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

氨基酸是生命的基石，在生物学中被用来制备各种类型的重要物质(即蛋白质、多肽、激素等)。小肽已被证明具有生物活性，并可用于各种场合。然而，小肽经常被内源酶的存在所降解，最终降低了它们以有效方式实现其生物学功能的能力。非天然氨基酸，即自然界中没有或很少发现的氨基酸，已经显示出一种能力，使小肽具有稳定的酶降解能力。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，它们显示出广泛的生物活性。MRG已经开发出允许从常见的合成中间体中制备各种非天然氨基酸的技术。MRG开发的合成策略允许并行制备各种对生长抑素和神经降压素重要的非天然氨基酸。非天然氨基酸将被用来取代生长抑素和神经降压素中的特定氨基酸。这些多肽类似物将被测试它们抵抗酶降解的能力和执行其生物学功能的能力。这项研究的一个主要目的是扩大MRG开发的技术范围，制备各种新的非天然氨基酸，并研究它们对多肽稳定性和功能的影响。项目的广泛影响：本研究开发的方法将通过提供高效的非天然氨基酸制备方法，对科学界产生广泛的影响。本项目中制备的多肽还将为生长抑素和神经降压素的结构与功能关系提供有价值的信息。这些方法和材料将在生物有机和材料科学中得到广泛的应用。该项目是一个跨学科的项目，将酶学、传统有机合成、生物化学和质谱学等领域合并为一个与生物科学和化学相关的项目。该项目将在密西西比州培训下一代科学家，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水平的课程。这门课程的标题是“质谱学：对m/z以上的人有用”，将培训研究生如何使用USM的NSF资助的质谱学设施。本课程将利用MRG中开发的一种分析方法来确定酶促水解反应的对映选择性(这一过程是上述合成方法的核心)。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利用这些设施，MRG将能够使用该课程从学生在课程中进行的测试中获得急需的数据。质谱学已经成为分析各种分子的常规方法，成功完成这门课程的学生将获得可以转移到各种工作机会的技能。所获得的技能将使学生在瞬息万变的全球就业市场中具有很强的竞争力。

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.