Self-Assemble and Programmable Nucleus Permeable Polyamides that Target Specific DNA Sequences with Slow Off-rates and High Affinity: Development of a Molecular Tool Kit

在化学系有机动力学项目的支持下，密歇根州荷兰霍普学院的摩西·李教授和W。格鲁吉亚州立大学的大卫Wilson将开发一类具有极好结合亲和力和序列特异性的H-pin聚酰胺，并开发一种新的策略，使用新的？在核DNA结合促进？战略该项目的成功结果将对小分子-DNA相互作用和控制基因表达的能力产生深远的影响。作为潜在的药物和DNA靶向诊断剂，它最终将有助于个性化医疗领域的发展。最近的工作已经导致了新化合物的设计，例如偏端霉素的聚酰胺类似物，其能够识别基因启动子中的特定DNA序列。这些化合物通常难以进入细胞并定位在细胞核中。这种生物屏障一直是推进聚酰胺领域的主要绊脚石，化学和生物界都在努力克服这种物理障碍。这项工作将开发新的策略和探索基础科学，使科学家能够识别细胞中的特定基因并控制其功能。格鲁吉亚州立大学的大卫·威尔逊有一个强大的更广泛的影响组成部分。它通过研究主题促进跨学科学习，学生将学习化学，生物化学，分子和细胞生物学的各个子学科。这将更好地教育学生的未来，并有助于确保美国？的竞争优势。此外，还将特别重视对妇女和来自科学领域代表性不足群体的学生的培训。李教授和威尔逊有一个长期和成功的记录，从事这些学生在他们的研究计划。学生将通过希望学院从两年制社区学院招募？的NSF资助的S-STEM项目或通过参与芝加哥社区学院联盟的NSF本科生研究合作（URC）项目。高中生也将有机会通过希望学院的跨文化研究计划（REACH）参与这个项目。

With the support of the Organic Dynamics Program in the Chemistry Division, Professor Moses Lee at Hope College in Holland, Michigan and Professor W. David Wilson at Georgia State University will develop a class of H-pin polyamides that possess superb binding affinities and sequence specificity, and develop a new strategy for improving cell permeability using a new ?in nucleus DNA binding promoted? strategy. A successful outcome from this project will have a profound impact in the area of small-molecule-DNA interactions and the ability to control the gene expression. It will ultimately contribute to the advancement of the personalized medicine field, as potential medicines and DNA targeted diagnostic agents. Recent work has led to the design of novel compounds, such as the polyamide analogs of distamycin, which are capable of recognizing specific DNA sequences in the promoters of genes. These compounds generally have difficulty in entering cells and localizing in the nucleus. This biological barrier has been the major stumbling block in advancing the polyamide field and there is a major effort among the chemistry and biology communities to overcome this physical obstacle. This work will develop new strategies and explore fundamental science that will enable scientists to recognize specific genes in cells and control their function.This proposal by Professor Lee at Hope College and Professor W. David Wilson at Georgia State University has a strong broader impacts component. It fosters an interdisciplinary learning through research theme in which students will learn various sub-disciplines of chemistry, biochemistry, molecular and cell biology. This will better educate students for the future and help to ensure America?s competitive edge. In addition, special emphasis will be placed on the training of woman and students from groups underrepresented in the sciences. Professors Lee and Wilson have a long and successful record of engaging these students in their research programs. Students will be recruited from two-year community colleges either through Hope College?s NSF funded S-STEM program or through participation in the NSF Undergraduate Research Collaboratives (URC) program of the Chicago Community Colleges Consortium. High school students will also have an opportunity to participate in this project through the Hope College program called Research Across Cultures at Hope (REACH).