analogues will be tested for their ability to resist degradation by enzymes and for their ability to carry out their biological function. It is a key aim of this research to expand the scope of the techniques developed by the MRG to prepare a wide variety of novel unnatural amino acids and study their effect on peptide stability and function.Broader Impacts of the Project: The methods developed in this research will have a broad impact to the scientific community by providing efficient methods of preparing unnatural amino acids. The peptides prepared in this project will also provide valuable information on the structure-function relationships for Somatostatin and Neurotensin. The methods and materials will find broad applicability in bioorganic and materials sciences. The project is an interdisciplinary project that merges the areas of enzymology, traditional organic synthesis, biological chemistry, and mass spectrometry into a single project relevant to the biological sciences and chemistry. The project will allow for the training of the next generation of scientists in the state of Mississippi and will provide significant educational opportunities for graduate research assistants, undergraduate students, and economically disadvantaged high school student participants. The project will use some of the developed methodology from the MRG to teach a class at the graduate level. The class is titled "Mass Spectrometry: Useful for more than m/z" and will train graduate students on the use of NSF-funded mass spectrometry facilities at USM. The course will utilize an assay developed in the MRG to determine enantioselectivity from an enzymatic hydrolysis reaction (a process that is central to the synthetic methodology described above). The students will learn how to use the facilities so that they can make use of them in their own research endeavors and the MRG will be able to use the course to obtain the much needed data from the assays that the students will perform during the course. Mass spectrometry has become a routine method of analyzing a variety of molecules and the students who successfully complete the course will have gained skills that are transferable to a variety of job opportunities. The acquired skills will make the students highly competitive in an ever changing global job market.

氨基酸是生命的基石，在生物学中用于制备各种类型的重要材料（即蛋白质、肽、激素等）。小肽已被证明具有生物活性，可用于多种情况。 然而，小肽经常因内源酶的存在而降解，最终降低其有效实现生物功能的能力。 非天然氨基酸，即在自然界中未发现或很少发现的氨基酸，已显示出赋予小肽酶促降解稳定性的能力。 马斯特森研究小组 (MRG) 对两种小肽（生长抑素和神经降压素）特别感兴趣，它们表现出广泛的生物活性。 MRG 开发的技术可以从常见的合成中间体制备各种非天然氨基酸。 MRG 开发的合成策略允许平行制备对生长抑素和神经降压素很重要的多种非天然氨基酸。 非天然氨基酸将用于替代生长抑素和神经降压素中的特定氨基酸。 将测试肽类似物抵抗酶降解的能力以及执行其生物功能的能力。 这项研究的一个关键目标是扩大 MRG 开发的技术范围，以制备多种新型非天然氨基酸，并研究它们对肽稳定性和功能的影响。该项目的更广泛影响：本项目开发的方法研究将通过提供制备非天然氨基酸的有效方法对科学界产生广泛的影响。 该项目制备的肽还将提供关于生长抑素和神经降压素的结构-功能关系的有价值的信息。 这些方法和材料将在生物有机和材料科学中具有广泛的适用性。 该项目是一个跨学科项目，将酶学、传统有机合成、生物化学和质谱领域合并为与生物科学和化学相关的单个项目。 该项目将培训密西西比州的下一代科学家，并将为研究生研究助理、本科生和经济困难的高中生参与者提供重要的教育机会。 该项目将使用 MRG 开发的一些方法来教授研究生课程。 该课程的标题是“质谱：对于不止 m/z 有用”，并将培训研究生如何使用 USM 资助的 NSF 质谱设施。 本课程将利用 MRG 开发的测定法来确定酶水解反应（上述合成方法的核心过程）的对映选择性。 学生将学习如何使用这些设施，以便他们可以在自己的研究工作中使用它们，并且 MRG 将能够使用该课程从学生在课程期间进行的分析中获取急需的数据。 质谱分析已成为分析各种分子的常规方法，成功完成课程的学生将获得可转移到各种工作机会的技能。 获得的技能将使学生在不断变化的全球就业市场中具有高度竞争力。