Chiroptical Induced CPL-Based Tool as a Probe of Biological Substrates

基于手性光学诱导 CPL 的工具作为生物底物的探针

• 批准号: 8009847
• 负责人: Gilles Muller
• 金额: $ 10.65万
• 依托单位: SAN JOSE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009847
• 关键词: Accounting; Affect; Amino Acids; Anions; Binding; Binding Proteins; Binding Sites; Biocompatible Materials; Biological; Biological Process; Cardiovascular Diseases; Circular Dichroism; Complement; Congenital Abnormality; Defect; Development; Discrimination; Divalent Cations; Education; Educational process of instructing; Effectiveness; Electron Transport Complex III; Environment; Enzyme Activation; Equilibrium; Europium; Fingerprint; Funding; Funding Agency; Grant; Hand; Health; Image; Ions; Isomerism; Knowledge; Laboratories; Lanthanoid Series Elements; Leadership; Left; Luminescent Measurements; Measures; Metal Ion Binding; Metals; Methodology; Methods; Minority; Minority-Serving Institution; Molecular; Morning Sickness; Muscle Contraction; Neuraxis; Nucleic Acids; Optics; Pattern; Pharmaceutical Preparations; Preparation; Process; Property; Proteins; Reporting; Research; Research Personnel; Research Project Grants; Salts; Sampling; Science; Secure; Shapes; Signal Transduction; Site; Solutions; Spectrum Analysis; Staging; Structure; Students; Synaptic Transmission; System; Temperature; Testing; Thalidomide; Time; Training; Woman; Work; analytical tool; base; cancer therapy; career development; chiral molecule; chromophore; enantiomer; improved; interest; luminescence; molecular recognition; protein structure; sensory system; stereochemistry; three dimensional structure; tool

DESCRIPTION (provided by applicant): The long-term objective of this research project is to develop circularly polarized luminescence (CPL) as a tool for enantioselective recognition of biomolecules and for investigating chiral structures in metal-containing biomolecular systems. Molecular chirality-the property whereby two mirror images of a molecule cannot be superimposed on each other-is crucial to modern drug research. While the difference between chiral structures may seem trivially small, the slight change in the compounds' three-dimensional structure profoundly alters the given compound's interaction with its surroundings. For example, in the 1960s, racemic thalidomide was widely used to treat morning sickness. One of the enantiomers was effective at reducing morning sickness, but unfortunately the drug's other enantiomer caused birth defects. For this reason, it is easy to understand why single-enantiomer drugs are attractive, and researchers are looking at them as possible treatments for cancer, cardiovascular disease, and central nervous system (CNS) defects. In 2009, estimates suggest that enantiopure drugs will produce $15 billion in revenue. The central hypothesis of this proposal is that CPL is an advancement over the common circular dichroism (CD) method due to its superiority in sensitivity, reliability, ease of use, and minimal sample preparation. Of special importance is that our methodological refinement of directly and selectively exciting the lanthanide(III) ion (Ln(III) = Eu, Tb) will increase discrimination between luminescent sites, making interpretation easier (i.e. CPL will reflect the time- averaged local helicity around the Ln(III) ion). Of special interest is the importance of using CPL for selectively studying only luminescent chromophores present in the systems of interest; CD, in contrast, is affected by most chromophores and/or equilibrium mixtures in an additive manner. More specifically, the study will (1) investigate the sensitivity and selectively of CPL spectroscopy used as an analytical tool for enantioselective recognition of biomolecules such as amino acids, (2) examine the effectiveness of CPL spectroscopy as a probe into the existence of chiral lanthanide structures and as an indicator of changes in the chiral structures, and (3) demonstrate the importance of using europium(III) CPL spectroscopy to understand the relationships between the chiral structures of proteins and their ability to bind metal ions (i.e. Ca(II), Mg(II)) where these metal ions are substituted by Eu(III) ions. PUBLIC HEALTH RELEVANCE: With the knowledge that metal-binding proteins may account for as many as 40% of all proteins, this research field has gained a considerable interest and is still growing with the continuous discovery of new processes and functions of this class of proteins. Of special importance is to understand the function of the spectroscopically silent alkaline earth divalent cations Mg(II) and Ca(II) in many biological processes (i.e. enzyme activation, nucleic acid stabilization, muscle contraction, secretion, or synaptic transmission). On the other hand, the study of enantiomeric recognition of biological substrates is an ongoing active research because it can provide valuable information concerning molecular recognition mechanisms in biological materials.

描述（由申请人提供）：本研究项目的长期目标是开发圆偏振发光（CPL）作为生物分子对映选择性识别和研究含金属生物分子体系中手性结构的工具。分子手性--一个分子的两个镜像不能相互叠加的特性--对现代药物研究至关重要。虽然手性结构之间的差异似乎微不足道，但化合物三维结构的微小变化深刻地改变了给定化合物与其周围环境的相互作用。例如，在20世纪60年代，外消旋沙利度胺被广泛用于治疗晨吐。其中一种对映异构体可以有效地减少晨吐，但不幸的是，该药物的另一种对映异构体会导致出生缺陷。因此，很容易理解为什么单一对映体药物具有吸引力，研究人员正在将其视为癌症，心血管疾病和中枢神经系统（CNS）缺陷的可能治疗方法。2009年，估计对映体纯药物将产生150亿美元的收入。该建议的中心假设是，CPL是一个进步，由于其优越性的灵敏度，可靠性，易用性和最小的样品制备的普通圆二色性（CD）的方法。特别重要的是，我们直接和选择性地激发镧系元素（III）离子（Ln（III）= Eu，Tb）的方法学改进将增加发光位点之间的区分，使得解释更容易（即CPL将反映Ln（III）离子周围的时间平均局部螺旋度）。特别感兴趣的是使用CPL的重要性，选择性地研究只存在于感兴趣的系统中的发光发色团;相反，CD受大多数发色团和/或平衡混合物以添加剂的方式。更具体地说，该研究将（1）研究CPL光谱学作为生物分子如氨基酸的对映体选择性识别的分析工具的灵敏度和选择性，（2）研究CPL光谱学作为手性镧系元素结构存在的探针和作为手性结构变化的指示剂的有效性，和（3）证明了使用铕（III）CPL光谱来理解蛋白质的手性结构与它们结合金属离子（即Ca（II）、Mg（II））的能力之间的关系的重要性，其中这些金属离子被Eu（III）离子取代。 公共卫生相关性：随着金属结合蛋白质在蛋白质中所占比例高达40%，这一研究领域已经引起了人们极大的兴趣，并且随着这类蛋白质的新过程和功能的不断发现，这一研究领域仍在不断发展。特别重要的是要了解光谱沉默的碱土金属二价阳离子Mg（II）和Ca（II）在许多生物过程（即酶激活，核酸稳定，肌肉收缩，分泌或突触传递）中的功能。另一方面，生物底物对映体识别的研究是一个正在进行的活跃的研究，因为它可以提供有关生物材料中分子识别机制的有价值的信息。