A Market Review Of DNA-encoded Libraries Technology In Drug Discovery

by Irina Bilous    Contributor 

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The interest of pharma organizations in DNA-encoded chemical libraries (DEL) technology has been growing over the years, with numerous pharma organizations now having their own screening programs using DELs, or outsourcing capabilities from specialized DEL providers.

This report provides a bird's view on the DEL market, including a brief summary of DEL technology benefits and limitations, key players, major research deals, and several examples of successful hit discovery programs using DELs. 

Historical context

The concept of DNA-encoded libraries (DEL) appeared in the early 1990th when scientists from Scripps Research Institute published a paper on “Encoded combinatorial chemistry”. The main principle of DEL technology is to encode each compound in the library with unique DNA barcode. Thereby library of billion compounds can be screened as a mix in a single test tube and the active compounds are identified by amplification and sequencing of the DNA  barcodes. 

At the initial stage, companies pioneering in DEL development were faced with a lack of relevant methods for DNA sequencing. Scientists from Praecis Pharmaceuticals then founded a company which managed to sequence DEL libraries. Praecis and Nuevolution were the first to have taken a chance on DEL in the 2000s. In 2005 and subsequent years the second generation sequencing has emerged making DEL a much more attractive and economically feasible approach in drug discovery. 

 

An overview of DEL technology

DEL technology comes from the merge of DNA encoding and combinatorial chemistry. The most popular method to build DEL is “split and pool” approach. At the first step of the synthesis, chemical building blocks (BBs) are tagged with DNA barcodes. In the second step, they are mixed together and then split into different portions. Next, a new set of building blocks is added to the chemical reaction, and then, corresponding DNA barcodes are attached and linked with previous DNA molecules. Thus, DNA encodes each step of chemical synthesis for each compound. 


* Reproduced from C&EN

 

Size and costs of DELs

“Split and pool” method enables to build libraries containing up to 10^10 compounds. For example, HitGen’s libraries contain 400 billion molecules, X-chem provides 200 million compounds for screening, and Nuevolution has assembled a collection of 40 trillions of compounds. To compare, the size of a common HTS library is restricted to several million compounds due to the prohibitive cost of synthesizing and managing larger collections. Overall, the cost of creating and screening HTS library of 1 million compounds would cost millions of dollars  (approximately $1,100 per compound), while screening a DEL library of 800 thousand compounds would cost on the order of $150.000. 

 

Hit discovery using DELs

Screening of the DELs is conducted in single test tubes, where the target protein is incubated with a library. The target proteins can be anchored on a solid support, commonly magnetic beads.  After thorough washing, only high-affinity ligands remain associated with a target. After DNA sequencing and decoding of the structure of active compounds, the last should be resynthesized to repeat the affinity binding assay. A lot of different selection strategies can be applied, even phenotypic screening is compatible with DELs.

DEL is suitable for the synthesis and screening of small molecules, macrocyclic compounds, and peptides. Scientists are harnessing chemical properties of DNA, especially the principle of complementarity, for developing new strategies for library design.

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Comments:

  • Mufei 2020/05/15, 04:17 AM

    DELFinder (https://delopen.org/scripts), a tool for tracking DEL Technology available online, you will get more information about DNA encoded library.

    reply
    • BiopharmaTrend 2020/12/17, 11:46 AM

      Thank you for providing this useful resource, Mufei

      reply

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