Specificity of Intercalation Reactions

描述(由申请人提供)：DNA是小分子治疗剂中代表性较低的靶标。缺乏DNA靶向药物的一个原因是，控制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。为了制定针对特定DNA位点的设计原则，需要彻底了解现有化合物与DNA结合的机制，这些化合物具有独特类型的选择性。这个项目的长期目标是了解DNA插层反应的机理，特别强调序列和结构选择性结合的能量基础。一个成功和高效的基础科学项目正在寻求更新，该项目已经为DNA靶向药物开发提供了几个有希望的途径。四链G-四链DNA结构是基因组中重要的功能元件，是治疗药物的重要靶点。G-四链体是端粒生物学中重要的功能元件，在许多基因，特别是癌基因的表达中，G-四联体是重要的控制元件。下一个资助期的研究将集中于G-四链结构、折叠和稳定性的生物物理研究，以及它们与类药物分子的选择性相互作用。具体目标包括：1.确定200个核苷酸的单链DNA悬垂的结构，这是人类端粒的一个保守特征。2.测定了高阶四链结构的热力学稳定性和折叠动力学。3.药物与特定四链结构结合的热力学和动力学测定，包括端粒DNA中的高阶结构和c-myc启动子中发现的G-四链“沉默”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，并将为合理设计新的小分子来选择性地针对功能重要的四链体结构提供基本的机制信息。

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.