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: 7761712
• 负责人: Gilles Muller
• 金额: $ 10.76万
• 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/7761712
• 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; 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; public health relevance; 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(申请人提供)：本研究项目的长期目标是开发圆偏振发光(CPL)作为生物分子的对映选择性识别和研究含金属生物分子体系中的手性结构的工具。分子手性--分子的两个镜像不能相互重叠的特性--对现代药物研究至关重要。虽然手性结构之间的差异看起来微不足道，但化合物三维结构的微小变化却深刻地改变了给定化合物与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。其中一种对映体有效地减少了晨吐，但不幸的是，该药物的另一种对映体导致了出生缺陷。出于这个原因，很容易理解为什么单一对映体药物具有吸引力，研究人员正在将它们视为癌症、心血管疾病和中枢神经系统(CNS)缺陷的可能治疗方法。据估计，2009年，对映性药物将产生150亿美元的收入。这一建议的中心假设是，CPL是相对于普通圆二色(CD)方法的进步，因为它在灵敏度、可靠性、易用性和最少的样品制备方面具有优势。特别重要的是，我们对直接和选择性激发稀土(III)离子(Ln(III)=Eu，Tb)的方法进行了改进，这将增加发光位置之间的区分，使解释变得更容易(即CPL将反映Ln(III)离子周围的时间平均局部螺旋度)。特别令人感兴趣的是，使用CPL选择性地只研究存在于感兴趣体系中的发光生色团的重要性；相比之下，CD以相加的方式受到大多数生色团和/或平衡混合物的影响。更具体地说，这项研究将(1)考察CPL光谱作为分析工具用于对氨基酸等生物分子的对映选择性识别的灵敏度和选择性，(2)考察CPL光谱作为探查手性稀土结构的存在和手性结构变化的指示剂的有效性，以及(3)论证使用Eu(III)CPL光谱来了解蛋白质的手性结构与其与金属离子(即Ca(II)，Mg(II))结合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：随着金属结合蛋白可能占所有蛋白质的40%的知识，这一研究领域已经获得了相当大的兴趣，并随着这类蛋白质新的过程和功能的不断发现而不断增长。特别重要的是要了解光谱上沉默的碱土二价阳离子镁(II)和钙(II)在许多生物过程中的功能(即酶激活、核酸稳定、肌肉收缩、分泌或突触传递)。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研究，因为它可以提供关于生物材料中分子识别机制的有价值的信息。