Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy

  • Angew Chem Int Ed Engl. 2015 Sep 28;54(40):11760-4. doi: 10.1002/anie.201506225.
Hao-Nan Chang  1 ,  Bei-Yuan Liu  2 ,  Yun-Kun Qi  1 ,  Yang Zhou  2 ,  Yan-Ping Chen  2 ,  Kai-Mai Pan  1 ,  Wen-Wen Li  2 ,  Xiu-Man Zhou  2 ,  Wei-Wei Ma  3 ,  Cai-Yun Fu  4 ,  Yuan-Ming Qi  2 ,  Lei Liu  5 ,  Yan-Feng Gao  6
Affiliations
  • 1. Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084 (China).
  • 2. School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province (China).
  • 3. Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, Institute for Immunobiology, School of Life Medicine, Tsinghua University, Beijing 100084 (China).
  • 4. School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province (China).
  • 5. Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084 (China). [email protected].
  • 6. School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province (China). [email protected].
PMID: 26259671 DOI: 10.1002/anie.201506225
Abstract

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for Cancer Immunotherapy.

Keywords
antibodies; antitumor agents; cancer immunotherapy; protein chemical synthesis; protein-protein interactions.
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