Digital one-disc-one-compound array for high-throughput discovery of cancer-targe

描述（由申请人提供）：拟议研究的目的是开发一种微流体引导的数字编码组合方法，称为数字一盘一化合物（ODOC）阵列，将最先进的组合化学与新兴的微流体，微加工，编码和矩阵理论相结合，用于以低成本发现高通量，高效率和高准确度的癌症靶向分子。组合化学作为生物学和医学不可或缺的工具，使生物分子的高效模块化合成和特异性生物靶标先导化合物的高通量探索成为可能。然而，现有的组合策略只允许大规模合成或化学寻址，但不能两者兼而有之。此外，高昂的设备成本和复杂的化学处理限制了它们仅在实验室中的应用。根据所提出的研究，我们的目标是解决大规模组合合成，数字分子鉴定，合成通量，平行筛选和组合体化学的定量分析作为一个整体，通过引入批量制造的微盘载体与数字条形码和矩阵导向的组合合成在可重构的微流体网络。具体而言，将在数字ODOC阵列上设计和合成癌症整合素靶向肽文库，随后在阵列上对细胞-配体相互作用进行微流控定量筛选通过每个单个化合物盘的定量细胞结合获得的全面的结构-活性关系（SAR）数据促进了用于癌症的快速优化的聚焦文库的设计。靶向配体具有比先前发现的那些更高的特异性和亲和力。简而言之，所提出的数字ODOC阵列一旦开发出来，将为靶向各种类型癌细胞受体的生物分子的高通量高效筛选、优化和表征提供变革性范例。

DESCRIPTION (provided by applicant): The objective of the proposed research is to develop a microfluidics-guided digitally encoded combinatorial method, referred to as digital one-disc-one-compound (ODOC) array, integrating state-of-the-art combinatorial chemistry with emerging microfluidics, microfabrication, encoding and matrix theories, for discovery of cancer-targeting molecules with high throughput, high efficiency and high accuracy at low cost. As an indispensable tool for biology and medicine, combinatorial chemistry has enabled high-efficiency modular synthesis of biomolecules and high-throughput exploration of the lead compounds for specific biological targets. However, existing combinatorial strategies only allow either large-scale synthesis or chemical addressability, but not both. Moreover, high equipment cost and complex chemical processing limit their utility to laboratories only. Under the proposed research, we aim at addressing large- scale combinatorial synthesis, digital molecular identification, synthetic throughput, parallel screening, and quantitative analysis of combinatoria chemistry as a whole, by introducing batch-fabricated microdisc carriers with digital barcodes and matrix-directed combinatorial synthesis in reconfigurable microfluidic networks. Specifically, cancer integrin-targeting peptide libraries will be designed and synthesized on the digital ODOC array, followed by microfluidic quantitative screening of the cell-ligand interactions on the array Comprehensive structure-activity relationship (SAR) data obtained by quantitative cell binding of every single compound-disc facilitates design of focused libraries for rapid optimization of cancer-targeting ligands with higher specificity and affinity than those previously discovered. In brief, the proposed digital ODOC array, once developed, will provide a transformative paradigm for high-throughput high-efficiency screening, optimization, and characterization of biomolecules targeting at various types of cancer cell receptors.