Specificity of Intercalation Reactions

描述（由申请人提供）：DNA是小分子治疗剂的代表性不足的靶标。缺乏DNA靶向药物的一个原因是，对DNA的序列和结构选择性配体的基本分子机制仍然知之甚少。为了开发针对特定DNA位点的设计原则，需要彻底了解以独特类型的选择性结合DNA的现有化合物的结合机制。该项目的长期目标是了解DNA嵌入反应的机制，特别强调序列和结构选择性结合的能量基础。更新是寻求一个成功的和高产的基础科学计划，产生了几个有前途的途径，DNA靶向药物的开发。四链G-四链体DNA结构已经成为基因组中重要的功能元件，并且代表了治疗药物的重要新靶标。G-四链体是端粒生物学中重要的功能元件，并且正在成为许多基因，特别是癌基因表达的重要控制元件。下一个资助期的研究将集中在G-四链体结构、折叠和稳定性的生物物理研究，以及它们与药物样分子的选择性相互作用。具体目标包括：1.确定200 nt单链DNA突出端的结构，这是人类端粒的保守特征。2.高阶四链体结构的热力学稳定性和折叠动力学的测定。3.确定药物与特定四链体结构结合的热力学和动力学，包括端粒DNA中的高阶结构和c-myc启动子中发现的G-四链体“沉默物”元件。这些研究的结果将加深我们对功能重要的G-四链体的结构和稳定性的理解，并将提供基本的机制信息，用于新的小分子的合理设计，以选择性地靶向功能重要的四链体结构。

DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligands to DNA remain poorly understood. In order to develop design principles for targeting specific DNA sites, a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of selectivity is needed. The long-range goal of this project is to understand the mechanism of DNA intercalation reactions, with particular emphasis on the energetic basis of sequence- and structural-selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Four-stranded G-quadruplex DNA structures have emerged as important functional elements within the genome, and represent important new targets for therapeutic drugs. G-quadruplexes are functional elements that are important in telomere biology, and are emerging as important control elements in the expression of many genes, particularly oncogenes. Research in the next funding period will focus on biophysical studies of G-quadruplex structure, folding and stability, and on their selective interactions specific quadruplex structures with drug-like molecules. Specific aims include: 1. Determination of the structure of the 200 nt single-stranded DNA overhang that is a conserved feature of human telomeres. 2. Determination of the thermodynamic stability of higher-order quadruplex structures and the kinetics of the folding. 3. Determination of the thermodynamics and kinetics of drug binding to specific quadruplex structures, including the higher-order structures in telomeric DNA and the G-quadruplex "silencer" element found in the c-myc promoter. The results of these proposed studies will deepen our understanding of the structure and stability of functionally important G-quadruplexes, and will provide fundamental mechanistic information of use in the rational design of new small molecules to selectively target functionally important quadruplex structures.