DNA编码化合物库技术新进展及其在生物医药领域的应用与展望

Progress of DNA Encoded Compound Library Technology and Its Applications and Perspectives in Biomedicine

关键词:  DNA编码化合物库技术  组合化学  亲和筛选  药物发现

Key words:  DNA encoded compound library  combinatorial chemistry  affinity screening  drug discovery

摘要:

随着医药领域对靶向调节特定生命活动过程的新分子化合物的需求日益增加，高效、低成本地发现亲和配体分子的新型小分子药物筛选技术——DNA编码的化合物库(DNA encoded compound library，DEL)筛选技术应运而生。DEL作为组合化合物库，可以是简单小分子化合物的集合，也可以是具有高级空间结构的复杂小分子库，每个化合物都以共价方式与特异的DNA序列偶联，因而可将库中所有化合物与靶标蛋白进行合并筛选，随后使用高通量测序对DNA编码序列进行测序来鉴定结合的配体分子。近年来，应用DEL技术筛选开发候选药物的例子已越来越多地被报道，本文回顾和总结了DEL技术的实施流程，特别是DEL库构建和亲和筛选方法的最新研究进展，展示了利用DEL技术筛选开发的最新亲和配体分子，并对DEL技术在生命科学领域的应用前景作了展望。

Abstract:

With the increasing demand of discovering new molecules that specifically modulate certain biological processes in pharmaceutical industry and life sciences, a novel small molecule screening technology for efficient and cost-effective discovery of affinity ligand molecules, the DNA encoded compound library(DEL) screening technology has been developed. DEL is a combinatorial chemical library comprising an unprecedented number of either simple chemicals or those with highly sophisticated structures. Each compound in the library is attached to a unique DNA tag in a covalent manner, allowing the compounds to be pooled and screened against a target protein. The binding hits can subsequently be identified based on the DNA codes through high-throughput sequencing. In recent years, the application of DEL technology in the development of clinical drug candidates has been widely reported. This paper reviews and summarizes the process and progress of DEL technology, especially recent advancements in DEL library construction and affinity screening methods, demonstrates the latest affinity ligand molecules screened and developed by DEL technology. The perspectives of the application of DEL in life sciences including biomedicine and other fields are discussed.