Streamlining hit discovery and optimization with a yoctoliter scale DNA reactor

Area of Science:

• Biotechnology
• Medicinal Chemistry
• Molecular Biology

Background:

• DNA-encoded technology (DET) enables the creation of vast small molecule libraries (10^9-10^12 compounds).
• The YoctoReactor (yR) represents a novel advancement in DET with a unique design.
• DET facilitates rapid identification of drug-like hits.

Purpose of the Study:

• To present the fundamental principles of the yR drug discovery platform.
• To evaluate the yR's potential as an alternative to existing hit discovery methods.
• To highlight the yR's capability to deliver high-quality, selective drug-like hits with immediate structure-activity relationships (SAR).

Main Methods:

• Combinatorial synthesis encoding billions of compounds via DNA self-assembly into 3D DNA junctions.
• Utilizing yoctoliter-scale reactors at the core of DNA junctions for single-molecule, DNA-encoded reactions.
• Employing molecular evolution in a single-tube approach for hit identification, bypassing traditional high-throughput screening (HTS).

Main Results:

• The yR platform facilitates the control and encoding of billions of distinct chemical entities.
• Single-molecule reactions occur within yoctoliter reaction volumes.
• Rapid identification of drug-like hit families is achieved through an integrated molecular evolution process.

Conclusions:

• The yR technology offers a highly parallelizable and scalable method for drug discovery.
• It circumvents the limitations of conventional high-throughput screening (HTS).
• yR technology addresses bottlenecks in early-stage drug discovery and emerging fields like functional genomics, systems biology, and proteomics.