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

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

Author information

1
Southern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA; University of Alabama at Birmingham Comprehensive Cancer Center, Department of Cell, Developmental and Integrative Biology, Birmingham, AL, 35294, USA. Electronic address: rboohaker@southernresearch.org.
2
Southern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA.
3
Spring Hill College, Department of Chemistry, Mobile, AL, 36608, USA.
4
Wake Forest University, Department of Chemistry, Winston-Salem, NC, 27109, USA.
5
Southern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA; University of Alabama at Birmingham Comprehensive Cancer Center, Department of Cell, Developmental and Integrative Biology, Birmingham, AL, 35294, USA; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China. Electronic address: bxu@southernresearch.org.

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

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