Rational design and development of a peptide inhibitor for the PD-1/PD-Ll interaction
Rational design and development of a peptide inhibitor for the PD-1/PD-Ll interaction
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PD-1/PD-L1 相互作用的肽抑制剂的合理设计和开发
DOI：
10.1016/j.canlet.2018.04.031
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Xu, Bo
中科院分区：
文献类型：
--
作者：
Boohaker, Rebecca J.;Sambandam, Vijaya;Xu, Bo
我们在这里报告了PD-1/PD-L1相互作用的肽抑制剂的合理设计和验证，试图开发一种可行的替代目前的抑制性抗体。我们通过生物层干涉测量和计算机对接模拟证明，PD-LI肽模拟物（PL 120131）可以通过与PD-1结合来干扰PD-1/PD-L1相互作用。我们发现PL 120131能够抑制PD-1介导的凋亡信号通路，并拯救Jurkat细胞和原代淋巴细胞免于凋亡。此外，我们表明P1120131治疗允许CTL抗肿瘤活性。此外，PL 120131可以比抗PD-1阻断抗体更好地维持3D共培养模型中T细胞的共培养存活性和活性。总之，这种PD-1/PD-L1抑制肽的表征提供了关于抑制PD-L1结合同时保持CTL活力和活性的能力的见解，这可以进一步开发基于抗体的免疫疗法的替代方案。(C)2018爱思唯尔出版社
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-LI 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 P1120131 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-Ll binding while maintaining CTL viability and activity that can further the development of alternatives to antibody based immunotherapies. (C) 2018 Published by Elsevier B.V.