Discovery of d‑Miniprotein Inhibitors of PD-1/PD-L1 Interaction via Mirror-Image Phage Display against Synthetic d‑PD‑1.

ABSTRACT: As a member of the immune checkpoint, PD-1 is acknowledged as a key player in immune regulation and a hot target for cancer immunotherapy. The broad and flat binding interface of PD-1 to PD-L1 poses a challenge to non-antibody inhibitor discovery. In this work, through mirror-image phage display, we developed the first d-miniprotein inhibitor of PD-1/PD-L1 interaction, ^D PDI-49, with nanomolar affinity to PD-1 and single-digit micromolar EC₅₀ in a cell-based inhibition assay. The binding mode between ^D PDI-49 and PD-1 was studied by NMR and MD simulations. For comparison, we screened several commercial and in-house short peptide libraries against synthetic d-PD-1. The failure in identifying a hit structure with inhibition activit

SUBMITTER: Zhou H 

PROVIDER: S-EPMC12728642 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature