Specificity of Intercalation Reactions

描述（由申请人提供）：DNA是小分子治疗剂未被充分代表的靶标。DNA靶向药物缺乏的一个原因是控制DNA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，需要对现有化合物的结合机制有透彻的了解，这些化合物以独特的选择性与DNA结合。该项目的长期目标是了解DNA插入反应的机制，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，已经产生了几个有希望的途径dna靶向药物的开发。四链g -四重体DNA结构已成为基因组中重要的功能元件，并代表了治疗药物的重要新靶点。g -四联体是端粒生物学中重要的功能元件，并且在许多基因，特别是癌基因的表达中成为重要的控制元件。下一个资助期的研究将集中在g-四联体结构、折叠和稳定性的生物物理学研究，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。测定200 nt单链DNA悬垂的结构，这是人类端粒的一个保守特征。2. 确定高阶四重结构的热力学稳定性和折叠动力学。3. 确定药物与特定四重结构结合的热力学和动力学，包括端粒DNA的高阶结构和c-myc启动子中发现的g -四重“沉默者”元件。这些研究结果将加深我们对功能重要的g -四重结构的结构和稳定性的理解，并将为合理设计新的小分子以选择性地靶向功能重要的四重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.