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，密歇根州霍普学院的摩西·李教授和佐治亚州立大学的W·大卫·威尔逊教授将开发一类具有极好的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，利用一种新的促进DNA结合的核内DNA结合？策略。该项目的成功将在小分子-DNA相互作用领域和控制基因表达的能力方面产生深远的影响。它最终将有助于个性化医学领域的发展，成为潜在的药物和DNA靶向诊断试剂。最近的工作导致了新化合物的设计，例如地塞米松的聚酰胺类似物，它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于细胞核。这一生物障碍一直是推进聚酰胺领域的主要绊脚石，化学和生物界正在做出重大努力来克服这一物理障碍。这项工作将开发新的策略并探索基础科学，使科学家能够识别细胞中的特定基因并控制其功能。这项由霍普学院的李教授和佐治亚州立大学的W·大卫·威尔逊教授提出的建议具有强大的、更广泛的影响部分。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不同子学科。这将更好地为未来的学生教育，并有助于确保美国S的竞争优势。此外，还将特别重视对妇女和科学界代表性不足群体的学生的培训。李教授和威尔逊教授在让这些学生参与他们的研究项目方面有着长期而成功的记录。学生将从两年制社区学院招生，要么通过希望学院-S国家科学基金会资助的S-STEM项目，要么通过参加芝加哥社区学院联盟的国家科学基金会本科生研究合作项目。高中生还将有机会通过“希望大学”项目“希望的跨文化研究”(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).