摘要
以PD-1为靶标,设计了靶向结合PD-1的多肽P5-1;通过表面等离子共振(SPR)技术测得P5-1与PD-1的结合亲和力(KD)为0.21μmol/L,并通过分子水平竞争性实验验证P5-1可以阻断PD-1与PD-L1的结合;同时发现P5-1可恢复衰竭的Jurkat T细胞分泌IL-2的水平。本研究可为开发靶向PD-1的多肽阻断剂的肿瘤免疫治疗提供研究基础。
Currently cancer immunotherapy is one of the most popular cancer treatments.Programmed death receptor 1/programmed death ligand-1(PD-1/PD-L1)signaling pathway is an important immune checkpoint.Blocking the PD-1/PD-L1 signaling pathway can reactivate the exhausted T cells and enhance the immune response.Therefore,the PD-1/PD-L1 pathway has become one of the new targets in the development of anticancer drug.The monoclonal antibodies(mAbs)targeting the PD-1/PD-L1 pathway have showed remarkable clinical efficacy in various malignancies.Several mAbs targeting PD-1(nivolumab and pembrolizumab)and PD-L1(atezolizumab,avelumab and durvalumab)have been approved by Food and Drug Administration(FDA)for cancer therapy.However,the disadvantages of antibody drugs,such as high production cost,low stability and immunogenicity,limit their clinical applications.Therefore,discovery of low-molecular-weight blockers that disrupting the PD-1/PD-L1 pathway may provide alternatives for addressing these issues.In this study,we used the E.coli expression system to express the extracellular domain of PD-1 and obtained the recombinant PD-1 after the refolding and purification process.We designed one peptide P5-1 by computer-aided drug design,which showed a KD value of 0.21μmol/L with PD-1.The Surface Plasmon Resonance(SPR)competitive binding assay indicated that the peptide P5-1 could block the interaction between PD-1 and PD-L1.Subsequently,we assessed the effect of the peptide P5-1 on IL-2 production of Jurkat T cells.The addition of IFN-γpretreated BxPC-3 cells led to significant decrease in the Jurkat T cells production of IL-2,while the addition of the peptide P5-1 could restore the IL-2 production.These results suggest that the peptide P5-1 can restore the suppressed function of Jurkat T cells by blocking the interaction between PD-1 and PD-L1.Our study provided a basis on developing peptide blockers targeting PD-1 as durg candidates for cancer immunotherapy.
作者
全丽娜
刁妍妍
李巧
李文杰
朱丽丽
李洪林
QUAN Lina;DIAO Yanyan;LI Qiao;LI Wenjie;ZHU Lili;LI Honglin(School of Pharmacy,Shanghai Key Laboratory of New Drug Design,East China University of Science and Technology,Shanghai 200237,China)
出处
《华东理工大学学报（自然科学版）》
CAS
CSCD
北大核心
2020年第1期35-40,共6页
Journal of East China University of Science and Technology
基金
中央高校基本科研业务费专项基金（222201714059）
国家重点研发计划课题（2016YFA0502304）
国家科技重大专项《重大新药创制》课题（2018ZX09711002）
关键词
PD-1
多肽阻断剂
抗肿瘤
免疫疗法
programmed death receptor 1(PD-1)
peptide blocker
anticancer
immunotherapy
