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

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...

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Bibliographic Details
Published in:Cancer letters 2018-10, Vol.434, p.11-21
Main Authors: Boohaker, Rebecca J., Sambandam, Vijaya, Segura, Isaac, Miller, James, Suto, Mark, Xu, Bo
Format: Article
Language:English
Subjects:
Antitumor agents
Apoptosis
Blocking antibodies
Cancer
CD8 T-cells
Cell culture
Computer simulation
Cytotoxicity
Data analysis
Design
Docking
Experiments
FDA approval
Flow cytometry
Homeostasis
Immune checkpoints
Immune system
Immunoglobulins
Immunotherapy
Interferometry
Ligands
Lymphocytes
Lymphocytes T
Medical prognosis
PD-1
PD-1 protein
PD-L1 protein
Peptide inhibitors
Peptide therapy
Peptides
Proteins
Sample variance
Signal transduction
Simulation
Survivability
Viability
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Summary: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. •A PDL1 peptide mimetic (PL120131) was developed to interfere with the PD-1/PD-L1 interaction.•PL120131 can inhibits PD-1 mediated apoptotic signaling pathway.•PL120131 treatment allows for CTL anti-tumor activity.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2018.04.031