Rational Design of Multivalent Anticancer Peptides Inhibiting PD-1/PD-L1 Interaction

Abstract

The ability of tumors to escape from immune destruction is attributed to the signaling transduction via the protein-protein interaction between programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) proteins. Therefore, pharmacological inhibition of the PD-1/PD-L1 interaction presents an important therapeutic strategy against a variety of tumors expressing PD-L1 on their cell surfaces. The use of monoclonal antibodies to interfere the interaction have exhibited excellent performance on treating aggressive tumors. However, therapeutic antibodies have some functional limitations, such as inadequate pharmacokinetics and tissue accessibility, and these deficiencies point to direction that peptide inhibitors are needed. In recent year, the peptide inhibitors of the PD1/PD-L1 interaction have been explored. However, these peptides exhibited low inhibitory activities. To obtain high-affinity inhibitory peptides targeting PD-1/PD-L1 interaction, in this work we designed a phage displayed multivalent peptide library strategy to screen multi-valent peptide inhibitors of PD-1/PD-L1 interaction. Selected peptides exhibited high affinities to PD-L1 in a low nanomolar concentration. In cell assay, the peptide inhibitors significantly inhibited cell-cell contacting. Therefore, Our work provides potential opportunities for the use of peptide in PD-L1 overexpressing cells as a new avenue in cancer medicine.