Dynamic combinatorial chemistry for nucleic acids

描述（由申请人提供）：拟议的研究将开发动态组合化学作为一种新的创新策略，允许生物样品中的DNA或RNA靶标在动态平衡条件下组装其自身的模板。这种化学结合了允许模板产生的引物引发与靶互补的DNA链的合成的元件。该方法的选择性使得可以靶向与人类基因组一样复杂的基因组中的单个DNA序列。然而，该过程的结构允许它以小双链体的有效性来区分单核苷酸变化。与应用分子进化基金会和火鸟生物分子基金会的基础研究/商业使命/计划一致（“我们不进行DNA分析。我们开发了使DNA测定更好的化学”），这将创建一个平台技术，满足目前无法获得的规格：探针的选择性，就像它是一个长的寡核苷酸，但通过探针的歧视，就像它是一个短的寡核苷酸。该平台技术应可应用于许多检测，包括人类诊断和研究市场。在初步研究中，概念证明表明，当目标是DNA时，这种组合化学架构符合新的规格。如果以RNA为靶点可以获得类似的成功，则将通过1期里程碑。人类医学的潜在商业应用是巨大的，首先是生物医学研究中的应用，这些工具将使我们能够检测信使RNA，RNAi和其他在生物学中重要的RNA分子。在过去的十年中，通过应用分子进化基金会的科学家创建的平台化学技术，推动了几种重要的诊断和药物开发工具。这些技术的商业影响远远超过其开发成本，因为它们提供了一套现有化学品无法提供的化学性能规格。拟议的工作将开发另一种平台技术，这一技术允许通过动态组合化学，酶学和核酸科学的新组合来检测核酸靶点。

DESCRIPTION (provided by applicant): The proposed research will develop dynamic combinatorial chemistry as a new and innovative strategy to allow a DNA or RNA target in a biological sample to assemble its own template under conditions of dynamic equilibrium. This chemistry incorporates element that allows the template-created primer to primes the synthesis of a strand of DNA complementary to the target. The selectivity of the process is such that a single DNA sequence in a genome as complex as the human genome can be targeted. The architecture of the process, however, allows it to discriminate against single nucleotide changes with the effectiveness of small duplexes. Consistent with the basic research/business mission/plan of the Foundation for Applied Molecular Evolution and Firebird Biomolecular ("We do not make DNA assays. We develop chemistry that makes DNA assays better"), this will create a platform technology that meets specifications that are unavailable at the present time: selectivity of a probe as if it were a long oligonucleotide, but discrimination by the probe as if it were a short oligonucleotide. This platform technology should have application in many assays, including in human diagnostics and research markets. In preliminary studies, a proof of concept showed that this combinatorial chemistry architecture met the novel specifications when the target was DNA. The Phase 1 milestone will be passed if similar success can be obtained with RNA as a target. Potential commercial applications in human medicine are substantial, starting with applications in biomedical research, where these tools will allow us to detect messenger RNA, RNAi, and other RNA molecules important in biology. Several important diagnostics and drug development tools been driven in the past decade through the creation of platform chemical technologies by scientists at the Foundation for Applied Molecular Evolution. Such technologies have commercial impact far beyond their development costs because they deliver a set of chemical performance specifications that is unavailable by existing chemistry. The proposed work will develop another platform technology, this one allowing the detection of nucleic acid targets through a novel combination of dynamic combinatorial chemistry, enzymology, and nucleic acid science.