SERPENTERCALATORS--NEW NUCLEIC ACID BINDING THERAPEUTICS

描述：本文件中描述的工作的广泛、长期目标 建议是制定生产治疗性药物的一般战略 核酸结合分子。拟议的研究将利用一系列 一种新的DNA结合分子，PI将其命名为“蛇形计算器” 因为当结合到原子核上时，较长的分子呈现出蛇形的形状 酸性双链。Serpentercalator对DNA有很高的亲和力，可以阻止 在体外，几种关键酶的活性，并合成了 固相技术。因此，蛇形切割器代表了最好的核素 酸结合体系目前可用于开展组合作业。 将研究两种不同的组合方法：1)当 与适当的结合分析相结合，所谓的“分子中的针” 干草堆“实验可以用来识别图书馆的成员 重要的生物活性。建议利用的具体目标1-3 组合库的这一方面，用来识别serpentercalator 对重要的核酸序列具有高度的亲和力和特异性。因为 在蛇形切割器的新颖设计中，绝大多数建议的 文库成员将拥有与高亲和力的核酸结合的能力 亲和力。因此，被提议的蛇类计算器的“分子干草堆” 应该是非常肥沃的。2)组合运算的另一个强大性质 图书馆的特点是它们提供了对 分子性质与生物活性之间的相关性。在 拟议的方法(具体目标4)，将是 根据重要的分子性质通过层析进行分级 (如疏水性、电荷性等)；然后，将对组分进行筛选 癌细胞系细胞毒活性的变化趋势。使用这种方法，真正 全面的分子特性-细胞毒性关系将是 最终确定了。由此产生的关系将作为 使用改进的属性丰富后续库的基础，提供 一种优化分子的迭代方法。 底线是拟议的全面研究将提供 对氨基酸如何调节序列特异性的巨大洞察力 核酸结合和分子总性质控制到什么程度 一系列化疗药物的细胞毒性。此外，a 潜在非常重要的抗癌和抗病毒药物的数量 化学治疗先导化合物将被生产和表征。

DESCRIPTION: The broad, long-term goal of the work described in this proposal is to develop general strategies for the production of therapeutic nucleic acid binding molecules. The proposed studies will utilize a series of new DNA-binding molecules that the PI has named "serpentercalators" because of the snake-like form the longer ones assume when bound to nucleic acid duplexes. Serpentercalators have very high affinity for DNA, can block in vitro the activities of several key enzymes, and are synthesized using solid phase techniques. Thus, serpentercalators represent the best nucleic acid binding system currently available for carrying out combinatorial work. Two different combinatorial approaches will be investigated: 1) When coupled to an appropriate binding assay, so-called "needle in the molecular haystack" experiments can be used to identify members of a library that have important biological activity. Specific aims 1-3 of the proposal exploit this aspect of combinatorial libraries to identify serpentercalators with high affinity and specificity for important nucleic acid sequences. Because of the serpentercalators' novel design, the vast majority of the proposed library members will possess the ability to bind nucleic acids with high affinity. Thus, the proposed "molecular haystacks" of serpentercalators should be very fertile. 2) Another powerful attribute of combinatorial libraries is that they provide for the comprehensive identification of correlations between molecular properties and biological activity. In the proposed approach (specific aim 4), serpentercalator libraries will be fractionated by chromatography according to important molecular properties (e.g. hydrophobicity, charge etc.); then, the fractions will be screened for trends in cancer cell line cytotoxic activity. Using this approach, truly comprehensive molecular property-cytotoxicity relationships will be conclusively identified. The resulting relationships will serve as the basis for enriching subsequent libraries with improved properties, providing an iterative approach to optimized molecules. The bottom line is that the proposed comprehensive studies will provide tremendous insight into how amino acids can modulate sequence specificity in nucleic acid binding and to what extent gross molecular properties control cytotoxicity within a series of chemotherapeutic agents. In addition, a number of potentially very important anticancer and antiviral chemotherapeutic lead compounds will be produced and characterized.