Structure-Guided Optimization and Functional Characterization of Small Molecule Antagonists Targeting CD28...

Area of Science:

• Immunology
• Pharmacology
• Structural Biology

Background:

• CD28 is a critical costimulatory receptor for T-cell activation, essential for adaptive immunity.
• Dysregulated CD28 signaling contributes to autoimmune diseases and inflammatory conditions.
• The CD28 receptor's dimer interface has historically limited small molecule inhibitor development.

Purpose of the Study:

• To identify and optimize a small molecule inhibitor for the CD28 receptor.
• To develop a non-biologic therapeutic targeting CD28-mediated immune responses.
• To explore new avenues for immune checkpoint blockade therapies.

Main Methods:

• Structure-activity relationship (SAR) study of CD28 inhibitor chemotypes.
• Biophysical profiling and functional assays to evaluate compound efficacy.
• Molecular docking and dynamics simulations to elucidate binding mechanisms.

Main Results:

• Identification of BPU11, a potent small molecule CD28 inhibitor with improved pharmacokinetic properties.
• BPU11 effectively disrupted CD28-B7 interactions in biochemical and cellular assays.
• BPU11 suppressed T-cell activation in preclinical models, mimicking biologic antagonists.
• Structural analysis revealed BPU11 binds to a lipophilic canyon on CD28.

Conclusions:

• BPU11 represents a promising small molecule inhibitor for CD28, expanding therapeutic options beyond biologics.
• This discovery provides a foundation for developing novel immunotherapies targeting CD28.
• The findings broaden the scope of immune checkpoint blockade strategies.