SERPENTERCALATORS--NEW NUCLEIC ACID BINDING THERAPEUTICS

描述：本文所述工作的广泛、长期目标 建议是制定生产治疗药物的一般战略， 核酸结合分子。 拟议的研究将利用一系列 PI将其命名为"蛇形噬菌体"的新型DNA结合分子 由于蛇的形状，当与核结合时， 酸性双链体。 蛇白蚁对DNA有很高的亲和力，可以阻断 在体外的几个关键酶的活性，并合成使用 固相技术 因此，蛇蚁代表了最好的核酸 酸结合系统目前可用于进行组合工作。 将研究两种不同的组合方法：1）当 结合适当的结合测定，即所谓的"分子中的针"， 可以使用"干草堆"实验来鉴定具有以下特征的文库成员： 重要的生物活性。 提案的具体目标1 - 3利用 这方面的组合文库，以确定蛇形白蚁与 对重要核酸序列具有高亲和力和特异性。 因为 在蛇形动物的新颖设计中，绝大多数建议 文库成员将具有结合核酸的能力， 亲和力 因此，被提出的蛇形翼龙的"分子干草堆" 应该非常肥沃。 2)另一个强大的属性组合 图书馆是他们提供全面的识别 分子特性和生物活性之间的相关性。 在 建议的方法（具体目标4），serpentercalator库将 根据重要的分子特性通过色谱法进行分级 (e.g.疏水性、电荷等）;然后，将筛选馏分， 癌细胞系细胞毒活性的趋势。 通过这种方式，真正 全面的分子特性-细胞毒性关系将是 最终确定。 由此产生的关系将作为 为用改进的性质丰富后续文库提供基础， 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， 核酸结合以及总体分子特性控制的程度 在一系列化疗剂中的细胞毒性。 另外还有按 许多潜在的非常重要的抗癌和抗病毒药物 将产生和表征化学治疗先导化合物。

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.