Computer-Designed Cyclic Peptides Block Cancer Immune Checkpoint PD-1

Two de novo designed heterochiral macrocyclic peptides (PD-i3, PD-i6) bind PD-1 and block the PD-1/PD-L1 interaction. NMR elucidation confirmed computational structure predictions. The Rosetta framework enables generalizable design of target-specific cyclic peptides.

Computational de novo design using Rosetta with large-scale backbone sampling, side-chain composition, and energy scoring. Heterochiral (D/L) cyclic peptide synthesis. Biophysical evaluation of PD-1 binding and PD-L1 blocking. NMR structure confirmation.

Current PD-1 checkpoint inhibitors are expensive antibodies requiring IV infusion. Small cyclic peptides could potentially be cheaper, more stable, and potentially orally available — democratizing access to cancer immunotherapy.

This demonstrates that computational platforms can now design bioactive cyclic peptides targeting specific protein surfaces — a capability that could accelerate drug discovery across oncology, autoimmunity, and infectious disease by making "undruggable" targets accessible.

Biophysical binding data only — no cell-based or in vivo anti-tumor efficacy testing. Binding affinity compared to antibody checkpoint inhibitors not reported. Oral bioavailability and stability in biological fluids not assessed.