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Lab-on-a-chip platform for high throughput drug discovery with DNA-encoded chemical libraries

 
: Grünzner, Stefan; Reddavide, Francesco V.; Steinfelder, Christian; Cui, M.; Busek, Mathias; Klotzbach, Udo; Sonntag, Frank; Zhang, Yixin

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Fulltext urn:nbn:de:0011-n-4359129 (3.3 MByte PDF)
MD5 Fingerprint: 1c82aee3c972b10dfd51045170761b8e
Copyright Society of Photo-Optical Instrumentation Engineers. One print or electronic copy may be made for personal use only. Systematic reproduction and distribution, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper are prohibited.
Created on: 30.5.2017


Gray, B.L. ; Society of Photo-Optical Instrumentation Engineers -SPIE-, Bellingham/Wash.:
Microfluidics, BioMEMS, and Medical Microsystems XV : San Francisco, California, United States, 28 - 30 January 2017
Bellingham, WA: SPIE, 2017 (Proceedings of SPIE 10061)
Paper 1006111, 13 pp.
Conference "Microfluidics, BioMEMS, and Medical Microsystems" <15, 2017, San Francisco/Calif.>
Bundesministerium für Wirtschaft und Technologie BMWi
03Z2E512; Plasmafügen
Plasmafügen
English
Conference Paper, Electronic Publication
Fraunhofer IWS ()
Lab-on-a-Chip; Microfluidics; DNA-encoded chemical libraries; drug discovery; dynamic combinatorial chemistry

Abstract
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 °C in the heated chamber to melt the double strands of the DNA and less than 15 °C 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.

: http://publica.fraunhofer.de/documents/N-435912.html