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Updated: Jul 9, 2025
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A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules
Published on: March 10, 2017
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Data-driven discovery of innate immunomodulators via machine learning-guided high throughput screening
Yifeng Tang1, Jeremiah Y Kim1, Carman K M Ip2
1Pritzker School of Molecular Engineering, University of Chicago Chicago IL 60637 USA aesserkahn@uchicago.edu andrewferguson@uchicago.edu.
Chemical Science
|November 29, 2023
Summary
Researchers developed an AI pipeline to discover small molecules that modulate innate immune responses, crucial for vaccines and therapies. This approach efficiently identified novel compounds with significant immune-enhancing or suppressing capabilities.
Area of Science:
- Immunology
- Computational Biology
- Drug Discovery
Background:
- The innate immune response is critical for vaccine and immunotherapy efficacy.
- Controlling innate immune signaling can mitigate adverse inflammation and boost therapeutic immune stimulation.
Purpose of the Study:
- To develop a machine learning-enabled active learning pipeline for discovering small molecule immunomodulators.
- To guide in vitro experimental screening of molecules that alter innate immune signaling pathways.
Main Methods:
- Utilized in vitro high-throughput screening (HTS) to measure modulation of NF-κB and IRF pathways.
- Employed deep representational learning, Gaussian process regression, and Bayesian optimization for predictive modeling.
- Interleaved model training with HTS for active learning-guided library traversal.
Main Results:
- Discovered novel immunomodulators by screening ~2% of a 139,998-molecule library.
- Identified molecules suppressing NF-κB activity (up to 15-fold) and elevating NF-κB (up to 5-fold) and IRF (up to 6-fold) activity.
- Validated immunomodulatory effects, with one molecule enhancing IFN-β production by 3-fold with a STING agonist.
Conclusions:
- The ML-enabled screening pipeline efficiently discovers small molecule immunomodulators.
- Novel molecules were identified with potent capacity to enhance or suppress innate immune signaling.
- This approach can significantly improve prophylactic vaccination and immunotherapy development.
