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首页> 外文会议>Microfluidics, bioMEMS, and medical microsystems XV >Lab-on-a-chip platform for high throughput drug discovery with DNA-encoded chemical libraries
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Lab-on-a-chip platform for high throughput drug discovery with DNA-encoded chemical libraries

机译：芯片实验室平台，用于通过DNA编码的化学文库进行高通量药物发现

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摘要

The fast development of DNA-encoded chemical libraries (DECL) in the past 10 years has received great attention from pharmaceutical industries. It applies the selection approach for small molecular drug discovery. Because of the limited choices of DNA-compatible chemical reactions, most DNA-encoded chemical libraries have a narrow structural diversity and low synthetic yield. There is also a poor correlation between the ranking of compounds resulted from analyzing the sequencing data and the affinity measured through biochemical assays. By combining DECL with dynamical chemical library, the resulting DNA-encoded dynamic library (EDCCL) explores the thermodynamic equilibrium of reversible reactions as well as the advantages of DNA encoded compounds for manipulation/detection, thus leads to enhanced signal-to-noise ratio of the selection process and higher library quality. However, the library dynamics are caused by the weak interactions between the DNA strands, which also result in relatively low affinity of the bidentate interaction, as compared to a stable DNA duplex. To take advantage of both stably assembled dual-pharmacophore libraries and EDCCLs, we extended the concept of EDCCLs to heat-induced EDCCLs (hi-EDCCLs), in which the heat-induced recombination process of stable DNA duplexes and affinity capture are carried out separately. To replace the extremely laborious and repetitive manual process, a fully automated device will facilitate the use of DECL in drug discovery. Herein we describe a novel lab-on-a-chip platform for high throughput drug discovery with hi-EDCCL. A microfluidic system with integrated actuation was designed which is able to provide a continuous sample circulation by reducing the volume to a minimum. It consists of a cooled and a heated chamber for constant circulation. The system is capable to generate stable temperatures above 75 ℃ in the heated chamber to melt the double strands of the DNA and less than 15 ℃ in the cooled chamber, to reanneal the reshuffled library. In the binding chamber (the cooled chamber) specific retaining structures are integrated. These hold back beads functionalized with the target protein, while the chamber is continuously flushed with library molecules. Afterwards the whole system can be flushed with buffer to wash out unspecific bound molecules. Finally the protein-loaded beads with attached molecules can be eluted for further investigation.
机译：在过去的十年中，DNA编码化学文库（DECL）的快速发展引起了制药行业的极大关注。它适用于小分子药物发现的选择方法。由于DNA相容性化学反应的选择有限，大多数DNA编码的化学文库具有狭窄的结构多样性和较低的合成产率。通过分析测序数据得到的化合物的排名与通过生化分析测得的亲和力之间也存在不良关联。通过将DECL与动态化学文库结合使用，所得的DNA编码的动态文库（EDCCL）探索了可逆反应的热力学平衡以及DNA编码的化合物在操作/检测方面的优势，从而提高了ECL的信噪比。选择过程和更高的图书馆质量。但是，文库动力学是由DNA链之间的弱相互作用引起的，与稳定的DNA双链体相比，这也导致二齿相互作用的亲和力相对较低。为了利用稳定组装的双药效团库和EDCCL的优势，我们将EDCCL的概念扩展到热诱导的EDCCL（hi-EDCCL），在热诱导的EDCCL中，稳定的DNA双链体的热诱导重组过程和亲和力捕获分别进行。为了取代极其费力且重复的手动过程，全自动设备将促进DECL在药物发现中的使用。在这里，我们描述了一种新型的芯片实验室平台，可通过hi-EDCCL进行高通量药物发现。设计了具有集成驱动的微流体系统，该系统能够通过将体积减小到最小来提供连续的样品循环。它由一个用于持续循环的冷却室和加热室组成。该系统能够在加热室中产生高于75℃的稳定温度，以融化DNA的双链，而在冷却室中低于15℃，以重新退火改组的文库。在装订室（冷却室）中集成了特定的固定结构。这些会阻止被目标蛋白功能化的珠子，而腔室会连续被文库分子冲洗。然后，可以用缓冲液冲洗整个系统，以洗去非特异性结合的分子。最后，可以洗脱带有附着分子的蛋白质珠，以进行进一步研究。

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  • 来源
    《Microfluidics, bioMEMS, and medical microsystems XV》|2017年|1006111.1-1006111.13|共13页
  • 会议地点 San Francisco(US)
  • 作者

    S. Grunzner; F. V. Reddavide; C. Steinfelder; M. Cui; M. Busek; U. Klotzbach; Y. Zhang; F. Sonntag;

  • 作者单位

    Technische Universitat Dresden, Institute of Manufacturing Technology, Dresden, Germany,Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany;

    B CUBE Center for Molecular Bioengineering, Technische Universitat Dresden, Dresden, Germany;

    Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany;

    B CUBE Center for Molecular Bioengineering, Technische Universitat Dresden, Dresden, Germany;

    Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany;

    Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany;

    B CUBE Center for Molecular Bioengineering, Technische Universitat Dresden, Dresden, Germany;

    Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany;

  • 会议组织
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Lab-on-a-chip; Microfluidics; DNA-encoded chemical libraries; Drug discovery; Dynamic combinatorial chemistry;

    机译：芯片实验室；微流体； DNA编码的化学文库；药物发现；动态组合化学;

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