Heterocycle Binding and Biology in the DNA Minor Groove

DNA 小沟中的杂环结合和生物学

• 批准号: 7174197
• 负责人: W David Wilson
• 金额: $ 31.04万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174197
• 关键词: AT Rich Sequence; Accounting; Address; Affinity; Binding; Binding Sites; Biological; Biological Testing; Biology; Cations; Characteristics; Classification; Clinical; Complex; DB75; DNA; DNA Binding; DNA Sequence; DNA Structure; DNA-Protein Interaction; Development; Disease; Drug Design; Enhancers; Enzymes; Eukaryotic Cell; Exhibits; Genetic Transcription; Goals; HMGA1a Protein; Human; Ions; Kinetoplast DNA; Leishmania; Libraries; Malaria; Methods; Minor Groove; Modeling; Modification; Molecular; Nature; New Agents; Organism; Parasites; Parents; Peptides; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Positioning Attribute; Prodrugs; Property; Protein Inhibition; Proteins; Range; Research; Research Personnel; Schedule; Shapes; Site; Solvents; Specificity; Structure; System; Testing; Therapeutic; Thermodynamics; Topoisomerase II; Toxic effect; Trypanosoma; Trypanosomiasis; Work; antimicrobial drug; base; combinatorial chemistry; design; in vivo; insight; killings; microorganism; molecular recognition; novel; programs; stoichiometry

DESCRIPTION (provided by applicant): Heterocyclic cations, developed by our collaborative research groups, bind specifically to extended AT sequences in the DNA minor groove. These compounds have shown clinical biological activity with low human toxicity against several parasitic microorganisms, and an orally available prodrug has progressed through Phase II clinical trials against several parasitic organisms. The compound is scheduled to begin Phase III trials against human trypanosomiasis in October 2004. Biophysical and in vivo biological studies clearly suggest that the target of action of the compounds is DNA and, in particular, the kinetoplast DNA (kDNA) of kinetoplastid microorganisms, such as trypanosomes and leishmania. The heterocyclic cations have shown in vivo ability to block transcription enhancer binding to AT rich sequences and to redistribute the topoisomerase II enzyme, which is critical for replication of the unique kDNA system into AT rich regions. Our hypothesis is that both of these effects require synergistic action of closely bound drug molecules in the AT rich kDNA. The research in this proposal is designed to develop new DNA-targeted antimicrobial drugs by providing a better understanding of the molecular basis of the biological action of the dications in parasites. We will use both parallel and combinatorial chemistry approaches to develop systematic and rational sets of new compounds to address specific questions about the heterocycle-DNA complexes. A battery of traditional, as well as novel biophysical methods, will be used to evaluate the interactions of the compounds with different DNA sequences, such as those that they target in the microorganisms. We are specifically focused on the effects on DNA structure and protein inhibition of cooperative binding of the compounds at closely spaced AT rich binding sites. Both long and short range effects of the compounds on DNA structure and properties will be evaluated. Detailed structural studies will be conducted with selected compounds that we feel can provide fundamental insight into the molecular recognition mechanisms. We will test the ability of the compounds to inhibit transcription enhancers that selectively target AT rich sequences by using model peptide systems, as well as in vivo analysis of protein inhibition. All new compounds will be tested against several microorganisms, and the results will be correlated with their ability to bind DNA and inhibit protein-DNA interactions and functions.

描述（由申请人提供）：由我们的协作研究小组开发的杂环阳离子专门与DNA小凹槽中的序列扩展。这些化合物已经显示出对几种寄生微生物的人类毒性低的临床生物学活性，并且通过对几种寄生生物的II期临床试验进行了口服的前药。该化合物计划于2004年10月开始针对人类锥虫病的III期试验。生物物理和体内生物学研究清楚地表明，这些化合物的作用靶标是DNA，尤其是动力学生体DNA（kDNA），诸如动型微生物的动力学和诸如Trypanososomes和leishmania and leishmania and。杂环阳离子已经显示出在体内能够阻断在富序列上结合转录增强子并重新分布拓扑异构酶II酶的能力，这对于将独特的kDNA系统复制到丰富的区域至关重要。我们的假设是，这两种效应都需要在富kDNA中紧密结合的药物分子的协同作用。该提案中的研究旨在通过更好地理解寄生虫中diCations生物学作用的分子基础来开发新的靶向DNA靶向抗菌药物。我们将使用平行和组合化学方法来开发系统和合理的新化合物集，以解决有关杂环-DNA复合物的特定问题。一系列传统的以及新型的生物物理方法将用于评估化合物与不同DNA序列的相互作用，例如它们在微生物中靶向的序列。我们专门针对对DNA结构和蛋白质抑制的影响，对在丰富结合位点紧密间隔的化合物的合作结合。将评估化合物对DNA结构和特性的长范围和短范围影响。详细的结构研究将使用我们认为可以提供对分子识别机制的基本见解的选定化合物进行。我们将测试化合物通过使用模型肽系统以及蛋白质抑制的体内分析抑制在丰富序列中抑制转录增强子的能力。所有新化合物将针对几种微生物进行测试，结果将与它们结合DNA并抑制蛋白-DNA相互作用和功能的能力相关。