Translating the Genome into Drugs

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.
• 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.