Rational design and development of a peptide inhibitor for the PD-1/PD-L1 interaction

Cancer Lett. 2018 Oct 10;434:11-21. doi: 10.1016/j.canlet.2018.04.031. Epub 2018 Jun 18.

Abstract

We report here the rational design and validation of a peptide inhibitor to the PD-1/PD-L1 interaction as an attempt to develop a viable alternative to current inhibitory antibodies. We demonstrated, by biolayer interferometry and in silico docking simulations, that a PD-L1 peptide mimetic (PL120131) can interfere with the PD-1/PD-L1 interaction by binding to PD-1. We show that PL120131 is capable of inhibiting PD-1 mediated apoptotic signaling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. Additionally, we show that PL120131 treatment allows for CTL anti-tumor activity. Furthermore, PL120131 can maintain co-culture survivability and activity of T Cells in a 3D co-culture model better than the anti-PD-1 blocking antibody. Together, the characterization of this PD-1/PD-L1 inhibiting peptide provides insight regarding the ability to inhibit PD-L1 binding while maintaining CTL viability and activity that can further the development of alternatives to antibody based immunotherapies.

Keywords: CD8 T-cells; Immune checkpoints; PD-1; Peptide therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / chemistry
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Drug Design
  • Humans
  • Jurkat Cells
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Mice
  • Molecular Docking Simulation*
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / chemistry
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Binding / drug effects
  • Signal Transduction / drug effects

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor