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: 8206689
• 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/8206689
• 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; undergraduate student

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）：该研究项目的长期目标是开发循环极化的发光（CPL），作为对映射识别生物分子并研究金属生物分子系统中的手性结构的工具。分子手性 - 分子的两个镜像不能叠加在彼此上 - 对现代药物研究至关重要。虽然手性结构之间的差异似乎在很小的情况下很小，但化合物的三维结构的轻微变化深刻地改变了给定的化合物与周围环境的相互作用。例如，在1960年代，甲状酸院胺被广泛用于治疗孕吐。其中一位对映异构体可有效减少孕吐，但不幸的是，该药物的其他映异构体引起了先天缺陷。因此，很容易理解为什么单南综合药物很有吸引力，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，估计表明，对映药将产生150亿美元的收入。该提议的中心假设是，由于其在敏感性，可靠性，易用性和最少样本制备方面的优势，CPL是对常见圆二色性（CD）方法的进步。至关重要的是，我们直接和有选择地激发灯笼（III）离子（III）= EU，TB）的方法学改进将增加发光位点之间的歧视，从而使解释更加容易（即CPL将反映LN（III）离子周围的时间平均局部螺旋。特别感兴趣的是使用CPL选择仅研究感兴趣系统中存在的发光发色团的重要性；相比之下，CD受大多数发色团和/或平衡混合物的影响。更具体地说，研究将（1）研究CPL光谱法的敏感性和选择性，用于对映射识别生物分子（例如氨基酸）的分析工具，（2）检查CPL光谱症作为对手性灯笼结构的存在的探针的有效性，该探测器的存在，并指示了（3）的指标（（3） CPL光谱学了解蛋白质的手性结构及其结合金属离子的能力（即Ca（ii），mg（ii）），其中这些金属离子被EU（III）离子取代。 公共卫生相关性：鉴于知道金属结合蛋白可能占所有蛋白质的40％，因此该研究领域引起了极大的兴趣，并且随着连续发现该类别蛋白质的新过程和功能的不断增长。特别重要的是要了解光谱上沉默的碱性二价阳离子Mg（II）和Ca（ii）在许多生物学过程中的功能（即酶活性，核酸稳定，肌肉收缩，分泌或突发传播）。另一方面，对对映体识别生物底物的研究是一项持续的积极研究，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。