RNA/DNA BINDING MOLECULES AS TELOMERASE INHIBITORS

这个项目的目标是设计和合成小型 能够识别和稳定RNA/DNA的分子 异源双链(R/D)。我们假设能够做到的分子 这将有效地抑制端粒酶，端粒酶是抗癌的靶标。 心理治疗。端粒酶是一种延伸端粒的酶，单个C- 位于染色体末端的富链。它被假设为 通过端粒酶在癌细胞中维持端粒 不受控制的细胞分裂，从而导致肿瘤生长。端粒酶是一种 含有单链核糖核蛋白的核糖核蛋白 与富含G的端粒互补的序列。端粒酶的RNA 与DNA连接并作为端粒延伸的模板， 从而形成R/D。在合成端粒的一个重复之后 序列中，RNA和DNA链分离、移位、再退火和 重复聚合反应。我们预计，对一个小的 分子连接到在活性中心形成的R/D的小凹槽 将稳定双重结构并防止两者分离 思特斯。这是在识别分子的小分子中观察到的 DNA/DNA双链的小凹槽(D/D)。两者之间存在显著差异 在R/D和D/D之间，应该允许定制特定的D/D 分子是R/D特定的分子。已确定的主要差异 R/D的小凹槽深度减小，宽度增加 相对于D/D，以及2‘羟基的存在。我们 将利用分子建模技术来设计可以 利用这些差异并通过以下方式评估设计的有效性 与核苷酸靶标以及最终与端粒酶的结合分析 抑制力。

The objectives of this project are to design and synthesize small molecules which are able to recognize and stabilize RNA/DNA heteroduplexes (R/D). We hypothesize that molecules that are able to do this will be effective at inhibiting telomerase, a target for anticancer therapy. Telomerase is an enzyme which extends telomeres, the single C- rich strand at the end of chromosomes. It is hypothesized that the maintenance of telomeres by telomerase in cancerous cells allows uncontrolled cell division, and therefore tumor growth. Telomerase is a ribonucleoprotein which contains a single strand of RNA that has a sequence complementary to the G-rich telomere. The RNA from telomerase anneals to the DNA and acts as a template to extension of the telomere, thus forming an R/D. After synthesis of one repeat of the telomeric sequence, the RNA and DNA strands separate, translocate, reanneal and repeat the polymerization. We anticipate that the binding of a small molecule to the minor groove of the R/D that forms at the active site will stabilize the duplex structure and prevent separation of the two strands. This is what is observed with small molecules that recognize the minor groove of DNA/DNA duplexes (D/D). There are significant differences between R/D and D/D that should allow the tailoring of D/D specific molecules to be R/D specific molecules. The main differences identified are a decreased depth and increased width in the minor groove of R/D relative to D/D, as well as the presence of the 2' hydroxyl group. We will utilize molecular modeling techniques to design molecules which can exploit these differences and assess the validity of design through binding analysis to nucleotide targets and eventually telomerase inhibition.