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The central dogma explains the flow of genetic information from DNA nucleotides to the amino acid sequence of proteins.
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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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Author Spotlight: Cost-Effective Transcriptomic Drug Screening - Unlocking New Targets
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Translating the Genome into Drugs.

Anjali Dixit, Huda Barhoosh, Brian M Paegel

    Accounts of Chemical Research
    |February 9, 2023
    PubMed
    Summary

    We developed a DNA-encoded library (DEL) platform for miniaturized screening to enable genome-scale drug discovery. This technology overcomes limitations of traditional high-throughput screening (HTS) for identifying novel drug candidates from vast chemical libraries.

    Area of Science:

    • Drug Discovery
    • Genomics
    • Chemical Biology

    Background:

    • The Human Genome Project's goal of translating DNA sequence into drugs remains largely unfulfilled.
    • Current high-throughput screening (HTS) methods are inadequate for genome-scale drug discovery due to the lack of direct coding for chemical interactions.
    • Innovations in sequencing have democratized genomics but not chemical biology, leaving many proteins undruggable.

    Purpose of the Study:

    • To develop a novel platform for genome-scale drug discovery by revolutionizing molecular screening.
    • To overcome the limitations of current screening technologies for identifying bioactive small molecules.
    • To enable the exploration of previously undruggable proteomic targets.

    Main Methods:

    • Development of solid-phase DNA-encoded libraries (DELs) on microscopic beads.

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  • Miniaturization of screening using 100 pL microfluidic droplets.
  • Integration of photocleavage, incubation, droplet sorting, and DNA sequencing for rapid identification of bioactive compounds.

    • Main Results:

    • A scalable library synthesis and screening platform was established using DEL technology.
    • Proof-of-concept projects demonstrated the utility of the platform for current clinical targets.
    • The system successfully identifies chemical structures of bioactive compounds from miniaturized libraries.

    Conclusions:

    • The developed DEL platform offers a path towards achieving genome-scale drug discovery.
    • Addressing proteome-scale assay development and druggability requires advanced synthesis and analytical technologies.
    • This approach promises to fulfill the Genome Project's vision of proteome-wide control of cellular pharmacology.