Platform for Massively Parallel Selection of Aptamer Ligands

适体配体大规模并行选择平台

• 批准号: 7745690
• 负责人: George W Jackson
• 金额: $ 12.36万
• 依托单位: BIOTEX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745690
• 关键词: Address; Affinity; Antibodies; Binding; Biological Markers; Characteristics; Classification; Cloning; Cluster Analysis; Computer software; Coupled; Custom; DNA; DNA Library; DNA Sequence Analysis; Data; Development; Diagnostic; Effectiveness; Evaluation; Evolution; Glass; Goals; Image; In Situ Hybridization; Individual; Label; Libraries; Ligands; Linux; Marketing; Methods; Nucleic Acids; Oligonucleotides; Paper; Pharmaceutical Preparations; Phase; Positioning Attribute; Procedures; Process; Protein Array; Proteins; Pyroxylin; RNA; RNA library; Recovery; Reporting; Research; Running; Safety; Services; Slide; Small Business Innovation Research Grant; Specificity; Subgroup; Surface; Surface Plasmon Resonance; System; Technology; Testing; Therapeutic; Time; Writing; aptamer; base; combinatorial; cost; density; drug candidate; drug development; innovation; interest; lead series; next generation; novel; novel therapeutics; public health relevance; tool

DESCRIPTION (provided by applicant): Aptamers have emerged as one of the most promising classes of drug leads and diagnostic ligands presently available. Aptamers, nucleic acid ligands derived from large combinatorial libraries, typically have affinities and specificities that rival antibodies, yet they have a number of significant advantages for therapeutic and diagnostic applications. Unfortunately, the present process for aptamer development is low-throughput and tedious as DNA or RNA libraries are screened against only a single target. This project focuses on developing the methods and tools to allow large combinatorial to be screened against arrays of thousands of proteins simultaneously. Such protein arrays are increasing available with content of high therapeutic and diagnostic value. The key to achieving this is developing the necessary steps to decipher which aptamers (once selected) correspond to which target. So-called "next generation" sequencing will greatly enable the proposed process coupled with the necessary "sequence- tagging" approaches developed in this project. Once our massively parallel aptamer selection process is developed, we will be in a position to create high affinity aptamer ligands to thousands of proteins in roughly 1 week. The developed ligands will can then be further characterized as promising drug candidates, diagnostic labels, and other research applications. PUBLIC HEALTH RELEVANCE: A recent white paper by the US Federal Drug Administration finds that there exists a critical problem in bringing novel drugs to market, something the FDA describes as the 'pipeline problem'. According to this and other reports drug companies spend an average of $0.8-1.7 billion dollars on the discovery, development and approval of any one individual drug. To make matters worse, the time from the initial testing of a drug candidate and to its eventual marketing can take up to 20 years. Thus, the FDA report strongly urges the incorporation of novel quantitative predictive tools for the assessment of safety and efficacy of new drug leads and diagnostic ligands early in the drug development process. This project provides for the parallel development and evaluation of enormous combinatorial libraries of DNA or RNA 'aptamers' against of thousands of protein targets of potential 'druggable' interest. If successful, the technology could provide for unprecented throughput of drug leads and diagnostic ligands.

描述（由申请人提供）：适体已成为目前可用的最有前途的一类药物先导物和诊断配体。适体，衍生自大型组合文库的核酸配体，通常具有与抗体竞争的亲和力和特异性，但它们对于治疗和诊断应用具有许多显著的优点。不幸的是，目前用于适体开发的方法是低通量和冗长的，因为DNA或RNA文库仅针对单一靶标进行筛选。该项目的重点是开发方法和工具，以允许同时对数千种蛋白质的阵列进行大的组合筛选。这种蛋白质阵列越来越多地具有高治疗和诊断价值的内容。实现这一目标的关键是开发必要的步骤来破译哪些适体（一旦选择）对应于哪个靶标。所谓的“下一代”测序将极大地使所提出的过程与该项目中开发的必要的“序列标记”方法相结合。一旦我们的大规模并行适体选择过程被开发出来，我们将能够在大约1周内为数千种蛋白质创建高亲和力适体配体。然后，开发的配体可以进一步表征为有前途的候选药物、诊断标记和其他研究应用。公共卫生关系：美国联邦药品管理局最近的一份白色文件发现，在将新药推向市场方面存在一个关键问题，FDA称之为“管道问题”。根据这份报告和其他报告，制药公司平均花费8亿至17亿美元用于发现、开发和批准任何一种药物。更糟糕的是，从候选药物的初步测试到最终上市的时间可能长达20年。因此，FDA的报告强烈敦促在药物开发过程的早期引入新的定量预测工具，用于评估新药先导化合物和诊断配体的安全性和有效性。该项目提供了针对数千种潜在的“可药用”蛋白质靶标的DNA或RNA“适体”的巨大组合文库的并行开发和评估。如果成功，该技术可以提供前所未有的药物先导物和诊断配体的通量。