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An Integrated Biophysical Fragment Screening Approach Identifies Novel Binders of the CD28 Immune Receptor
Biorxiv : the Preprint Server for Biology
|December 15, 2025
Summary
Researchers used fragment-based screening to find small molecules that bind to CD28, a key T cell receptor. This study pioneers a new method for discovering drugs targeting CD28 for immune-mediated diseases.
Area of Science:
- Immunology
- Structural Biology
- Drug Discovery
Background:
- CD28 is a crucial costimulatory receptor for T cell activation.
- Dysregulation of CD28 is implicated in various immune disorders.
- Targeting CD28 with small molecules is challenging due to its large binding interface.
Purpose of the Study:
- To identify small-molecule chemotypes that can bind to human CD28.
- To establish a fragment-based screening approach for CD28 ligand discovery.
Main Methods:
- Fragment-based high-throughput screening (HTS) of a 3,200-member library.
- Temperature-related intensity change (TRIC) technology for initial screening.
- Surface plasmon resonance (SPR) for binding validation.
- Molecular docking for binding orientation analysis.
Main Results:
- Identified 36 primary hits from HTS, with a 1.13% hit rate.
- Confirmed two fragments as direct binders to CD28 using SPR.
- Molecular docking suggested a plausible binding mode for a fragment (PPIF3).
Conclusions:
- Fragment-based screening is effective for identifying CD28 binders.
- This study presents the first demonstration of small molecules engaging the CD28 protein-protein interaction interface.
- A biophysics-driven workflow for CD28 ligand discovery was established, enabling future drug development.
