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Mega-High-Throughput Screening Platform for the Discovery of Biologically Relevant Sequence-Defined Non-Natural
Michal Avital-Shmilovici1, Xiaohe Liu1, Thomas Shaler1
1SRI Biosciences Division, SRI International, Menlo Park, California 94025, United States.
ACS Central Science
|February 2, 2022
Summary
We developed a novel ultra-high-throughput screening platform to rapidly screen and sequence massive chemical libraries. This technology accelerates molecular discovery by overcoming previous bottlenecks in analyzing billions of synthetic compounds.
Area of Science:
- Chemical Biology
- Drug Discovery
- High-Throughput Screening
Background:
- Combinatorial chemistry enables synthesis of vast compound libraries (millions to billions).
- Efficient screening and sequencing of these libraries remain a significant bottleneck for molecular discovery.
- Existing technologies limit the scale and speed of analyzing large synthetic molecule libraries.
Purpose of the Study:
- To develop a novel technology for screening and sequencing large libraries of synthetic molecules (up to 1 billion compounds).
- To overcome the limitations of current methods in analyzing massive chemical libraries.
- To accelerate the pace of molecular discovery through ultra-high-throughput screening.
Main Methods:
- Utilized fiber-optic array scanning technology (FAST) for screening bead-based libraries.
- Achieved screening rates of 5 million compounds per minute (∼83,000 Hz).
- Employed chemical fragmentation and high-resolution mass spectrometry for sequencing at the femtomole scale.
Main Results:
- Successfully screened libraries of synthetic non-natural polymers (1.77M and 1B compounds).
- Identified hits with low nanomolar binding affinities against multiple protein targets (K-Ras, ASGPR, IL-6, IL-6R, TNFα).
- Discovered competitive inhibitors for K-Ras and uptake ligands for ASGPR.
Conclusions:
- The developed platform enables ultra-high-throughput screening and sequencing of billion-compound libraries.
- This technology significantly advances molecular discovery by addressing key bottlenecks.
- Demonstrated versatility in identifying potent binders and functional ligands for therapeutic targets.
