Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity

Area of Science:

• Immunology
• Protein Engineering
• Computational Biology

Background:

• Chronic stimulation of the programmed cell death-1 (PD-1) pathway inhibits T-cell anti-tumor and anti-viral responses.
• Blocking the PD-1 pathway can restore T-cell function and has therapeutic potential.
• PD-1 interacts with ligands PD-L1 and PD-L2, which are involved in immune checkpoint regulation.

Purpose of the Study:

• To engineer a human PD-1 protein interface with specificity for PD-L1.
• To achieve tissue-specific disruption of the PD-1 pathway for therapeutic advantage.
• To demonstrate a computational approach for re-engineering protein-ligand interactions.

Main Methods:

• Utilized ProtLID, a computational framework employing a residue-based pharmacophore approach.
• Custom-designed a human PD-1 interface for selective binding to human PD-L1.
• Conducted cell assay experiments to validate designed protein interfaces.

Main Results:

• Achieved a human PD-1 interface with high specificity for PD-L1 and minimal affinity for PD-L2.
• Half of the single-point mutant designs demonstrated statistically significant selectivity.
• Nine designs maintained near wild-type affinity for PD-L1 while exhibiting enhanced specificity.

Conclusions:

• The study successfully demonstrated the engineering of a PD-1 interface with PD-L1 specificity using computational design.
• This proof-of-concept validates a generalizable strategy for re-engineering protein interfaces to achieve desired specificity.
• The developed approach holds potential for creating targeted therapeutics to modulate immune responses.