NEW CARBOHYDRATE BASED DNA BINDERS

这是香农奖，为这项研究提供部分支持 项目低于指定研究所的资助范围，但 都处于最优秀的边缘。香农奖旨在提供 支持测试该方法的可行性；开发进一步的测试 改进研究方法；对可用的数据进行二次分析 数据集；或执行可演示PI的离散项目 研究能力或为已经功成名就的 申请。下面的摘要摘自原始文件 由首席调查员提交。 描述：首席研究人员表示，小分子 与DNA结合通常作为抗肿瘤药物具有治疗作用 因为它们干扰DNA处理酶和转录 导致新DNA结合剂产生的因素和研究 因此很重要，因为它们增加了 开发具有理想性能的抗肿瘤药物。他指出， 碳水化合物是设计新DNA的理想构件 粘合剂有几个原因；第一，碳水化合物相对较硬 分子，这是结合方面的一个显著优势，第二， 碳水化合物含有一系列的羟基，可以转化为 其他与DNA相互作用的官能团，第三，大自然有 已经提供了一组DNA结合碳水化合物(已知的成分 抗肿瘤药物)在新DNA的设计中用作起始结构 活页夹。这项拟议的研究的目标是探索 碳水化合物作为设计新DNA结合剂的支架。这个 具体目标据说是： I.碱性区域碳水化合物模拟物的合成与评价 多肽二聚体。 A)合成α-(1-4)连接的碳水化合物聚合物作为仿制品 α-螺旋多肽。 B)通过将碳水化合物官能化来模拟bZIP碱性区域 含碱性基团的聚合物。 C)评估单体和二聚体的DNA结合特性 碳水化合物碱性区域的模拟。 二、功能化小沟槽粘结剂的合成与评价 基于Calicheamicin寡糖。 A)开发基于Calicheamin的碳水化合物支架 可以快速合成的低聚糖。 B)使低聚糖具有官能团 类似氨基酸侧链以增加结合亲和力。 Calicheamin A-B-E二聚体的合成与鉴定 三糖。 A)合成Calicheamicin A-B-E三糖二聚体。 B)评价结合亲和力和特异性。 C)应用二聚化策略来创建高亲和力 来自简化碳水化合物支架的碳水化合物基DNA结合剂。

This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION: The principal investigator states that small molecules that bind to DNA frequently have therapeutic utility as antitumor agents because they interfere with DNA processing enzymes and transcription factors and that studies that lead to the generation of new DNA binders are therefore important because they increase the possibility of developing antitumor agents with desirable properties. He notes that carbohydrates are ideal building blocks to use in the design of new DNA binders for several reasons; first, carbohydrates are relatively rigid molecules, which is a significant advantage in binding, second, carbohydrates contain an array of hydroxyls which can be converted to other functional groups that interact with DNA, third, Nature has already provided a set of DNA binding carbohydrates (components of known antitumor agents) to use as starting structures in the design of new DNA binders. The goal of the proposed research is to explore the potential of carbohydrates as scaffolds for the design of new DNA binders. The specific aims are said to be: I. The synthesis and evaluation of carbohydrate mimics of basic region peptide dimers. a) To synthesize alpha-(1-4) linked carbohydrate polymers as mimics for alpha-helical peptides. b) To make bZIP basic region mimics by functionalizing the carbohydrate polymers with basic groups. c) To evaluate the DNA binding properties of both monomers and dimers of the carbohydrate basic region mimics. II. The synthesis and evaluation of functionalized minor groove binders based on the calicheamicin oligosaccharide. a) To develop a carbohydrate scaffold based on the calicheamicin oligosaccharide that can be synthesized rapidly. b) To functionalize the oligosaccharide with functional groups resembling amino acid side chains to increase the binding affinity. III. The synthesis and evaluation of dimers of the calicheamicin A-B-E trisaccharide. a) To synthesize a dimer of the calicheamicin A-B-E trisaccharide. b) To evaluate the binding affinity and specificity. c) To apply the dimerization strategy to creating high affinity carbohydrate-based DNA binders from a simplified carbohydrate scaffold.