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

被引:417
作者
Chang, Hao-Nan [1 ]
Liu, Bei-Yuan [2 ]
Qi, Yun-Kun [1 ]
Zhou, Yang [2 ]
Chen, Yan-Ping [2 ]
Pan, Kai-Mai [1 ]
Li, Wen-Wen [2 ]
Zhou, Xiu-Man [2 ]
Ma, Wei-Wei [3 ]
Fu, Cai-Yun [4 ]
Qi, Yuan-Ming [2 ]
Liu, Lei [1 ]
Gao, Yan-Feng [2 ]
机构
[1] Tsinghua Univ, Key Lab Bioorgan Phosphorus Chem & Chem Biol, Tsinghua Peking Ctr Life Sci, Minist Educ,Dept Chem, Beijing 100084, Peoples R China
[2] Zhengzhou Univ, Sch Life Sci, Zhengzhou 450001, Henan Province, Peoples R China
[3] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Lab Dynam Immunobiol, Inst Immunobiol,Sch Life Med, Beijing 100084, Peoples R China
[4] Zhejiang Sci Tech Univ, Sch Life Sci, Hangzhou 310018, Zhejiang, Peoples R China
关键词
antibodies; antitumor agents; cancer immunotherapy; protein chemical synthesis; protein-protein interactions; CHEMICAL-SYNTHESIS; ANTI-PD-L1; ANTIBODY; IMMUNE-SYSTEM; INHIBITORS; DESULFURIZATION; VISUALIZATION; POLYPEPTIDES; DISCOVERY; LIGATION; BLOCKADE;
D O I
10.1002/anie.201506225
中图分类号
O6 [化学];
学科分类号
070301 [无机化学];
摘要
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 mu m 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.
引用
收藏
页码:11760 / 11764
页数:5
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