Heterocycle Cation Recognition of the DNA Minor Groove.

DNA 小沟的杂环阳离子识别。

• 批准号: 8425069
• 负责人: W David Wilson
• 金额: $ 38.11万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425069
• 关键词: Accounting; Address; Affinity; Africa; African Trypanosomiasis; Amino Acid Motifs; Antiparasitic Agents; Area; Base Pairing; Binding; Binding Sites; Biological; Biological Testing; Cations; Cells; Chagas Disease; Circular DNA; Clinical; Collaborations; Complex; Coupled; Crystallography; DB75; DNA; DNA Sequence; DNA Structure; Daughter; Development; Diamidine; Disease; Drug Receptors; Eukaryotic Cell; Exhibits; Funding; Genome; Genomics; Goals; Grant; Human; Infection; Kinetoplast DNA; Knowledge; Letters; Libraries; Link; London; Maintenance; Major Groove; Methods; Minor Groove; Mitochondria; Modeling; Molecular; New Agents; Parasites; Parasitic Diseases; Parents; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Population; Prodrugs; Proteome; Public Health; Quinolone Antibiotic; Reaction; Research; Research Design; Risk; Site; Specificity; Structure; Testing; Therapeutic; Thermodynamics; Toxic effect; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis; Water; Work; base; cellular targeting; design; drug development; flexibility; improved; innovation; interfacial; kDNA Minicircles; microorganism; news; novel; public health relevance; receptor; small molecule; uptake

DESCRIPTION (provided by applicant): Although about 40% of the world population is at risk of deadly parasitic disease infections, there are insufficient safe, reliable drugs for treatment of or under development for these diseases. The field is limited by ideas for novel cellular receptors or types of drugs. The research in this proposal is focused on methods to address both problems. We propose compounds that can selectively target a unique cellular target, the thousands of AT-rich, DNA minicircles that are interlocked into the parasite mitochondrial kinetoplast genome. Our proposal has plans for innovative approaches to inhibit the complex replication reactions of the minicircles involved with opening, copying and restructuring daughter/parent kinetoplasts. We will approach the problem from a fundamental basis and will design and synthesize new types of compounds to interfere with kinetoplast replication. We will conduct biophysical studies on both model and kinetoplast DNAs with the innovative new compounds and the results will be correlated with cell uptake and distribution studies that are done by collaborating groups of recognized parasite biologists. Three specific aims describe new directions in our research that are largely based on discoveries from the funded project. Our general hypothesis is: we can establish a fundamental basis for the design of new types of compounds that have therapeutic potential as a result of synergistic effects on the nonstandard DNA sequences and structures of the kinetoplast. To do this research two collaborating groups will conduct focused compound synthesis along with biophysical characterization of DNA complexes to answer specific questions that are very difficult to answer by other approaches. Under aim 1 we build on a discovery that shows the classical model for minor groove binding is too limited and that linear compounds can bind strongly and specifically to DNA by using interfacial water. We will explore the limits on linear compound binding and determine if there is a thermodynamic signature for complexes with a bound water. Under aim 2 we propose completely new types of compounds, which are designed to mimic protein motifs and cause significant bending of DNA. One set uses two connected AT site binding units with a short linker to bend the helix into the minor groove. The other set uses a strong binding minor groove motif with a partial intercalating wedge to bend DNA into the major groove. Such effects on structure should be particularly pronounced at the kinetoplast of parasites. Under aim 3 we use the fact that kinetoplasts are AT rich but their AT sequences are broken into small units that are typically separated by one or two GC base pairs. We propose compounds with strong-binding AT motifs that are linked with groups that specifically recognize intervening GC base pairs. This added GC selectivity, coupled to specific terminal AT recognizing motifs, will provide high specificity for sites that are quite common in kinetoplast DNA. We have a unique, collaborative research team, which has rewritten the mechanism for small molecule-minor groove complex formation and for design of compounds for DNA therapeutics, to carry out this research.

描述（由申请人提供）：尽管大约40％的世界人口有致命的寄生疾病感染的风险，但这些疾病的安全性，可靠的药物不足以治疗或正在开发的这些疾病。该领域受到新型细胞受体或药物类型的想法的限制。该提案中的研究集中在解决这两个问题的方法上。我们提出的化合物可以选择性地靶向独特的细胞靶标，即成千上万的富含DNA的小圆圈，它们互锁到寄生虫线粒体动力学基因组中。我们的建议计划了创新方法，以抑制与开放，复制和重组女儿/家长动力学相关的小圆圈的复杂复制反应。我们将从基本的基础上解决该问题，并将设计和合成新型化合物以干扰动力学复制。我们将使用创新的新化合物对模型和动力学DNA进行生物物理研究，结果将与通过合作认可的寄生虫生物学家组协作进行的细胞摄取和分布研究相关。三个具体目的描述了我们的研究中的新方向，这些方向主要基于资助项目的发现。我们的一般假设是：我们可以为设计具有治疗潜力的新型化合物的设计基本基础，这是由于对动力学的非标准DNA序列和结构的协同作用而产生的。为了进行这项研究，两个合作组将进行集中的化合物合成以及DNA复合物的生物物理表征，以回答其他方法很难回答的特定问题。在AIM 1下，我们建立在一个发现的基础上，该发现显示了小凹槽结合的经典模型过于限制，并且线性化合物可以通过使用界面水强烈，专门与DNA结合。我们将探索线性化合物结合的限制，并确定是否有与结合水的复合物的热力学特征。在AIM 2下，我们提出了全新类型的化合物，这些化合物旨在模仿蛋白质基序并引起DNA的明显弯曲。一组使用两个连接在现场绑定单元的连接单元，将螺旋弯曲到小凹槽中。另一组使用具有强的结合小凹槽基序，其中有部分插入楔块将DNA弯曲到主要凹槽中。这种对结构的影响应特别明显在寄生虫的动力学上。在AIM 3下，我们使用的是，动力学成形素在富集中，但它们的序列分为通常由一个或两个GC碱基对隔开的小单元。我们提出的化合物在基序上具有较强的结合，这些化合物与专门识别中间GC碱基对的组相关。这增加了GC选择性，并在识别基序中耦合到特定终端，将为动力学DNA中常见的位点提供高特异性。我们有一个独特的协作研究团队，该团队重写了小分子磨牙凹槽复合物的机制，并为DNA Therapeutics的化合物设计了这项研究。